Medicine › Endocrinology, Diabetes and Metabolism

Diabetes Treatment and Management

Works Count: 83747

Wikipedia

Description

This cluster of papers focuses on the management of diabetes mellitus, with a particular emphasis on cardiovascular outcomes, glucose control, and the use of incretin hormones, SGLT2 inhibitors, and dipeptidyl peptidase-4 inhibitors. It also covers topics such as heart failure, glycemic control, insulin therapy, and clinical guidelines for the treatment of type 2 diabetes.

Keywords

Type 2 Diabetes; Cardiovascular Outcomes; Glucose Control; Incretin Hormones; SGLT2 Inhibitors; Dipeptidyl Peptidase-4 Inhibitors; Heart Failure; Glycemic Control; Insulin Therapy; Clinical Guidelines

Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes

2008-06-06

Anushka Patel , Stephen MacMahon , John Chalmers +7 more

In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain.We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose … In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain.We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately.After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001).A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

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Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

1993-01-01

Michael A. Nauck , Markus M. Heimesaat , Cathrine Ørskov +3 more

In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 … In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.

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Effects of Exenatide (Exendin-4) on Glycemic Control and Weight Over 30 Weeks in Metformin-Treated Patients With Type 2 Diabetes

2005-05-01

Ralph A. DeFronzo , Robert E. Ratner , Jenny Han +3 more

This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin … This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses.A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m(2) and HbA(1c) of 8.2 +/- 1.1%. After 4 weeks of placebo, subjects self-administered 5 microg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 microg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy.At week 30, HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg), -0.40 +/- 0.11% (5 microg), and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 microg), 32% (5 microg), and 13% (placebo) achieved HbA(1c) < or =7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg], -1.6 +/- 0.4 kg [5 microg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia.Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.

Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

2013-09-02

Benjamin M. Scirica , Deepak L. Bhatt , Eugene Braunwald +7 more

The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear.We randomly assigned 16,492 patients with type 2 diabetes who had … The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear.We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke.A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results were similar in the "on-treatment" analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. (Funded by AstraZeneca and Bristol-Myers Squibb; SAVOR-TIMI 53 ClinicalTrials.gov number, NCT01107886.).

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GLUCAGON-LIKE PEPTIDE-1 7-36: A PHYSIOLOGICAL INCRETIN IN MAN

1987-12-01

Bernhard Kreymann , Mohammad A. Ghatei , Gareth Williams +1 more

Biology of Incretins: GLP-1 and GIP

2007-05-01

Laurie L. Baggio , Daniel J. Drucker

The Physiology of Glucagon-like Peptide 1

2007-10-01

Jens J. Holst

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. … Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

2012-04-19

S. E. Inzucchi , Richard M. Bergenstal , John B. Buse +7 more

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Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes

2013-09-02

William B. White , Christopher P. Cannon , Simon Heller +7 more

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new … To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

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Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes

2003-01-29

Peter Gæde , Pernille Vedel , Nicolai Balle Larsen +3 more

Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional … Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria.The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin.The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79).A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent.

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Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes

2015-06-08

Jennifer B. Green , M. Angelyn Bethel , Paul W. Armstrong +7 more

Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.In … Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease.In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).

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Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

2015-09-17

Bernard Zinman , Christoph Wanner , John M. Lachin +7 more

The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk … The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

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Effects of Diet and Exercise in Preventing NIDDM in People With Impaired Glucose Tolerance: The Da Qing IGT and Diabetes Study

1997-04-01

Xiao-Ren Pan , Guang-Wei Li , Ying-Hua Hu +7 more

OBJECTIVE Individuals with impaired glucose tolerance (IGT) have a high risk of developing NIDDM. The purpose of this study was to determine whether diet and exercise interventions in those with … OBJECTIVE Individuals with impaired glucose tolerance (IGT) have a high risk of developing NIDDM. The purpose of this study was to determine whether diet and exercise interventions in those with IGT may delay the development of NIDDM, i.e., reduce the incidence of NIDDM, and thereby reduce the overall incidence of diabetic complications, such as cardiovascular, renal, and retinal disease, and the excess mortality attributable to these complications. RESEARCH DESIGN AND METHODS In 1986, 110,660 men and women from 33 health care clinics in the city of Da Qing, China, were screened for IGT and NIDDM. Of these individuals, 577 were classified (using World Health Organization criteria) as having IGT. Subjects were randomized by clinic into a clinical trial, either to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. Follow-up evaluation examinations were conducted at 2-year intervals over a 6-year period to identify subjects who developed NIDDM. Cox's proportional hazard analysis was used to determine if the incidence of NIDDM varied by treatment assignment. RESULTS The cumulative incidence of diabetes at 6 years was 67.7% (95% CI, 59.8–75.2) in the control group compared with 43.8% (95% CI, 35.5–52.3) in the diet group, 41.1% (95% CI, 33.4–49.4) in the exercise group, and 46.0% (95% CI, 37.3–54.7) in the diet-plus-exercise group (P &lt; 0.05). When analyzed by clinic, each of the active intervention groups differed significantly from the control clinics (P &lt; 0.05). The relative decrease in rate of development of diabetes in the active treatment groups was similar when subjects were stratified as lean or overweight (BMI &lt; or ≥ 25 kg/m2). In a proportional hazards analysis adjusted for differences in baseline BMI and fasting glucose, the diet, exercise, and diet-plus-exercise interventions were associated with 31% (P &lt; 0.03), 46% (P &lt; 0.0005), and 42% (P &lt; 0.005) reductions in risk of developing diabetes, respectively. CONCLUSIONS Diet and/or exercise interventions led to a significant decrease in the incidence of diabetes over a 6-year period among those with IGT.

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

2008-10-23

David M. Nathan , John B. Buse , Mayer B. Davidson +4 more

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new … The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

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Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future

2013-12-03

Steven E. Kahn , Mark E. Cooper , Stefano Del Prato

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Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary: The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD)

2006-06-13

L Rydén , Eberhard Standl , M. Bartnik +7 more

Guidelines and Expert Consensus documents aim to present management and recommendations based on all of the relevant evidence on a particular subject in order to help physicians to select the … Guidelines and Expert Consensus documents aim to present management and recommendations based on all of the relevant evidence on a particular subject in order to help physicians to select the best possible management strategies for the individual patient, suffering from a specific condition, taking into account not only the impact on outcome, but also the risk benefit ratio of a particular diagnostic or therapeutic procedure. The ESC recommendations for guidelines production can be found on the ESC website†. In brief, the ESC appoints experts in the field to carry out a comprehensive and critical evaluation of the use of diagnostic and therapeutic procedures and to assess the risk–benefit ratio of the therapies recommended for management and/or prevention of a given condition. The strength of evidence for or against particular procedures or treatments is weighed according to predefined scales for grading recommendations and levels of evidence, as outlined below. Once the document has been finalized and approved by all the experts involved in the Task Force, it is submitted to outside specialists for review. If necessary, the document is revised once more to be finally approved by the Committee for Practice Guidelines and selected members of the Board of the ESC. The ESC Committee for Practice Guidelines ( CPG ) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups, or consensus panels. The chosen experts in these writing panels are asked to provide disclosure statements of all relationships they may have, which might be perceived as real or potential conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. The Committee is also responsible for the endorsement of these Guidelines and Expert Consensus Documents or statements. | Classes of recommendations | |:-------------------------- | ------------------------------------------------------------------------------------------------------------------------ | | Class I | Evidence and/or general agreement that a given diagnostic procedure/treatment is beneficial, useful, and effective | | Class II | Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the treatment or procedure | | Class IIa | Weight of evidence/opinion is in favour of usefulness/efficacy | | Class IIb | Usefulness/efficacy is less well established by evidence/opinion | | Class III | Evidence or general agreement that the treatment or procedure is not useful/effective and, in some cases, may be harmful | Diabetes and cardiovascular diseases (CVD) often appear …

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The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes

2006-11-01

Daniel J. Drucker , Michael A. Nauck

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes

2014-12-13

Silvio E. Inzucchi , Richard M. Bergenstal , John B. Buse +7 more

In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type … In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient. The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2). Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …

A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease

2009-06-07

The BARI D Study Group

Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established.We randomly assigned 2368 patients with both type 2 diabetes and heart … Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established.We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention.At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003).Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)

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Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

2008-02-06

Peter Gæde , Henrik Lund‐Andersen , Hans‐Henrik Parving +1 more

Intensified multifactorial intervention — with tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents — has been shown to reduce the risk of nonfatal cardiovascular … Intensified multifactorial intervention — with tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents — has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes.

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10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes

2008-09-10

Rury R. Holman , Sanjoy K. Paul , M. Angelyn Bethel +2 more

During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving … During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)

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Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach

2012-04-20

Silvio E. Inzucchi , Richard M. Bergenstal , John B. Buse +7 more

Table 1dProperties of currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes mellitus Class Compound(s) Cellular mechanism Table 1dProperties of currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes mellitus Class Compound(s) Cellular mechanism

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Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)

1998-09-01

Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial

2005-11-01

A Keech , R. John Simes , Philip J. Barter +7 more

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.

1998-09-11

R. C. Turner , Charles Fox , Matthews +7 more

Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome

2015-12-02

Marc A. Pfeffer , Brian Claggett , Rafael Díaz +7 more

Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a … Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event.We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina.The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo.In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.).

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Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

2016-06-14

Christoph Wanner , Silvio E. Inzucchi , John M. Lachin +7 more

Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events … Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial.We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria.Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population.In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).

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Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

2016-06-13

Steven P. Marso , Gilbert H. Daniels , Kirstine Brown‐Frandsen +7 more

The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.In this double-blind trial, we randomly assigned patients … The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes.A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

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Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

2016-09-16

Steven P. Marso , Stephen C. Bain , Agostino Consoli +7 more

Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects … Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio.At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).

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Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators.

2000-01-22

Jfe Mann , Hertzel C. Gerstein , Salim Yusuf

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

2017-06-12

Bruce Neal , Vlado Perkovic , Kenneth W. Mahaffey +7 more

Canagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with … Canagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes.

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U.K. Prospective Diabetes Study 16: Overview of 6 Years' Therapy of Type II Diabetes: A Progressive Disease

1995-11-01

The objective of the U.K. Prospective Diabetes Study is to determine whether improved blood glucose control in type II diabetes will prevent the complications of diabetes and whether any specific … The objective of the U.K. Prospective Diabetes Study is to determine whether improved blood glucose control in type II diabetes will prevent the complications of diabetes and whether any specific therapy is advantageous or disadvantageous. The study will report in 1998, when the median duration from randomization will be 11 years. This report is on the efficacy of therapy over 6 years of follow-up and the overall incidence of diabetic complications. Subjects comprised 4,209 newly diagnosed type II diabetic patients who after 3 months' diet were asymptomatic and had fasting plasma glucose (FPG) 6.0–15.0 mmol/l. The study consists of a randomized controlled trial with two main comparisons: 1) 3,867 patients with 1,138 allocated to conventional therapy, primarily with diet, and 2,729 allocated to intensive therapy with additional sulfonylurea or insulin, which increase insulin supply, aiming for FPG &lt;6 mmol/l; and 2) 753 obese patients with 411 allocated to conventional therapy and 342 allocated to intensive therapy with metformin, which enhances insulin sensitivity. In the first comparison, in 2,287 subjects studied for 6 years, intensive therapy with sulfonylurea and insulin similarly improved glucose control compared with conventional therapy, with median FPG at 1 year of 6.8 and 8.2 mmol/l, respectively (P &lt; 0.0001). and median HbA1c of 6.1 and 6.8%, respectively (P &lt; 0.0001). During the next 5 years, the FPG increased progressively on all therapies (P &lt; 0.0001) with medians at 6 years in the conventional and intensive groups, FPG 9.5 and 7.8 mmol/l, and HbA1c 8.0 and 7.1%, respectively. The glycemic deterioration was associated with progressive loss of β-cell function. In the second comparison, in 548 obese subjects studied for 6 years, metformin improved glucose control similarly to intensive therapy with sulfonylurea or insulin. Metformin did not increase body weight or increase the incidence of hypoglycemia to the same extent as therapy with sulfonylurea or insulin. A high incidence of clinical complications occurred by 6-year follow-up. Of all subjects, 18.0% had suffered one or more diabetes-related clinical endpoints, with 12.1% having a macrovascular and 5.7% a microvascular endpoint. Sulfonylurea, metformin, and insulin therapies were similarly effective in improving glucose control compared with a policy of diet therapy. The study is examining whether the continued improved glucose control, obtained by intensive therapy compared with conventional therapy (median over 6 years HbA1c 6.6% compared with 7.4%), will be clinically advantageous in maintaining health.

