Search

Aims/hypothesisIncreased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins.MethodsWe measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S(I)) in 182 subjects (76 M/106F).ResultsAdiponectin concentrations were higher in women than in men (7.4+/-2.9 vs 5.4+/-2.3 micro g/ml, p

Insulin transported from plasma into the central nervous system (CNS) is hypothesized to contribute to the negative feedback regulation of body adiposity. Because CNS insulin uptake is likely mediated by [...]

Objective: To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control.Research Design and Methods: We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT.Results: Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change.Conclusions: Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK. [ABSTRACT FROM AUTHOR]

Objective: C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown.Research Design and Methods: In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years.Results: Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by -47.6% relative to glyburide and by -30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and -2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = -0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups.Conclusions: Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to characterize differences in the acute insulin response to glucose (AIR(g)) relative to insulin sensitivity (S(I)) in black and white premenopausal normoglycemic South African women matched for body fatness.Research Design and Methods: Cross-sectional analysis including 57 black and white South African women matched for BMI, S(I), AIR(g), and the disposition index (AIR(g) x S(I)) were performed using a frequently sampled intravenous glucose tolerance test with minimal model analysis, and similar measures were analyzed using an oral glucose tolerance test (OGTT). Body composition was assessed by dual-energy X-ray absorptiometry and computed tomography.Results: S(I) was significantly lower (4.4 +/- 0.8 vs. 9.4 +/- 0.8 and 2.9 +/- 0.8 vs. 6.0 +/- 0. 8 x 10(-5) min(-1)/[pmol/l], P < 0.001) and AIR(g) was significantly higher (1,028 +/- 255 vs. 352 +/- 246 and 1,968 +/- 229 vs. 469 +/- 246 pmol/l, P < 0.001), despite similar body fatness (30.9 +/- 1.4 vs. 29.7 +/- 1.3 and 46.8 +/- 1.2 vs. 44.4 +/- 1.3%) in the normal-weight and obese black women compared with their white counterparts, respectively. Disposition index, a marker of beta-cell function, was not different between ethnic groups (3,811 +/- 538 vs. 2,966 +/- 518 and 3,646 +/- 485 vs. 2,353 +/- 518 x 10(-5) min, P = 0.10). Similar results were obtained for the OGTT-derived measures.Conclusions: Black South African women are more insulin resistant than their white counterparts but compensate by increasing their insulin response to maintain normal glucose levels, suggesting an appropriate beta-cell response for the level of insulin sensitivity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD age 59.6 +/- 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test (FSIGT), followed by a 2-h meal tolerance test (MTT), was performed at 2, 8, and 10 weeks. From the FSIGT, the acute insulin response to glucose (AIR(g)) and insulin sensitivity index (S(I)) were determined and used to compute the disposition index (AIR(g) x S(I)) as a measure of beta-cell function. RESULTS: Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean +/- SEM AIR(g) increased from 224 +/- 44 to 286 +/- 52 pmol/l (P < 0.05), and S(I) improved from 2.8 +/- 0.5 to 3.5 +/- 0.5 x 10(-5) x min(-1) x pmol(-1) x l (P < 0.01), resulting in an increase in the disposition index from 688 +/- 180 to 1,164 +/- 318 x 10(-5)/min (P < 0.05). These effects were not sustained after washout. During the MTT, the incremental area under the glucose curve was significantly decreased after treatment (240 +/- 15 vs. 191 +/- 14 mmol x l(-1) x min(-1); P = 0.002), but this effect was not sustained after washout. CONCLUSIONS: The DPP-4 inhibitor vildagliptin improves insulin sensitivity and beta-cell function, leading to improved postprandial glycemia in subjects with IFG, who are known to have beta-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The relative roles of insulin resistance and beta-cell dysfunction in the pathogenesis of impaired glucose tolerance (IGT) and type 2 diabetes are debated. First-degree relatives of individuals with type 2 diabetes are at increased risk of developing hyperglycemia. RESEARCH DESIGN AND METHODS: We evaluated the evolution of insulin sensitivity, beta-cell function, glucose effectiveness, and glucose tolerance over 7 years in 33 nondiabetic, first-degree relatives of type 2 diabetic individuals using frequently sampled tolbutamide-modified intravenous and oral glucose tolerance tests. RESULTS: Subjects gained weight, and their waist circumference increased (P < 0.05). Insulin sensitivity, the acute insulin response to glucose, and glucose effectiveness did not change significantly. However, when we accounted for the modulating effect of insulin sensitivity on insulin release, beta-cell function determined as the disposition index decreased by 22% (P < 0.05). This decrease was associated with declines in intravenous and oral glucose tolerance (P < 0.05 and P < 0.001, respectively). Of the subjects with normal glucose tolerance at the first assessment, we compared those who progressed to IGT with those who did not. The disposition index was 50% lower in the progressors than in the nonprogressors at follow-up (P < 0.05). CONCLUSIONS: The decline in glucose tolerance over time in first-degree relatives of type 2 diabetic individuals is strongly related to the loss of beta-cell function. Thus, early interventions to slow the decline in beta-cell function should be considered in high-risk individuals. [ABSTRACT FROM AUTHOR]