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes

2017-09-14

Rury R. Holman , M. Angelyn Bethel , Robert J. Mentz +7 more

The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.We randomly assigned patients with type 2 diabetes, with or without … The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .).

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Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables

2018-03-05

Emma Ahlqvist , Petter Storm , Annemari Käräjämäki +7 more

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Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

2018-10-05

Melanie J. Davies , David A. D’Alessio , Judith Fradkin +7 more

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management … The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication, and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.

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SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

2018-11-10

Thomas A. Zelniker , Stephen D. Wiviott , Itamar Raz +7 more

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

2018-11-10

Stephen D. Wiviott , Itamar Raz , Marc P. Bonaca +7 more

The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.We randomly assigned patients with type 2 … The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause.We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001).In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

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Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

2019-04-15

Vlado Perkovic , Meg Jardine , Bruce Neal +7 more

Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory … Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.

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Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial

2019-06-09

Hertzel C. Gerstein , Helen M. Colhoun , Gilles R. Dagenais +7 more

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

2019-09-19

John J.V. McMurray , Scott D. Solomon , Silvio E. Inzucchi +7 more

In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed … In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.

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The Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes

2001-09-20

Hans‐Henrik Parving , Hendrik Lehnert , J. Bröchner‐Mortensen +3 more

Microalbuminuria and hypertension are risk factors for the development of diabetic nephropathy. Blockade of the renin-angiotensin system reduces progression to diabetic nephropathy in type 1 diabetic patients, whereas similar data … Microalbuminuria and hypertension are risk factors for the development of diabetic nephropathy. Blockade of the renin-angiotensin system reduces progression to diabetic nephropathy in type 1 diabetic patients, whereas similar data are lacking for hypertensive type 2 diabetic subjects. We evaluated the renoprotective effect of an angiotensin II receptor antagonist, irbesartan, in hypertensive type 2 diabetic patients with microalbuminuria.Five hundred and ninety hypertensive type 2 diabetic patients with microalbuminuria were enrolled in this multinational, randomised, double-blind, placebo-controlled study of irbesartan 150 mg/daily or 300 mg/daily or matching placebo for two years. The primary outcome was time to progression to diabetic nephropathy, defined as a persistent overnight albuminuria > 200 micrograms/min and at least a 30 per cent increase from baseline.Baseline characteristics in the three groups were similar. Ten patients (5.2 per cent) receiving irbesartan 300 mg and 19 patients (9.7 per cent) receiving irbesartan 150 mg daily reached the primary end point, as compared to 30 (14.9 per cent) patients on placebo (hazard ratio 0.30 [95 per cent confidence interval 0.14 to 0.61], p < 0.001 and 0.61 [95 per cent confidence interval 0.34 to 1.08] p = 0.08), respectively). The average blood pressure throughout the study was 144/83, 143/83, and 141/81 mmHg in the placebo, irbesartan 150 mg and 300 mg group, respectively (p = 0.004 for systolic blood pressure). Serious adverse events were less frequent in the patients treated with irbesartan (p = 0.02).Irbesartan is renoprotective independently of its blood pressure lowering effect in type 2 diabetic subjects with microalbuminuria. It is safe and well tolerated.

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Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure

2020-08-28

Milton Packer , Stefan D. Anker , Javed Butler +7 more

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects … Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.

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Dapagliflozin in Patients with Chronic Kidney Disease

2020-09-24

Hiddo J.L. Heerspink , Bergur V. Stefánsson , Ricardo Correa–Rotter +7 more

Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 … Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.

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Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure

2020-11-17

Deepak L. Bhatt , Michael Szarek , Philippe Gabríel Steg +7 more

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of … Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure. However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown.We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo. The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor.A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group). The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001). The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22); the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14). Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose.In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo. (Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934.).

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Once-Weekly Semaglutide in Adults with Overweight or Obesity

2021-02-10

John Wilding , Rachel L. Batterham , Salvatore Calanna +7 more

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct … Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

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ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD

2013-08-30

Authors Task Force Members , Lars Rydén , Peter J. Grant +7 more

with the European Association for the Study of Diabetes (EASD). with the European Association for the Study of Diabetes (EASD).

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Empagliflozin in Heart Failure with a Preserved Ejection Fraction

2021-08-27

Stefan D. Anker , Javed Butler , Gerasimos Filippatos +7 more

Sodium–glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure … Sodium–glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain.

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Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

2022-08-27

Scott D. Solomon , John J.V. McMurray , Brian Claggett +7 more

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% … Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.

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Enzyme and metabolic inhibitors

1963-01-01

John Leyden Webb

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A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management

2015-07-01

F. Xavier Pi‐Sunyer , Arne Astrup , Ken Fujioka +7 more

Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have … Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously.We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight.At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P<0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group.In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.).

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Stability Indicating Rp-Hplc for Method Development and Validation for Simultaneous Estimation of Empagliflozin and Nateglinide in Bulk Drug

2025-06-25

Kajol , Aditi Kaushik , Nikhil Sharma | Jordan Journal of Pharmaceutical Sciences

A simple, accurate, and precise stability-indicating RP-HPLC method was developed and validated for the simultaneous estimation of Empagliflozin and Nateglinide in bulk drug form. Chromatographic separation was performed on a … A simple, accurate, and precise stability-indicating RP-HPLC method was developed and validated for the simultaneous estimation of Empagliflozin and Nateglinide in bulk drug form. Chromatographic separation was performed on a Shim-pack C-18 column (250 × 4.6 mm, 5 µm) using a mobile phase of Acetonitrile: Water (90:10, v/v) adjusted to pH 3. The UV detection wavelength was set at 216 nm, the flow rate was maintained at 1 mL/min, and the injection volume was 20 µL. The retention times for Empagliflozin and Nateglinide were found to be 2.770 and 3.682 minutes, respectively. This method was validated according to ICH Q2(R1) guidelines for linearity, accuracy, precision, limit of detection (LOD), limit of quantification (LOQ), and robustness. A linear response was observed in the concentration range of 5–25 µg/mL for Empagliflozin and 10–50 µg/mL for Nateglinide. The LOD and LOQ for Empagliflozin were found to be 14.0502 µg/mL and 42.576 µg/mL, respectively, while for Nateglinide, they were 6.5398 µg/mL and 19.8178 µg/mL. Stress studies were performed in accordance with ICH Q1A(R2) guidelines. The drugs were subjected to stress conditions including photolytic, oxidative, thermal degradation, and acid/base hydrolysis to develop a stability-indicating method. The degraded products were effectively extracted and analyzed from the sample.

<scp>EffiCacy</scp> and safety of <scp>ANagliptin</scp> when added to <scp>iNsulin</scp> and metformin therapy in patients with uncontrolled type 2 <scp>diAbetes</scp>; randomized, placebo‐controlled, double‐blind, multicentre trial (<scp>CANNA</scp> study)

2025-06-25

Ji Eun Jun , Sung Hee Choi , Min Kyong Moon +6 more | Diabetes Obesity and Metabolism

Kommentar zu „SGLT2-Inhibitoren und Nierenfunktion“

2025-06-25

| DMW - Deutsche Medizinische Wochenschrift

SGLT2-Inhibitoren und Nierenfunktion

2025-06-25

| DMW - Deutsche Medizinische Wochenschrift

SGLT2 inhibitors may increase creatinine clearance: data mining utilizing the FDA Adverse Event Report System database and pharmacokinetic study with rats

2025-06-25

Yuichi Uwai , Tomohiro Nabekura | Pharmacology

Introduction: Augmented renal clearance is a condition in which creatinine clearance exceeds 130 ml/min/1.73 m². The present study aimed to identify drugs that increase creatinine clearance. Methods: We initially investigated … Introduction: Augmented renal clearance is a condition in which creatinine clearance exceeds 130 ml/min/1.73 m². The present study aimed to identify drugs that increase creatinine clearance. Methods: We initially investigated drugs associated with an upsurge in the reporting frequencies of “creatinine renal clearance increased” (CRCI) and “glomerular filtration rate increased” (GFRI) using the FDA Adverse Event Reporting System (FAERS) database. Effect of the drugs on renal clearance of creatinine and lithium was examined using rats. Results: The database contained 625 reports on CRCI and GFRI. Among the primary suspect drugs identified, empagliflozin had the highest number of reports (29), followed by canagliflozin (27), emtricitabine/tenofovir (21), and sacubitril/valsartan (21). Dapagliflozin had 16 reports. Reporting odds ratios (95% confidence intervals) for empagliflozin, canagliflozin, and dapagliflozin were 29.7 (20.5–43.1), 28.6 (19.5–42.1), and 19.7 (12.0–32.3), respectively. In rats infused with phlorizin, a typical inhibitor of sodium-glucose cotransporters (SGLTs), increases were observed in fractional glucose excretion, creatinine clearance, and the renal clearance of lithium. The plasma concentration of creatinine remained unchanged, while that of lithium decreased. Renal glucose excretion in rats administered phlorizin correlated with creatinine clearance (r = 0.859). Conclusion: These results suggest that SGLT2 inhibitors may increase renal clearance of creatinine or drugs.

Associations of semaglutide with Alzheimer's disease-related dementias in patients with type 2 diabetes: A real-world target trial emulation study

2025-06-24

William Yang Wang , Pamela B. Davis , Xin Qi +5 more | Journal of Alzheimer s Disease

BackgroundAlmost half of the dementia cases are preventable. Semaglutide treats several medical conditions that are risk factors for dementia.ObjectiveWe aim to investigate if semaglutide is associated with a decreased risk … BackgroundAlmost half of the dementia cases are preventable. Semaglutide treats several medical conditions that are risk factors for dementia.ObjectiveWe aim to investigate if semaglutide is associated with a decreased risk of dementia.MethodsWe conducted emulation target trials based on a nationwide population-based database of patient electronic health records (EHRs) in the US among 1,710,995 eligible patients with type 2 diabetes (T2D) comparing semaglutide with other antidiabetic medications. First-time diagnosis of Alzheimer's disease-related dementia (ADRD) including vascular dementia, frontotemporal dementia, Lewy body dementia and other dementias were examined using Cox proportional hazards and Kaplan-Meier survival analyses during a 3-year follow-up. Models were adjusted by propensity-score matching.ResultsWe show that semaglutide was associated with a significantly reduced risk of overall ADRD incidence with a hazard ratio ranging from 0.54 (0.49-0.59) compared with insulin, 0.67 (0.61-0.74) compared with metformin, to 0.80 (0.72-0.89) compared with older generation glucagon-like peptide-1 agonists (GLP-1RAs). The association varied for specific dementia types, with significantly reduced risk of vascular dementia and no evidence of associations with frontotemporal and Lewy body dementias.ConclusionsThese findings provide evidence supporting protective effects of semaglutide on dementias in patients with T2D. Future works are needed to establish the causal relationships through randomized clinical trials and to characterize the underlying mechanisms.

Commentary on ‘Effect of dapagliflozin on the no-reflow phenomenon in patients with acute myocardial infarction and type iI diabetes mellitus’

2025-06-24

Cédric Davidsen | Acta Cardiologica

Efficacy and safety of combination therapy using <scp>SGLT2</scp> and <scp>DPP4</scp> inhibitors to treat type 2 diabetes: An updated systematic review and meta‐analysis with focus on an Asian subpopulation

2025-06-24

Myung Jin Kim , Yun Kyung Cho , Se Hee Kim +3 more | Diabetes Obesity and Metabolism

This updated meta-analysis investigates the efficacy and safety of combining sodium-glucose cotransporter 2 inhibitors (SGLT2is) with dipeptidyl peptidase-4 inhibitors (DPP4is) in treating type 2 diabetes (T2D), especially in Asian subpopulations. … This updated meta-analysis investigates the efficacy and safety of combining sodium-glucose cotransporter 2 inhibitors (SGLT2is) with dipeptidyl peptidase-4 inhibitors (DPP4is) in treating type 2 diabetes (T2D), especially in Asian subpopulations. A systematic review was conducted on randomized controlled trials (RCTs) published through January 2024 that compared SGLT2i/DPP4i combination therapy with DPP4i or SGLT2i monotherapy. The primary outcome was haemoglobin A1c (HbA1c) changes. Subgroup analyses were conducted based on the baseline HbA1c level (using 8.0%-8.5% as the cut-off) and racial groups (Asian vs. non-Asian). This analysis included 17 RCTs with 7588 participants. Compared to DPP4i, the SGLT2i/DPP4i combination significantly reduced HbA1c (mean difference [MD] -0.57%, 95% confidence interval [CI] -0.67 to -0.46%), while promoting modest weight loss (MD -1.57 kg, 95% CI -1.93 to -1.20 kg). When compared to SGLT2i, SGLT2i/DPP4i promoted further reductions in HbA1c (MD -0.46%, 95% CI -0.55 to -0.38%) with no significant effects on body weight. Subgroup analyses revealed that the efficacy of adding DPP4i in reducing HbA1c was more pronounced in Asian participants (MD -0.55%, 95% CI -0.71 to -0.39) than in non-Asian participants (MD -0.38%, 95% CI -0.46 to -0.31). The combination therapy was associated with a similar risk of hypoglycaemia compared to both monotherapy groups, with no statistically significant differences observed. Combination therapy of SGLT2i and DPP4i improves glycaemic control in T2D, with enhanced DPP4i efficacy noted in Asian populations, highlighting its role in personalized diabetes management for these patients.

Unveiling the anticancer potential of SGLT-2 inhibitors: mechanisms and prospects in clinical oncology—a narrative review

2025-06-24

Jiaxin Li , Jie Qiao , Zhang Shi-tong +7 more | European journal of medical research

In recent years, cancer has become more prevalent among younger populations, increasing the burden on public health and the economy. Current cancer treatments are often costly and have long trial … In recent years, cancer has become more prevalent among younger populations, increasing the burden on public health and the economy. Current cancer treatments are often costly and have long trial periods. Sodium-glucose cotransporter-2 inhibitors (SGLT-2is), including dapagliflozin and canagliflozin, were originally developed for blood glucose control, but have shown promise in anticancer applications. These inhibitors work by inhibiting glucose uptake in tumor cells, thus limiting the energy supply needed for tumor growth. For instance, in lung and hepatocellular cancers, SGLT-2is have been demonstrated to reduce tumor volume and suppress metastasis by modulating key signaling pathways, such as AMPK/mTOR and HIF-1α. Additionally, their ability to enhance the efficacy of chemotherapy and immunotherapy further underscores their potential in cancer treatment. Numerous studies have been conducted on this topic. Diabetes mellitus (DM) is increasingly affecting younger populations and overlaps significantly with cancer. DM patients face higher cancer risks, particularly for liver, colorectal, and pancreatic cancers, with studies indicating up to a 20% increased risk. This highlights the need to consider both conditions in treatment strategies and understand the mechanisms linking DM and cancer to improve outcomes. This study explores the relationship between SGLT-2is and cancer, focusing on their mechanisms in various tumor types and their synergistic effects in combination with other therapies. In the current study, we determined the relationship between SGLT-2is and cancer, and elaborated on the role and mechanisms of SGLT-2is in tumors at different primary sites. In addition, we introduced the anti-tumor effects of SGLT-2is in combination with other means and the underlying mechanisms. From the single-operator to combined-operator level, we reveal the prospects of SGLT-2is in clinical oncology and the future outlook.

Tirzepatide and cardiometabolic parameters in obesity: Summary of current evidence

2025-06-24

Naveed Sattar , Luis‐Emilio García‐Pérez , Ángel Rodríguez +3 more | Diabetes Obesity and Metabolism

Abstract Globally, cardiovascular diseases (CVDs) account for around one‐third of all deaths. Clinical trial evidence suggests that treatment of people with obesity or type 2 diabetes (T2D) and CVD with … Abstract Globally, cardiovascular diseases (CVDs) account for around one‐third of all deaths. Clinical trial evidence suggests that treatment of people with obesity or type 2 diabetes (T2D) and CVD with glucagon‐like peptide‐1 (GLP‐1) receptor agonists reduces the risk of major adverse cardiovascular events, heart failure outcomes and all‐cause mortality. Tirzepatide is a once‐weekly, dual glucose‐dependent insulinotropic polypeptide (GIP) and GLP‐1 receptor agonist that has demonstrated dose‐dependent efficacy in people with obesity, T2D or both, in terms of glycaemic control and bodyweight reduction in clinical trials. This narrative review summarizes the current evidence regarding the effects of tirzepatide treatment on cardiometabolic parameters, including lipid profile, blood pressure and markers of renal function. Additionally, it summarizes the reported impact of tirzepatide treatment on other relevant parameters, such as body composition, liver fat, progression to T2D among individuals with prediabetes, and incidence of heart failure events. Considering the changing landscape of clinical trial evidence of tirzepatide's effects, this review aims to compile the available evidence, which suggests a promising outlook for the cardiometabolic benefits of tirzepatide.

The effects of anti‐obesity medications on bone metabolism: A critical appraisal

2025-06-24

Athanasios D. Anastasilakis , Julien Paccou , Andrea Palermo +1 more | Diabetes Obesity and Metabolism

Abstract The development of novel sophisticated medications that induce weight loss has revolutionized the management of people living with obesity (PwO). However, when body weight is reduced, muscle and bone … Abstract The development of novel sophisticated medications that induce weight loss has revolutionized the management of people living with obesity (PwO). However, when body weight is reduced, muscle and bone are lost along with fat. In the present review, we quote and discuss existing evidence on the effects of the major anti‐obesity medications on bone metabolism. Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists have shown a positive impact in preclinical studies but a neutral or negative, albeit not clinically significant, effect on bone turnover markers and bone mineral density in clinical studies. Nevertheless, fracture risk does not seem to increase with GLP‐1R agonists use, at least in clinically relevant doses. Limited, mostly preclinical, data suggest that other incretin analogues, including dual GLP‐1R and glucose‐dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonists, dual GLP‐1R and glucagon receptor (GCGR) agonists, and triple GLP‐1R, GIPR and GCGR agonists, may have a positive effect on bone. Preclinical data with amylin analogues imply the same. Activin type II receptor (ActRII) antagonists may combine anti‐obesity effects with simultaneous muscle and bone mass preservation and could be used either as monotherapy or in combination with incretin analogues. The bone effects of opioid receptor antagonists and setmelanotide are largely unknown, while the impact of the combination of phentermine with topiramate is assumed to be negative. Finally, very limited clinical evidence suggests that orlistat may have a neutral effect on bone metabolism.

Inequity in adherence to empagliflozin and dulaglutide for type 2 diabetes in Aotearoa New Zealand

2025-06-24

Sara Mustafa , Christopher Mayo , Ryan Paul +4 more | Diabetes Obesity and Metabolism

Hochrisikopatienten mit Typ-2-Diabetes: Semaglutid auch als orale Therapie wirksam

2025-06-24

Robert H. G. Schwinger | CardioVasc

Prädiabetes: Kein Thema in den neuen ESC-Leitlinien

2025-06-24

Marlo Verket , Julia Brandts , Dirk Müller‐Wieland | CardioVasc

Is combination treatment of heart failure with reduced ejection fraction with an SGLT2 inhibitor and sacubitril/valsartan better than either agent used alone?

2025-06-24

Fariha Qureshi , Thomas Satre | Evidence-Based Practice

SGLT2 inhibitors as metabolic modulators: beyond glycemic control in type 2 diabetes

2025-06-24

Qian Wu , Jian Zhang , Fuli Zhang +1 more | Frontiers in Endocrinology

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, and its management has evolved from mere glycemic control to multitarget metabolic regulation. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated … Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, and its management has evolved from mere glycemic control to multitarget metabolic regulation. Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated extensive pleiotropic effects in treating T2DM, and its complications through unique mechanisms. SGLT2is promote urinary glucose excretion, leading to a negative energy balance that triggers lipid metabolic reprogramming and fuel switching in the body. This process significantly reduces visceral fat deposition and improves insulin resistance and the inflammatory status. Additionally, SGLT2is provide a metabolic foundation for cardiovascular, hepatic, and renal protection through multiple pathways, including remodeling cardiac structure, enhancing myocardial metabolism, reducing uric acid levels, and alleviating renal hypoxia. With respect to combination therapy, the pairing of SGLT2is with other hypoglycemic agents and cardiovascular protective drugs has synergistic effects; however, potential adverse reactions should also be considered. Future research should investigate the precise application and long-term safety of SGLT2is as well as develop individualized treatment strategies on the basis of patients’ metabolic phenotypes, complications, and drug tolerability to maximize clinical benefits for patients. This review systematically explores the significant roles of SGLT2is in metabolic regulation, cardiovascular protection, and combination therapy, with the aim of providing a comprehensive foundation for optimizing individualized treatment strategies in T2DM management.

<scp>PIONEER REAL Spain</scp>: A multicentre, prospective, real‐world study of oral semaglutide use in adults with type 2 diabetes

2025-06-24

Elías Delgado , Cristóbal Morales , Cristina Abreu +7 more | Diabetes Obesity and Metabolism

Abstract Aims This study evaluated clinical outcomes of oral semaglutide treatment in adults with type 2 diabetes (T2D) in a real‐world setting in Spain as part of the 13‐country PIONEER … Abstract Aims This study evaluated clinical outcomes of oral semaglutide treatment in adults with type 2 diabetes (T2D) in a real‐world setting in Spain as part of the 13‐country PIONEER REAL programme. Materials and Methods This multicentre, prospective, non‐interventional, single‐arm study (NCT05443334) followed participants for 34–44 weeks. Participants were treated as part of routine clinical practice and were naïve to injectable glucose‐lowering medication. The primary endpoint was the change in glycated haemoglobin (HbA 1c ) from baseline to end of study (EOS). Secondary endpoints included changes in body weight, the proportion of participants with HbA 1c <7% at EOS, and treatment satisfaction. Selected outcomes were stratified (post hoc) by sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) co‐use and T2D duration. Results While 430 participants completed the study, 392 were on treatment at EOS. Estimated change in HbA 1c was −1.4%‐points (95%CI −1.5, −1.3; p < 0.0001) and in body weight −6.8% (95%CI −7.4, −6.1; p < 0.0001). In participants using SGLT2is, change in HbA 1c was −1.8%‐points (95%CI −2.1, −1.6; p < 0.0001) versus −1.2%‐points (95%CI −1.3, −1.1; p < 0.0001) in participants without SGLT2is. HbA 1c change was −1.4%‐points (95%CI −1.6, −1.3; p < 0.0001) in participants with T2D duration ≤5 years versus −1.2%‐points (95%CI −1.3, −1.0; p < 0.0001) with T2D duration >5 years. At EOS, 77.4% of participants achieved an HbA 1c level <7% and 33.3% had ≥1%‐point reduction in HbA 1c and ≥5% body weight reduction. Treatment satisfaction increased, and no new safety concerns were identified. Conclusions Oral semaglutide treatment improved glycaemic control and reduced body weight in Spanish clinical practice. Early intervention and SGLT2i co‐treatment were associated with more favourable outcomes.

[Integrating single-cell analysis and epharmalib reverse virtual screening to predict novel vascular endothelial cell targets of dapagliflozin in treating diabetic cardiomyopathy].

2025-06-24

Xiaoqian Yang , Ki‐Jeong Na , Chen Yan +1 more | PubMed

Objective: To investigate endothelial cell heterogeneity in diabetic cardiomyopathy (DCM) and identify potential therapeutic targets of dapagliflozin in cardiac vascular endothelial cells. Methods: ePharmaLib reverse virtual screening was performed on … Objective: To investigate endothelial cell heterogeneity in diabetic cardiomyopathy (DCM) and identify potential therapeutic targets of dapagliflozin in cardiac vascular endothelial cells. Methods: ePharmaLib reverse virtual screening was performed on 15 148 protein crystals to identified the binding interactions between human-derived proteins and dapagliflozin. Subsequently, single-cell RNA sequencing data (PRJNA1069235) from wild-type mice (control group) and db/db mice (DCM group) were integrated, then dimensionality reduction and clustering analysis were performed to identify endothelial cell subpopulations in the heart tissue of DCM mice, followed by functional annotation. Cell-cell communication analysis was explored to investigate fibroblast-endothelial cell interactions. The Agilent Mouse ceRNA Microarray chip was used to perform transcriptomic analysis of heart tissue from mice fed a high-fat diet and treated with dapagliflozin. Intersection analysis of reverse virtual screening results, single-cell RNA sequencing results and chip analysis data was performed to identify common differentially expressed genes. In vitro, human umbilical vein endothelial cells were divided into blank control group, tumor necrosis factor-α (TNF-α) group (TNF-α 10 mg/L), dapagliflozin low concentration group (TNF-α 10 mg/L+dagliazin 2 μmol/L), dapagliflozin medium concentration group (TNF-α 10 mg/L+dagliazin 5 μmol/L) and dapagliflozin high concentration group (TNF-α 10+dagliazin 10 μmol/L). Western blot and real-time reverse transcriptase polymerase chain reaction were used to detect the expression of inflammatory factors and differential genes. Results: ePharmaLib reverse virtual screening identified 168 human-derived proteins with potential binding affinity to dapagliflozin, and single-cell analysis identifiedf 6 types of endothelial cell subpopulations. Compared with the control group, the abundance of capillary endothelial cells was significantly lower in DCM group, while the abundance of microvascular and venous endothelial cells was significantly higher (P all<0.05). Cell-cell communication analysis showed significant expression of Pgf-Vegfr1 ligand-receptor pair. In addition, 15 differentially expressed genes were identified by intersection analysis of 168 dapagliflozin-binding proteins. Including Bcl2, Baz2b, Nos3, Ephb4, Cdk8, Pparg, Pde2a, Fgfr2, Fto, Stk24, Dlg1, Gsk3b, Pdpk1, Fas and Tnks2. Notably, Baz2b, Pparg, Fto and Gsk3b were differentially expressed in all cell subpopulations. Six differential genes, including Pde7a, Dlg1, Gsk3b, Nampt, Met and Adk, were obtained by the intersection of the chip analysis data with the virtual screening results of dapagliflozin. In vitro, compared to the human umbilical vein endothelial cells of TNF-α group, the expression levels of interleukin-6, interleukin-1β and p-P65 proteins and messenger RNA of Bcl2, Nos3, Cdk8, Pde2a, Dlg1, Pdpk1, Tnks2, Baz2b, Pparg, Fas, Pde7a and Nampt were significantly lower than dapagliflozin high concentration group (P all<0.05). Conclusions: Dapagliflozin may inhibit endothelial cell inflammatory responses and improve endothelial dysfunction in DCM by regulating key genes such as Dlg1, Bcl2, Nos3, Pde7a and Nampt.

Knowledge of Primary Health Care Physicians About the Novel Class of Type 2 Diabetes Medication in Qassim Province, Saudi Arabia

2025-06-24

Renad Alghofaili , Chandra Sekhar | Cureus

GLP-1RA may open a new era for MASLD treatment

2025-06-24

Feng Ye , Chengfu Xu | Clinical and Molecular Hepatology

Addressing cardio-metabolic risks in type 2 diabetes: evidence-based insights on efpeglenatide

2025-06-24

Rajesh Kumar , Sunil Kumar Singh , Shruti Singh +1 more | International Journal of Basic & Clinical Pharmacology

Type 2 diabetes (T2D) is a chronic metabolic disorder linked to significant complications, including cardiovascular disease (CVD) and chronic kidney disease (CKD). Efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 … Type 2 diabetes (T2D) is a chronic metabolic disorder linked to significant complications, including cardiovascular disease (CVD) and chronic kidney disease (CKD). Efpeglenatide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), has emerged as a promising therapy for addressing glycemic control, weight management, and cardio metabolic risks. A systematic review of randomized controlled trials (RCTs) was conducted using PRISMA guidelines. Searches in PubMed, Google Scholar, and Science Direct identified studies on efpeglenatide impact on T2D outcomes. Data on efficacy, safety, dose-response, and combination with sodium-glucose cotransporter-2 (SGLT2) inhibitors were extracted and analyzed. Out of 843 studies screened, 10 were included. The AMPLITUDE-O trial showed a 27% reduction in major adverse cardiovascular events (MACEs) (hazard ratio [HR]: 0.73, p=0.007) and significant renal benefits (HR: 0.68, p<0.001). Phase 2 trials demonstrated HbA1c reductions (0.6%-1.2%) and weight loss (up to 7.5%). Gastrointestinal side effects were common but mild to moderate, with no major safety concerns. Sub-analyses indicated that combining efpeglenatide with SGLT2 inhibitors did not diminish its efficacy, suggesting potential synergy in reducing cardio metabolic risks. Efpeglenatide demonstrates robust efficacy in glycemic control, weight loss, and reducing cardiovascular and renal risks, with a tolerable safety profile. Its long-acting properties and compatibility with SGLT2 inhibitors support its use in comprehensive, individualized T2D management. Further research is warranted to refine dosing strategies and evaluate long-term outcomes in diverse patient populations.

Semaglutide in Adults with Type 1 Diabetes and Obesity

2025-06-23

Viral N. Shah , Halis Kaan Aktürk , Davida F. Kruger +5 more | NEJM Evidence

Once-weekly semaglutide is approved for the management of type 2 diabetes and obesity. The efficacy and safety of semaglutide in adults with type 1 diabetes are not established. In this … Once-weekly semaglutide is approved for the management of type 2 diabetes and obesity. The efficacy and safety of semaglutide in adults with type 1 diabetes are not established. In this 26-week, double-blind trial, we randomly assigned 72 adults with type 1 diabetes using an automated insulin delivery (AID) system and with a body mass index of 30 or higher in a 1:1 ratio to receive once-weekly semaglutide up to 1 mg or placebo. The primary composite end point consisted of achieving all of the following elements: continuous glucose monitoring (CGM)-based time between 70 and 180 mg/dl of greater than 70% and time below 70 mg/dl of less than 4%; and weight reduction of at least 5%. A significantly greater percentage of patients in the semaglutide group than in the placebo group achieved the primary composite outcome (36% vs. 0%; between-group difference, 36 percentage points; 95% confidence interval [CI], 20.6 to 52.2; P<0.001). The difference in the least-squares mean change from baseline to week 26 for the semaglutide versus placebo group for glycated hemoglobin was -0.3 percentage points (95% CI, -0.6 to -0.05), for percentage of time with CGM glucose levels between 70 and 180 mg/dl it was 8.8 percentage points (95% CI, 3.9 to 13.7), and for body weight it was -8.8 kg (95% CI, -10.6 to -7.0). There were two severe hypoglycemia events in each group, and no diabetic ketoacidosis was reported. In adults with type 1 diabetes and obesity, semaglutide treatment, compared with AID use alone, significantly improved achievement of a composite of time in range of greater than 70%, with time below range of less than 4%, and a 5% body weight reduction. (Funded by Breakthrough T1D [Type 1 Diabetes]; ADJUST-T1D trial ; Clinicaltrials.gov number, NCT05537233).

Sodium-Glucose Cotransporter 2 Inhibitors, Erythrocytosis, and Thrombosis in Adults With Type 2 Diabetes

2025-06-23

Maor Lewis , Nitzan Burrack , Anthony Heymann +3 more | JAMA Network Open

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are widely used and have been shown to induce erythrocytosis. However, the clinical implications of this phenomenon, particularly its association with venous and arterial thrombotic … Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are widely used and have been shown to induce erythrocytosis. However, the clinical implications of this phenomenon, particularly its association with venous and arterial thrombotic events, remain uncertain. To assess the extent, temporal course, and thrombotic complications of SGLT2i-induced erythrocytosis. This retrospective cohort study used patient data from Israel's largest health care organization from January 1, 2015, through June 30, 2024. Adult patients aged 18 years or older with type 2 diabetes who initiated SGLT2is were identified and compared with those who initiated dipeptidyl peptidase 4 inhibitors (DPP-4is) or glucagon-like peptide 1 receptor agonists (GLP-1RAs) using a propensity score-matched, active-comparator, new-user cohort design. New initiation of an SGLT2i, a GLP-1RA, or a DPP-4i. Outcomes included erythrocytosis within 1 year of initiating SGLT2is, as well as arterial and venous thrombotic events until the end of follow-up. Prevalence rates, rate differences, and odds ratios (ORs) for new-onset erythrocytosis and hemoglobin increase greater than 0.5 g/dL with 95% CIs were calculated. Hazard ratios (HRs) and 95% CIs for thrombotic outcomes were estimated using time-varying Cox proportional hazards regression models. After 1:1 propensity score matching, a total of 137 552 adults were included in the SGLT2i vs DPP-4i cohort (68 776 pairs; SGLT2i initiators: mean [SD] age, 64.55 [12.03] years; 55.3% male; DPP-4i initiators: mean [SD] age, 64.73 [13.08] years; 53.5% male) and 131 512 adults in the SGLT2i vs GLP-1RA cohort (65 756 pairs; SGLT2i initiators: mean [SD] age, 63.73 [11.87] years; 52.0% male; GLP-1RA initiators: mean [SD] age, 62.77 [11.56] years; 51.4% female). Among SGLT2i initiators, erythrocytosis prevalence in the SGLT2i vs DPP-4i cohort increased by 5.5% (95% CI, 5.1%-5.8%) and in the SGLT2i vs GLP-1RA cohort by 5.8% (95% CI, 5.4%-6.2%). In the SGLT2i vs GLP-1RA cohort, hemoglobin increased by 0.37 g/dL (95% CI, 0.36-0.38 g/dL) and hematocrit by 1.50% (95% CI, 1.48%-1.53%). Male sex (adjusted OR [AOR], 4.12; 95% CI, 3.80-4.48), smoking (AOR, 2.00; 95% CI, 1.85-2.16), and the use of empagliflozin vs dapagliflozin (AOR, 1.16; 95% CI, 1.09-1.25) were associated with an increased risk of developing erythrocytosis. New-onset erythrocytosis was not associated with an increased risk of myocardial infarction (HR, 0.92; 95% CI, 0.58-1.44), venous thromboembolism (HR, 1.56; 95% CI, 0.68-3.60), or stroke (HR, 1.26; 95% CI, 0.84-1.90). In this cohort study of patients with type 2 diabetes, SGLT2i use was associated with a higher risk of erythrocytosis compared with DPP-4is and GLP-1RAs; however, erythrocytosis was not associated with thrombotic events. These findings provide important reassurance regarding the safety of SGLT2i-induced erythrocytosis.

Diagnosis and Treatment of Type 2 Diabetes in Adults

2025-06-23

Rita R. Kalyani , Joshua J. Neumiller , Nisa M. Maruthur +1 more | JAMA

Type 2 diabetes involves progressive loss of insulin secretion from pancreatic β cells in the setting of insulin resistance and manifests clinically as hyperglycemia. Type 2 diabetes accounts for 90% … Type 2 diabetes involves progressive loss of insulin secretion from pancreatic β cells in the setting of insulin resistance and manifests clinically as hyperglycemia. Type 2 diabetes accounts for 90% to 95% of all cases of diabetes globally, with estimates ranging from 589 million to 828 million people worldwide. In the US, type 2 diabetes affects approximately 1 in 6 adults. Risk factors for type 2 diabetes include older age, family history, overweight or obesity, physical inactivity, gestational diabetes, Hispanic ethnicity, and American Indian or Alaska Native, Asian, or Black race. Diabetes is diagnosed if fasting plasma glucose is greater than or equal to 126 mg/dL, hemoglobin A1C is greater than or equal to 6.5%, or 2-hour glucose during 75-g oral glucose tolerance testing is greater than or equal to 200 mg/dL. Approximately one-third of adults with type 2 diabetes have cardiovascular disease and 10.1% have severe vision difficulty or blindness. The prevalence of type 2 diabetes is 39.2% among patients with kidney failure. Although weight management is an important component of treatment for type 2 diabetes, no specific diet has been proven to be most effective for improving health outcomes. Physical activity can reduce hemoglobin A1C by 0.4% to 1.0% and improve cardiovascular risk factors (ie, hypertension and dyslipidemia). Randomized clinical trials have reported absolute reductions in microvascular disease (3.5%), such as retinopathy and nephropathy, myocardial infarction (3.3%-6.2%), and mortality (2.7%-4.9%), with intensive glucose-lowering strategies (hemoglobin A1C <7%) vs conventional treatment 2 decades after trial completion. First-line medications for type 2 diabetes include metformin and, in patients with cardiovascular or kidney comorbidities or at high cardiovascular risk, glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter 2 inhibitors (SGLT2is). Common add-on medications include dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RAs, dipeptidyl peptidase-4 inhibitors, sulfonylureas, and thiazolidinediones. Approximately one-third of patients with type 2 diabetes require treatment with insulin during their lifetime. Several randomized clinical trials have demonstrated benefits of specific SGLT2i and GLP-1RA medications compared with placebo for atherosclerotic cardiovascular disease (12%-26% risk reduction), heart failure (18%-25% risk reduction), and kidney disease (24%-39% risk reduction) over 2 to 5 years. Most trial participants with type 2 diabetes were taking metformin. High-potency GLP-1RA and dual GIP/GLP-1RA medications result in weight loss of greater than 5% in most individuals with type 2 diabetes, and weight loss may exceed 10%. Type 2 diabetes affects up to 14% of the global population and is associated with preventable long-term complications, such as cardiovascular disease, kidney failure, vision loss, and increased mortality. In addition to lifestyle modifications including diet, exercise, and weight management, metformin is generally first-line therapy for attainment of hemoglobin A1C targets. For individuals with type 2 diabetes and cardiovascular or kidney disease or at high cardiovascular risk, guidelines recommend early treatment with SGLT2i and/or GLP-1RA medications.

Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial

2025-06-23

Ania M. Jastreboff , Donna H. Ryan , Harold Bays +7 more | New England Journal of Medicine

Maridebart cafraglutide (known as MariTide) is a long-acting peptide-antibody conjugate that combines glucagon-like peptide-1 receptor agonism and glucose-dependent insulinotropic polypeptide receptor antagonism and that is intended for the treatment of … Maridebart cafraglutide (known as MariTide) is a long-acting peptide-antibody conjugate that combines glucagon-like peptide-1 receptor agonism and glucose-dependent insulinotropic polypeptide receptor antagonism and that is intended for the treatment of obesity. We conducted a phase 2, double-blind, randomized, placebo-controlled, dose-ranging trial that included 11 groups as two cohorts. Participants with obesity (obesity cohort) were randomly assigned in a 3:3:3:2:2:2:3 ratio to receive maridebart cafraglutide subcutaneously at a dose of 140, 280, or 420 mg every 4 weeks without dose escalation; 420 mg every 8 weeks without dose escalation; 420 mg every 4 weeks with 4-week dose escalation; 420 mg every 4 weeks with 12-week dose escalation; or placebo. Participants with obesity with type 2 diabetes (obesity-diabetes cohort) were randomly assigned in a 1:1:1:1 ratio to receive maridebart cafraglutide at a dose of 140, 280, or 420 mg every 4 weeks (all without dose escalation) or placebo. The primary end point was the percent change in body weight from baseline to week 52. We enrolled 592 participants. In the obesity cohort (465 participants; female sex, 63%; mean age, 47.9 years; mean body-mass index [BMI, the weight in kilograms divided by the square of the height in meters], 37.9), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand (intention-to-treat approach) ranged from -12.3% (95% confidence interval [CI], -15.0 to -9.7) to -16.2% (95% CI, -18.9 to -13.5) with maridebart cafraglutide, as compared with -2.5% (95% CI, -4.2 to -0.7) with placebo. In the obesity-diabetes cohort (127 participants; female sex, 42%; mean age, 55.1 years; mean BMI, 36.5), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand ranged from -8.4% (95% CI, -11.0 to -5.7) to -12.3% (95% CI, -15.3 to -9.2) with maridebart cafraglutide, as compared with -1.7% (95% CI, -2.9 to -0.6) with placebo. The mean change in the glycated hemoglobin level on the basis of the treatment policy estimand in this cohort was -1.2 to -1.6 percentage points in the maridebart cafraglutide groups and 0.1 percentage points in the placebo group. Gastrointestinal adverse events were common with maridebart cafraglutide, although less frequent with dose escalation and a lower starting dose. No unexpected safety signals emerged. In this phase 2 trial, once-monthly maridebart cafraglutide resulted in substantial weight reduction in participants with obesity with or without type 2 diabetes. (Funded by Amgen; ClinicalTrials.gov number, NCT05669599.).

Semaglutide for Type I Diabetes — A New Twist on an Old Story

2025-06-23

Clifford J. Rosen | NEJM Evidence

292-OR: Oral Semaglutide and Cardiovascular Outcomes by Baseline A1C and BMI in People with Type 2 Diabetes in the SOUL Trial

2025-06-23

SILVIO E. INZUCCHI , Rohana Abdul Ghani , John Deanfield +7 more | Diabetes

Introduction and Objective: In SOUL (NCT03914326), oral semaglutide (sema) 14 mg QD, a GLP-1 receptor agonist, reduced major adverse cardiovascular (CV) event (MACE) risk by 14%. GLP-1RAs are routinely prescribed … Introduction and Objective: In SOUL (NCT03914326), oral semaglutide (sema) 14 mg QD, a GLP-1 receptor agonist, reduced major adverse cardiovascular (CV) event (MACE) risk by 14%. GLP-1RAs are routinely prescribed to reduce A1c and BMI in type 2 diabetes (T2D). Whether the CV benefits of oral sema are influenced by baseline A1c or BMI is not fully known. Methods: SOUL’s primary outcome was time to first MACE, assessed for this post hoc analysis by baseline A1c, BMI and body weight using Cox regression. Results: People with T2D (n=9650; A1c 6.5–10%) and known atherosclerotic CV disease (ASCVD) or chronic kidney disease (CKD) were randomized to oral sema or placebo and followed for a mean of 47.5 months. We found significant differences in MACE outcomes associated with oral sema use by baseline A1c, with greater effects apparent with A1c &gt;8.0% (Fig.). When the data were further analyzed across four A1c strata, the MACE benefit from oral sema appeared to apply to those with A1c &gt;7%. The effects of oral sema on MACE were the same in those with BMI above / below 30 kg/m2, as well as across all four BMI strata, and above / below the mean body weight (87.9 kg) (Fig.). Conclusion: In SOUL, the CV benefits of oral sema appeared more pronounced with higher A1c levels at baseline but were consistent across various BMI categories. These data may help inform the individualized use of oral sema in people with T2D and ASCVD and/or CKD. Disclosure S.E. Inzucchi: Consultant; Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc, Pfizer Inc, Bayer Pharmaceuticals, Inc. R. Abdul Ghani: None. J. Deanfield: Other Relationship; Aegerion Pharmaceuticals, Amgen Inc, AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Merck & Co., Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Novo Nordisk A/S, Pfizer Inc. M.D.M. Engelmann: Employee; Novo Nordisk. G. Hovingh: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. O.K. Jeppesen: None. M. Kellerer: Advisory Panel; Abbott, Bayer Pharmaceuticals, Inc. Speaker's Bureau; Boehringer-Ingelheim, Johnson & Johnson Medical Devices Companies. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Sanofi. K. Mandavya: Employee; Novo Nordisk. J.F. Mann: Other Relationship; AstraZeneca, Bayer Pharmaceuticals, Inc. Advisory Panel; Novo Nordisk. Board Member; AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Novo Nordisk. Other Relationship; Sanofi. Consultant; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk. Research Support; AstraZeneca. Other Relationship; Boehringer-Ingelheim. Research Support; Novo Nordisk, Sanofi. Speaker's Bureau; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk, Novartis AG. Other Relationship; UpToDate Inc / KDIGO. N. Marx: Speaker's Bureau; Abbott, Amgen Inc, AstraZeneca. Advisory Panel; AstraZeneca. Speaker's Bureau; Bayer Pharmaceuticals, Inc. Advisory Panel; Bayer Pharmaceuticals, Inc. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Merck Sharp & Dohme Corp. Speaker's Bureau; Novo Nordisk. Advisory Panel; Novo Nordisk. Speaker's Bureau; Sanofi. Advisory Panel; Sanofi. Speaker's Bureau; Lilly Diabetes. C. Mathieu: Advisory Panel; Novo Nordisk, Sanofi, Eli Lilly and Company, Abbott, Medtronic, SAB Biotherapeutics, Inc, Roche Diabetes Care, Vertex Pharmaceuticals Incorporated, Biomea Fusion, Bayer Pharmaceuticals, Inc. D.K. McGuire: Consultant; Novo Nordisk. Advisory Panel; Novo Nordisk. Consultant; Lilly USA LLC. Advisory Panel; Lilly USA LLC. Consultant; Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim, AstraZeneca, ESPERION Therapeutics, Inc., NewAmsterdam Pharma, Pfizer Inc. Consultant; Applied Therapeutics, Lexicon Pharmaceuticals, Inc, Bayer Pharmaceuticals, Inc, Amgen Inc, Kailera, Idorsia, Alveus, Metsera. V. Mohan: Speaker's Bureau; Novo Nordisk. Advisory Panel; Abbott. Research Support; Servier Laboratories. Speaker's Bureau; USV Private Limited, Sanofi, Medtronic, Eli Lilly and Company. S.L. Mulvagh: Advisory Panel; Novo Nordisk, Merck & Co., Inc. R. Pop-Busui: Board Member; American Diabetes Association. Consultant; Averitas Pharma, Inc. Research Support; Bayer Pharmaceuticals, Inc. Other Relationship; Biogen. Research Support; Juvenile Diabetes Research Foundation (JDRF). Advisory Panel; Lexicon Pharmaceuticals, Inc, Novo Nordisk. Research Support; Novo Nordisk, National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Roche Diagnostics. N.R. Poulter: Consultant; Servier Laboratories, Alnylam Pharmaceuticals, Inc. Research Support; Servier Laboratories. Speaker's Bureau; AstraZeneca. Consultant; Aktiia. M. Ripa: Employee; Novo Nordisk. G. Roman: Advisory Panel; AstraZeneca. Consultant; Berlin-Chemie AG. Research Support; AstraZeneca. Advisory Panel; Boehringer-Ingelheim, Medtronic, Lilly Diabetes, Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Roche Diabetes Care, Sanofi, Viatris Inc. R. Sánchez García: None. M. Shechter: None. J.B. Buse: Other Relationship; Corcept Therapeutics, Dexcom, Inc., Novo Nordisk. Consultant; Altimmune Inc, Amgen Inc, ApStem, Aqua Medical, AstraZeneca, Boehringer-Ingelheim, CeQur, Eli Lilly and Company, embecta, GentiBio. Other Relationship; Glyscend Therapeutics. Consultant; Insulet Corporation, Medtronic. Other Relationship; Mellitus Health. Consultant; Metsera. Other Relationship; Pendulum Therapeutics, Praetego, Stability Health. Consultant; Tandem Diabetes Care, Inc, TERNS Pharmaceuticals, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S. Funding Novo Nordisk A/S

Reduced Incidence of Aortic Dissection in Patients With Type 2 Diabetes Treated With Sodium Glucose Transporter 2 Inhibitors

2025-06-23

Chi‐Jung Chung , Hsin‐Ying Lu , Mu‐Chi Chung +5 more | Journal of the American Heart Association

Inhibitors for sodium-glucose transport protein 2 (SGLT2) are being used widely in recent years to treat patients with type 2 diabetes (T2D). Studies demonstrated that SGLT2 inhibitors exhibit protective effect … Inhibitors for sodium-glucose transport protein 2 (SGLT2) are being used widely in recent years to treat patients with type 2 diabetes (T2D). Studies demonstrated that SGLT2 inhibitors exhibit protective effect for certain cardiovascular diseases. However, no study has explored the effect of SGLT2 inhibitors on risk of aortic dissection in patients with T2D. We extracted and retrospectively analyzed the data of all patients with T2D from Taiwan National Health Institution databases between May 1, 2016, and December 31, 2021. Patients with T2D taking DPP4 (dipeptidyl peptidase 4) inhibitors were included for comparison to exclude glucose lowering effect on aortic dissection. In this cohort, 242 563 patients received SGLT2 inhibitors (T2D-SGLT2i), and 376 062 patients received DPP4 inhibitors (T2D-DPP4i). The inverse probability of treatment weighting statistical method was performed, which avoids sample loss due to matching. The hazard ratios (HRs) and 95% CIs for these patients with T2D were calculated using multivariate Cox models to approximate the associations. The overall aortic dissection incidence per 100 000 patient-years was 14.83 for patients with T2D-SGLT2i and 29.56 for patients with T2D-DPP4i. Patients with T2D-SGLT2i were associated with a lower risk of aortic dissection as compared with patients with T2D-DPP4i after the adjustment of potential risk factors and comorbidity. Subgroup analysis indicated that use of SGLT2 inhibitor lowers the risk of aortic dissection in some subgroups of patients with T2D. Our study suggested that use of SGLT2 inhibitors correlated with lower risk of aortic dissection.

Bexagliflozin - evaluation of the clinical efficacy, safety profile and potential new applications of the SGLT2 inhibitor: a review of the literature

2025-06-23

Józef Muszyński | Journal of Medical Science

Introduction. Type 2 diabetes (T2DM) is a growing global health, social, and economic problem. T2DM is often accompanied by other diseases and is associated with complications such as kidney damage … Introduction. Type 2 diabetes (T2DM) is a growing global health, social, and economic problem. T2DM is often accompanied by other diseases and is associated with complications such as kidney damage and cardiovascular diseases. The 21st century has seen a breakthrough in treating T2DM, including incretins and flozins. This review focuses on bexagliflozin, a new SGLT-2 inhibitor approved by the FDA for treating T2DM. Its efficacy, safety, and potential benefits of new uses are analyzed. Material and methods. Sources were obtained using PubMed and Google Scholar, Medline using the keywords: bexagliflozin, EGT1442, new indications bexagliflozin, bexagliflozin trials. Results. Unlike other SGLT-2 inhibitors, bexagliflozin has a different molecular structure, which may increase its selectivity and efficacy. Preliminary results suggest that the drug may offer additional therapeutic benefits over other drugs in this group, particularly in the treatment of hypertension and cardiac arrhythmias. Studies are currently underway to investigate its potential use in the treatment of chronic kidney disease in children and in the treatment of sleep apnea. Conclusions. Bexagliflozin shows promise as a treatment for type 2 diabetes, with additional potential benefits in treating other conditions. Although the drug is relatively new to the market, preliminary studies indicate that it may offer advantages over other SGLT-2 inhibitors in some areas. Nevertheless, further clinical trials are needed to further evaluate its efficacy compared to other therapies and its potential in a wider range of applications.

Racial and ethnic disparities in early uptake of GLP-1 receptor agonists in patients with and without MASLD

2025-06-23

Sarpong Boateng , Prince A. Ameyaw , Yussif Issaka +2 more | Research Square (Research Square)

<title>Abstract</title> <bold>Background: </bold>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective in managing Type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD). While disparities in GLP-1 RA … <title>Abstract</title> <bold>Background: </bold>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective in managing Type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD). While disparities in GLP-1 RA prescriptions exist, little is known about racial and ethnic differences in early initiation, particularly in MASLD patients. This study evaluates racial and ethnic disparities in early GLP-1 RA uptake among eligible patients with and without MASLD <bold>Methods: </bold>We conducted a retrospective cohort study using the All of Us Research Program (2016–2022), including adults (≥18 years) with T2DM and/or obesity eligible for GLP-1 RA therapy. Early uptake was defined as a prescription within one year of eligibility. Race/ethnicity was categorized as non-Hispanic (NH) White, Black, Hispanic/Latino, Asian, or Other. Multivariable Cox regression models assessed associations between race/ethnicity and early prescription, adjusting for sociodemographic and clinical factors. A sub-analysis examined disparities among MASLD patients. <bold>Results: </bold>Among 89,019 eligible patients, 1.17% (n=1,039) initiated GLP-1 RA therapy within one year. Black (HR: 0.79, 95%CI: 0.65–0.95, p=0.014) and Hispanic/Latino (HR: 0.66, 95%CI: 0.53–0.82, p<0.001) patients had significantly lower uptake than NH Whites. Among MASLD patients, Asians had significantly higher early uptake (HR: 5.41, 95%CI: 2.2–13.6, p<0.001). Higher BMI, T2DM, and hyperlipidemia predicted early initiation, while older age, male sex, Black, and Hispanic race were associated with lower uptake <bold>Conclusion(s)</bold>: Significant racial and ethnic disparities exist in early GLP-1 RA uptake. Efforts are needed to promote equitable access and utilization, particularly for high-risk populations

Cardiovascular Outcomes of Perioperative Sodium‐Glucose Transporter 2 Inhibition in Cardiac Surgery Patients: An Open‐Label Randomized Pilot Study

2025-06-22

Lars Snel , Maartina J P Oosterom-Eijmael , Yugeesh R. Lankadeva +6 more | Acta Anaesthesiologica Scandinavica

ABSTRACT Background Previous studies have shown cardiovascular benefits of SGLT2 inhibitors. The aim of this study was to evaluate the cardiovascular effects of perioperative SGLT2 inhibition in patients undergoing cardiac … ABSTRACT Background Previous studies have shown cardiovascular benefits of SGLT2 inhibitors. The aim of this study was to evaluate the cardiovascular effects of perioperative SGLT2 inhibition in patients undergoing cardiac surgery. Methods In this open‐label pilot study, adult patients undergoing cardiac surgery were randomized to receive a daily dose of empagliflozin (10 mg; oral) 3 days before surgery until 2 days after surgery, or standard of care. Blood pressure, heart rate, postoperative diuresis, intravenous fluid administration, fluid balance, and vasoactive support were compared between groups during the first 24 postoperative hours. Results About 55 patients (sex: 73% male, age: 66 ± 10 years, BMI: 28 ± 4 kg/m 2 , empagliflozin n = 25, control n = 30) were included in this study and analyzed according to the intention‐to‐treat principle. Empagliflozin was associated with increased diuresis, mean difference 549 mL (95% CI 258–839, p < 0.001), and less positive fluid balance postoperatively, mean difference −1217 mL (95% CI −2373– −61, p = 0.039). Empagliflozin did not increase the amount of intravenous fluid administered. In the empagliflozin group, norepinephrine was infused for 11.8 ± 11.5 h compared to 19.3 ± 19.3 h in the control group ( p = 0.080). No significant between‐group differences were observed in postoperative blood pressure and heart rate. Conclusions Perioperative SGLT2 inhibition was associated with increased diuresis and lesser fluid accumulation without an increase in vasopressor requirement. These data warrant validation and further evaluation in a larger‐scale, double‐blind, placebo‐controlled trial. Editorial Comment In this sub‐study of the randomized MERCURI‐2 trial of perioperative empagliflozin for nondiabetics in cardiac surgery, the authors describe the hemodynamic outcomes and fluid status of the patients. The authors noted a higher urine output and a more negative fluid balance in the intervention group compared to the placebo group. An interesting observation is the trend towards lower noradrenaline usage, although this cannot be concluded with confidence based on this data. The findings support considering and further studying the use of these medications for patients with cardiovascular disease undergoing surgery. Trial Registration: https://onderzoekmetmensen.nl/en/trial/26563 Identifier: NL9561

Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes

2025-06-22

Melanie J. Davies , Harpreet S. Bajaj , Christa Broholm +7 more | New England Journal of Medicine

Cagrilintide and semaglutide have each been shown to induce weight loss as monotherapies. Data are needed on the coadministration of cagrilintide and semaglutide (called CagriSema) for weight management in adults … Cagrilintide and semaglutide have each been shown to induce weight loss as monotherapies. Data are needed on the coadministration of cagrilintide and semaglutide (called CagriSema) for weight management in adults with type 2 diabetes, including those in a subgroup who are undergoing continuous glucose monitoring. In this phase 3a, double-blind, randomized, placebo-controlled trial conducted in 12 countries, we assigned adults with a body-mass index of 27 or more, a glycated hemoglobin level of 7 to 10%, and type 2 diabetes in a 3:1 ratio to receive once-weekly cagrilintide-semaglutide (2.4 mg each) or placebo, along with lifestyle intervention, for 68 weeks. The two primary end points were the percent change in body weight and the percentage of patients with a weight reduction of at least 5%. Additional end points were changes in glycemic measures and safety assessments. Effect estimates were calculated with the use of the treatment-policy estimand (consistent with the intention-to-treat principle). A total of 1206 patients underwent randomization to either the cagrilintide-semaglutide group (904 patients) or the placebo group (302 patients). The estimated mean change in body weight from baseline to week 68 was -13.7% in the cagrilintide-semaglutide group and -3.4% in the placebo group (estimated difference, -10.4 percentage points; 95% confidence interval, -11.2 to -9.5; P<0.001). More patients in the cagrilintide-semaglutide group than in the placebo group had a weight reduction of 5% or more (P<0.001); the same was true of reductions of at least 10%, 15%, and 20% (P<0.001 for the last comparison). The percentage of patients who had a glycated hemoglobin level of 6.5% or less was 73.5% in the cagrilintide-semaglutide group and 15.9% in the placebo group. Gastrointestinal adverse events were reported by 72.5% of the patients in the cagrilintide-semaglutide group and 34.4% in the placebo group, most of which were transient and mild or moderate in severity. Once-weekly cagrilintide-semaglutide (at a dose of 2.4 mg each) resulted in a significantly lower body weight than placebo in adults with obesity and type 2 diabetes. (Funded by Novo Nordisk; REDEFINE 2 ClinicalTrials.gov number, NCT05394519.).

GLP-1 agonist-related psychiatric AEs

2025-06-21

| Reactions Weekly

Antihyperglycaemics

2025-06-21

| Reactions Weekly

Dapagliflozin

2025-06-21

| Reactions Weekly

Association between autoimmune diseases and glucagon-like peptide-1 receptor agonists: A real-world evidence study

2025-06-21

Young‐Ho Lee , Yu‐Wei Fang , Mon‐Ting Chen +3 more | Journal of Autoimmunity

The therapeutic advantages of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in diabetes management have been demonstrated. However, their potential association with autoimmune diseases remains unknown. Using a comprehensive real-world dataset, … The therapeutic advantages of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in diabetes management have been demonstrated. However, their potential association with autoimmune diseases remains unknown. Using a comprehensive real-world dataset, this study compared GLP-1 RAs against dipeptidyl peptidase-4 inhibitors (DPP-4is) with respect to the incidence of autoimmune diseases. This retrospective cohort study, with an active-comparator and new-user design, analyzed data from the TriNetX US Collaborative Network. We identified 4,841,560 patients aged over 18 years with type 2 diabetes from 1 January 2015 to 31 December 2022. Finally, 412,021 and 383,415 patients were included in the GLP-1 RAs and DPP-4is groups, respectively. Propensity score matching was used to balance baseline characteristics, and hazard ratios (HRs) were estimated with Cox regression models over an eight-year follow-up. After propensity score matching, each group included 290,770 patients. The analysis revealed that patients receiving GLP-1 RAs exhibited significantly higher risks of certain autoimmune conditions, including ulcerative colitis (HR, 1.11; 95 % CI, 1.04-1.19), rheumatoid arthritis (HR, 1.08; 95 % CI, 1.03-1.12), autoimmune thyroiditis (HR, 1.30; 95 % CI, 1.24-1.38), ankylosing spondylitis (HR, 1.30; 95 % CI, 1.13-1.51), and psoriasis (HR, 1.17; 95 % CI, 1.12-1.22), compared to those on DPP-4is. Moreover, sensitivity analyses consistently revealed a significant link between GLP-1 RAs use and autoimmune diseases. This study suggests that compared with DPP-4is, the use of GLP-1 RAs is linked to increased risks of certain autoimmune diseases. Careful monitoring might be required among patients on GLP-1 RAs.

Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes

2025-06-21

Julio Rosenstock , Stanley H. Hsia , Luis Nevárez Ruiz +7 more | New England Journal of Medicine

Orforglipron is a small-molecule, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist in clinical development for type 2 diabetes and weight management. Additional data on the efficacy and safety of orforglipron are … Orforglipron is a small-molecule, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist in clinical development for type 2 diabetes and weight management. Additional data on the efficacy and safety of orforglipron are needed. In this phase 3, double-blind, placebo-controlled trial, we randomly assigned participants in a 1:1:1:1 ratio to receive orforglipron at one of three doses (3 mg, 12 mg, or 36 mg) or placebo once daily for 40 weeks. Participants had type 2 diabetes treated only with diet and exercise, a glycated hemoglobin level of at least 7.0% but no more than 9.5%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 23.0. The primary end point was the change from baseline to week 40 in the glycated hemoglobin level. A key secondary end point was the percent change in body weight from baseline to week 40. A total of 559 participants underwent randomization. The mean glycated hemoglobin level at baseline was 8.0%. At week 40, the estimated mean change from baseline in the glycated hemoglobin level was -1.24 percentage points with the 3-mg dose, -1.47 percentage points with the 12-mg dose, -1.48 percentage points with the 36-mg dose, and -0.41 percentage points with placebo. All three doses of orforglipron were superior to placebo with respect to the primary end point; the estimated mean difference from placebo was -0.83 percentage points (95% confidence interval [CI], -1.10 to -0.56) with the 3-mg dose, -1.06 percentage points (95% CI, -1.33 to -0.79) with the 12-mg dose, and -1.07 percentage points (95% CI, -1.33 to -0.81) with the 36-mg dose (P<0.001 for all comparisons). The mean glycated hemoglobin level at week 40 was 6.5 to 6.7% with orforglipron. The percent change in body weight from baseline to week 40 was -4.5% with the 3-mg dose, -5.8% with the 12-mg dose, -7.6% with the 36-mg dose, and -1.7% with placebo. The most common adverse events were mild-to-moderate gastrointestinal events, most of which occurred during dose escalation. No episodes of severe hypoglycemia were reported. Permanent discontinuation of orforglipron or placebo due to adverse events occurred in 4.4 to 7.8% of participants receiving orforglipron and 1.4% of participants receiving placebo. In adults with early type 2 diabetes, orforglipron significantly reduced the glycated hemoglobin level over a period of 40 weeks. (Supported by Eli Lilly; ACHIEVE-1 ClinicalTrials.gov number, NCT05971940.).

The multifaceted modulations by dapagliflozin in preventing hyperglycemia-induced diabetic nephropathy through glucose transporters and PPARα

2025-06-20

Hsien-Hui Chung , Ching-Jiunn Tseng , Pei‐Wen Cheng | Journal of Diabetes & Metabolic Disorders

Signal mining of adverse drug events related to hypovolemia caused by SGLT2 inhibitors based on FAERS database

2025-06-20

Huan Li , Ziwan Guan | International Journal of Diabetes in Developing Countries

Abstract Background Hypovolemia is one of the most common adverse events (AE) of SGLT2is, which is overlooked, especially in the elderly population. Objective In this study, signal mining of AEs … Abstract Background Hypovolemia is one of the most common adverse events (AE) of SGLT2is, which is overlooked, especially in the elderly population. Objective In this study, signal mining of AEs caused by SGLT2is was conducted, and the AE signals related to hypovolemia in the real world after marketing were statistically analyzed, so as to provide reference for reducing AEs and for clinical rational drug use. Methods The FDA adverse event reporting system (FAERS) is an important data source for spontaneous reporting of AEs. A total of 46 quarterly data from 2013 Q1 to 2024 Q2 was extracted for analysis. In this study, disproportionality analysis was used to detect the signals of AEs and four methods including ROR, MHRA, BCPNN, and MGPS were combined. Results 5017 AE reports related to SGLT2is induced hypovolemia were included in the analysis. According to the ROR value of signal mining, empagliflozin had a higher risk of hypovolemia (ROR = 13.87), while canagliflozin had a higher risk of hypovolemic shock (ROR = 3.40). In stratification analysis by sex, the risk of hypovolemia-related AEs was higher in females using canagliflozin than in males. The most significant differences were hypovolaemia (female ROR = 10.98 vs. male ROR = 5.56). When stratified by age, it showed that patients < 18 years old, 18–44 years old, and > 75 years old had a higher risk of hypovolemia-related AEs than other age groups. Conclusions Hypovolemia related AEs caused by SGLT2is were found to be more common in women and elderly patients.

Effects of SGLT2 ablation or inhibition on corticosterone secretion in high-fat-fed mice: exploring a nexus with cytokine levels

2025-06-20

Brisnovali Niki Fanouriou , Isabelle Franco , Amira Abdelgawwad +6 more | Diabetologia

Abstract Aims/hypothesis Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing type 2 diabetes. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have emerged as effective treatments by promoting … Abstract Aims/hypothesis Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing type 2 diabetes. Sodium–glucose cotransporter 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. Methods To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high-fat-diet-fed control mice, mice treated chronically with dapagliflozin, and total-body Slc5a2 -knockout mice. Results SGLT2-null mice exhibited better glucose tolerance and insulin sensitivity (blood glucose during IPGTT AUC 0–90 min 1175 ± 57.4 mmol/l × min, mean ± SEM) compared with control (AUC 0–90 min 1857 ± 117.9 mmol/l × min, p =0.05) or dapagliflozin-treated mice (AUC 0–90 min 1506 ± 68.72 mmol/l × min, p =0.09), independent of glycosuria and body weight. Moreover, SGLT2-null mice demonstrated physiological regulation of corticosterone secretion, with lower morning levels than control mice ( p <0.01). Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly IL-6. Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 treatment increased SGLT2 expression in human kidney HK2 cells, suggesting a role for cytokines in the effects of hyperglycaemia. Conclusions/interpretation Collectively, our data elucidate a potential interplay between SGLT2 activity, immune modulation and metabolic homeostasis, as well as a potential feedback loop between SGLT2 expression and cytokine concentration. Graphical Abstract

Trends in hyperglycemic drug usage among Danish type 2 diabetes patients on second-line treatment and beyond: A nationwide cohort study

2025-06-20

Henrik Vitus Bering Laursen , Flemming Witt Udsen , Morten Hasselstrøm Jensen +2 more | medRxiv (Cold Spring Harbor Laboratory)

2 Abstract OBJECTIVE The paradigm shift introduced by the glucagon-like peptide-1 (GLP1) receptor agonist and sodium-glucose co-transporter-2 (SGLT2) inhibitor classes of drugs has led to changes in treatment practices in … 2 Abstract OBJECTIVE The paradigm shift introduced by the glucagon-like peptide-1 (GLP1) receptor agonist and sodium-glucose co-transporter-2 (SGLT2) inhibitor classes of drugs has led to changes in treatment practices in Denmark. The aim of this study was to investigate what these changes were before and after the implementation of the 2018 guidelines in Denmark. RESEARCH DESIGN AND METHODS Registry data on prescriptions was linked with other registries to create a descriptive overview of treatment patterns was carried out for a nationwide cohort of all individuals receiving at least two non-insulin anti-diabetic drugs (NIADs) between 2012 and 2021. RESULTS A cohort of 66,188 individuals was identified. The treatment patterns reflected significantly higher use of SGLT2 and GLP1 over time, eclipsing all other drugs, except for insulin, at later treatment stages. First-line use of SGLT2 and GLP1 also became higher over time, as did their likelihood of prescription at later stages. Their combined use rivaled insulin usage at similar stages by 2021. First-line use for women were high in the GLP1 group. CONCLUSIONS Our study finds that GLP1 and SGLT2 are used extensively for individuals who have tried multiple NIADs and may delay the use of insulin. Furthermore, there is an increased trend in their first-line use. Key messages – less than 6 sentences What is already known on this subject ○ Increase in use of SGLT2 and GLP1 is documented, but changes in treatment patterns specifically for a cohort of people with type 2 diabetes before and after the publication of the 2018 treatment guidelines has not. What did we find? ○ A marked increase in SGLT2 and GLP1 utilization, an indication that insulin initiation is postponed following this, and a preference for GLP1 in younger people in the cohort. What are the implications of our findings? ○ Introduction of SGLT2 and GLP1 has led to major changes in the treatment practice of type 2 diabetes. Systematic population-based monitoring is highly warranted to ensure that treatment practice remain compliant with clinical guidelines recommendations.

Health economic model assumptions of pharmaceutical treatment paths compared with real-world evidence for patients with type 2 diabetes: A nationwide cohort study

2025-06-20

Henrik Vitus Bering Laursen , Flemming Witt Udsen , Morten Hasselstrøm Jensen +2 more | medRxiv (Cold Spring Harbor Laboratory)

2 Abstract OBJECTIVE The glucagon-like peptide-1 (GLP1) and sodium-glucose co-transporter-2 (SGLT2) classes are increasingly being used around the globe to treat type 2 diabetes and its comorbidities. Decision-analytical models (DAMs) … 2 Abstract OBJECTIVE The glucagon-like peptide-1 (GLP1) and sodium-glucose co-transporter-2 (SGLT2) classes are increasingly being used around the globe to treat type 2 diabetes and its comorbidities. Decision-analytical models (DAMs) are used to evaluate the cost-effectiveness of the different products within these classes, but their assumptions regarding the treatment pathways and time until insulin may not reflect real-world practice. This study compares the model assumptions found in a recent review with registry data. RESEARCH DESIGN AND METHODS Real-world practice was represented by a nationwide registry-based cohort of 62,238 people with type 2 diabetes included in an early (2012 to 2018), and a late period (2019 to 2021). Treatment pathway assumptions were compared using counts and proportions. Time until insulin initiation was compared among groups starting on the comparators dipeptidyl peptidase-4 inhibitor (DPP4), GLP1, or SGLT2. Incidence rates, hazard ratios, and absolute risks were utilized. The latter were derived from cumulative incidence functions calculated using the Aalen-Johansen estimator, accounting for competing risks. RESULTS The treatment pathway assumptions of initiating insulin after a short time on the comparators did not correspond with our data. Neither did the assumptions surrounding time until insulin, as the time differed between comparator group, and inclusion period, with SGLT2 having the lowest risk. Further, time until insulin was observed to be much longer in real-world practice than in the model assumptions. CONCLUSIONS Key model assumptions used to inform decision-makers on the cost-effectiveness of expensive drug classes like GLP1 and SGLT2, are flawed and need to be updated.

The therapeutic potential of sodium glucose cotransporter-2 inhibitors in diabetic neuropathy

2025-06-20

Theodoros Panou , Evanthia Gouveri , Djordje S. Popovic +2 more | Experimental and Clinical Endocrinology & Diabetes

Diabetic neuropathy is a serious complication of diabetes mellitus (DM). Its commonest manifestation is diabetic peripheral neuropathy (DPN). Diabetic neuropathy may also affect the autonomic nervous system, cardiac autonomic neuropathy … Diabetic neuropathy is a serious complication of diabetes mellitus (DM). Its commonest manifestation is diabetic peripheral neuropathy (DPN). Diabetic neuropathy may also affect the autonomic nervous system, cardiac autonomic neuropathy (CAN) being its most widely studied manifestation. Treatment of DPN and CAN rests on glycaemic control and alleviation of symptoms, calling for improvement. To this purpose, the novel antidiabetic oral agents sodium glucose cotransporter 2 inhibitors (SGLT-2is) have been studied. Beyond their favourable effects on metabolic control, cardiovascular and renal outcomes, these agents appear to harbour some beneficial actions in DPN and CAN as well. The underlying mechanisms are not entirely clear, but appear to involve the 5' adenosine monophosphate-activated protein kinase (AMPK)-pathway. So far, clinical experience has been limited. Significant improvement in electrophysiological parameters and thermal perception has been observed among subjects with type 2 diabetes mellitus (T2DM) in small studies. However, contradictory findings have also been reported. The same ambiguous effect of SGLT-2is has been observed in CAN. Thus, future large studies are required to delineate the utility of SGLT-2is in DPN and/or CAN.

798-P: Semaglutide Effect during Mixed-Meal Tolerance Test (MMTT) with Fully Closed-Loop Therapy in Type 1 Diabetes (T1D)

2025-06-20

MELISSA-ROSINA PASQUA , JOELLE DOUMAT , ADNAN JAFAR +2 more | Diabetes

Introduction and Objective: We assessed glycemia, insulin needs, and C-peptide levels with semaglutide after MMTT in type 1 diabetes. Methods: This is a sub-analysis of a randomized crossover trial assessing … Introduction and Objective: We assessed glycemia, insulin needs, and C-peptide levels with semaglutide after MMTT in type 1 diabetes. Methods: This is a sub-analysis of a randomized crossover trial assessing semaglutide vs. placebo with automated insulin delivery (AID) in adults with T1D (NCT05205928). Participants performed a MMTT with 6 mL/kg of Boost, while using fully-closed-loop AID, after 12 weeks of semaglutide and placebo, in random order. Plasma glucose and C-peptide levels were measured over 120 minutes. C-peptide levels &lt;0.003 nmol/L assumed to be 0 nmol/L. Paired t-test was performed for parametric comparisons, with Wilcoxin signed-rank test for non-parametric comparisons. Results: Ten participants completed the MMTT, with 8 having C-peptide levels and 7 having pump data; 40% were female, with age 47 (SD 14) years and T1D duration 29 (11) years. All but one had baseline C-peptide of &lt; 0.003 pmol/L. Semaglutide reduced glucose AUC compared to placebo (p=0.006), but C-peptide AUC was not different between arms (p=0.35). Despite having lower glucose AUC, the insulin delivery by the AID was lower for semaglutide than placebo (p = 0.024). Conclusion: Semaglutide reduced glucose AUC during fully closed-loop therapy after weight-adjusted meal replacement, with less insulin output required from the AID. Further studies are needed to understand mechanistic of effects. Disclosure M. Pasqua: Speaker's Bureau; Abbott, Sanofi, Medtronic. J. Doumat: None. A. Jafar: None. M. Tsoukas: Speaker's Bureau; Novo Nordisk, Eli Lilly and Company, Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc, Sanofi. A. Haidar: Research Support; Tandem Diabetes Care, Inc. Consultant; Eli Lilly and Company, Abbott. Research Support; ADOCIA, Dexcom, Inc., Ypsomed AG, Bigfoot Biomedical, Inc. Funding Canada Research Chair in Artificial Pancreas Systems.

2043-LB: Universal Access to GLP1-RAs Could Reduce Global Obesity Prevalence by 20% and Save 28 Million Lives over Five Years—A Microsimulation Study

2025-06-20

Elizabeth W. Staton , PIAOPIAO LI , Jieun Lee +4 more | Diabetes

Introduction and Objective: GLP-1RA drugs have demonstrated benefits for people with type 2 diabetes mellitus (T2DM) or obesity, however, medication access is limited. This microsimulation study modeled the impact of … Introduction and Objective: GLP-1RA drugs have demonstrated benefits for people with type 2 diabetes mellitus (T2DM) or obesity, however, medication access is limited. This microsimulation study modeled the impact of increased access to semaglutide globally on the burden of 7 conditions. Methods: We developed and validated a microsimulation model incorporating age-, sex-, and country-specific prevalence and incidence data for T2DM, obesity, CVD, CKD, stroke, ESKD, and all-cause mortality, using data from the 2021 Global Burden of Disease and NCD-RisC studies. A simulation experiment was conducted to evaluate the effects of providing universal access to semaglutide on these key health outcomes over 5 years across 196 countries. Results: Of the worldwide adult population of approximately 6.1 billion, 19.0% met eligibility criteria for semaglutide use, based on a prevalence of 8.76% for type 2 diabetes and 16.4% for obesity. Universal access to semaglutide could reduce 5-year all-cause mortality by 7.41% (absolute change (AC): -0.29%, 95% CI: -0.47 to -0.10%; about 28M lives) and obesity prevalence by 21.9% (AC -5.42%, 95% CI: -6.48 to -4.36%; about 330M fewer obese individuals). Country specific results on all health outcomes are presented in Figure 1. Conclusion: Expanding access and affordability to GLP-1RA can significantly improve health worldwide. Disclosure E. Staton: None. P. Li: None. J. Lee: None. K. Narayan: None. M.K. Ali: Advisory Panel; Eli Lilly and Company. I. Graetz: Research Support; Pfizer Inc, PRIME Education, LLC. H. Shao: None. Funding National Institutes of Health (R01DK133465)

Comment on Komé et al. One Size Does Not Fit All: Understanding Microdosing Semaglutide for Diabetes in Multidose Pens

2025-06-20

Cristina Tejera Pérez | Diabetes Care

Efficacy and incidence of complications of hemodialysis in the treatment of diabetic nephropathy: a systematic review and meta-analysis

2025-06-20

Xiaojing Liu , Jingjing Zhou , Conghui Liu +1 more | Systematic Reviews

Diabetic kidney disease (DKD) progresses inexorably to kidney failure; whether initiating hemodialysis earlier than usual confers additional clinical benefit remains uncertain. The aim of this study is to evaluate the … Diabetic kidney disease (DKD) progresses inexorably to kidney failure; whether initiating hemodialysis earlier than usual confers additional clinical benefit remains uncertain. The aim of this study is to evaluate the effects of hemodialysis, compared with conventional medical care, on glycemic control, renal function, inflammatory markers, and treatment-related complications in adults with DKD. We searched eight databases (Chinese Biomedical Database, Wanfang, CNKI, PubMed, EMBASE, ScienceDirect, Cochrane Library and VIP) and conference proceedings from January 2010 to 30 March 2025. Randomized controlled trials comparing hemodialysis plus standard therapy with standard therapy were eligible for inclusion in adult DKD patients. Two reviewers independently screened records extracted data and assessed risk of bias with the Cochrane Handbook 5.3 tool. Mean differences (MD) and 95% confidence intervals (CI) were pooled with random-effects models. Eight studies (645 participants) met the criteria. Compared with controls, hemodialysis significantly reduced parathyroid hormone (MD = - 37.30, 95% CI - 43.16 to - 31.43; I2 = 0%), tumour necrosis factor-α (MD = - 15.29, 95% CI - 25.05 to - 5.53; I2 = 89%), interleukin-4 (MD = - 20.42, 95% CI - 25.89 to - 14.94; I2 = 42%), and interleukin-8 (MD = - 13.56, 95% CI - 20.85 to - 6.27; I2 = 76%). Glycemic indices improved (fasting glucose MD = - 0.80, 95% CI - 1.59 to - 0.02; HbA₁c MD = - 0.63, 95% CI - 1.34 to 0.08). Serum creatinine (MD = - 1.03, 95% CI - 1.69 to - 0.36) and blood urea nitrogen (MD = - 0.94, 95% CI - 1.49 to - 0.39) also fell, despite high heterogeneity (I2 ≥ 99%). Four studies reported complications; pooled analysis showed no significant difference in overall adverse events (risk ratio = 0.91, 95% CI 0.62 to 1.34). Evidence is based on small, single-center studies with unclear allocation concealment, substantial heterogeneity for several outcomes, and no assessment of long-term clinical endpoints. In adults with DKD, adjunctive hemodialysis improves biochemical surrogates of renal function, inflammation, and glycemic control without increasing short-term complications. Robust multicentre randomised trials powered for patient-important outcomes are warranted.