Background: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known.Methods: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function.Results: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons).Conclusions: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Context-The prognostic value of mild elevation of cardia specific troponin I (cTnI) levels is poorly defined, which can make interpretation of such an elevation diffi- cult. Objective.-To study the prognostic value of transient mild elevation of cTnI levels in the hospitalized patient population. Design.-We performed a case-control study that com- pared the outcome of patients hospitalized for any cause with at least 2 subsequent transient cTnI measurements of 0.1 ng/mL or higher and less than 1.5 nglmL with matched controls with cTnI levels less than 0.1 ng/mL. A cohort of 118 patients (mean ± SD age, 67.4 ± 14.0 years; 35.6% men) was followed up for an average ± SD of 11.9 ± 7.9 months. Seventy-one cases were matched with 37 controls in terms of demographics, coronary artery disease risk factors, and reason for admission. End points were all-cause mortality and major cardiovascular end points, including cardiovascular mortality, myocardial infarction, and revas- cularization. Results.-The total event rate was significantly increased in the case group compared with the control group at 12, 6, and 3 months (62.0% vs 24.3%, 59.2% vs 16.2%, and 47.9% vs 5.4%, respectively; P < .001). At 12, 6, and 3 months, the cases had a significant increase in all-cause mortality (43.7% vs 16.2%, 40.8% vs 8.1%, and 33.8% vs 0.0%, respectively; P = .005) and major cardiovascular end points (26.8% vs 8.1%, 26.8% vs 8.1%, and 21.1% vs 5.4%, respectively; P = .02) compared with controls. Conclusion.-Transient mild elevation of cml levels in hospitalized patients is associated with an increase in all- cause mortality and major cardiovascular complications. Such elevations of cml levels can be considered a marker for both all-cause and cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

Lifestyle modification reduces the risk of developing type 2 diabetes and may have its effect through improving insulin sensitivity, beta-cell function, or both. To determine whether diet and exercise improve insulin sensitivity and/or beta-cell function and to evaluate these effects over time, we quantified insulin sensitivity and the acute insulin response to glucose (AIRg) in 62 Japanese Americans (age 56.5 +/- 1.3 years; mean +/- SE) with impaired glucose tolerance (IGT) who were randomized to the American Heart Association (AHA) Step 2 diet plus endurance exercise (n = 30) versus the AHA Step 1 diet plus stretching (n = 32) for 24 months. beta-Cell function (disposition index [DI]) was calculated as S(i) x AIRg, where S(i) is the insulin sensitivity index. The incremental area under the curve for glucose (incAUCg) was calculated from a 75-g oral glucose tolerance test. Intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas were measured by computed tomography. At 24 months, the Step 2/endurance group had lower weight (63.1 +/- 2.4 vs. 71.3 +/- 2.9 kg; P = 0.004) and IAF (75.0 +/- 7.9 vs. 112.7 +/- 10.4 cm(2); P = 0.03) and SCF (196.5 +/- 18.0 vs. 227.7 +/- 19.9 cm(2); P < 0.001) areas, greater S(i) (4.7 +/- 0.5 vs. 3.3 +/- 0.3 x 10(-5) min . pmol(-1) . l(-1); P = 0.01), and a trend toward lower AIRg (294.9 +/- 50.0 vs. 305.4 +/- 30.0 pmol/l; P = 0.06) and incAUCg (8,217.3 +/- 350.7 vs. 8,902.0 +/- 367.2 mg . dl(-1) . 2 h(-1); P = 0.08) compared with the Step 1/stretching group after adjusting for baseline values. There was no difference in the DI (P = 0.7) between the groups. S(i) was associated with changes in weight (r = -0.426, P = 0.001) and IAF (r = -0.395, P = 0.003) and SCF (r = -0.341, P = 0.01) areas. Thus, the lifestyle modifications decreased weight and central adiposity and improved insulin sensitivity in Japanese Americans with IGT. However, such changes did not improve beta-cell function, suggesting that this degree of lifestyle modifications may be limited in preventing type 2 diabetes over the long term. [ABSTRACT FROM AUTHOR]

Background: Visceral adiposity is generally considered to play a key role in the metabolic syndrome.Objective: To examine the relationship between directly measured visceral adiposity and the risk for incident hypertension, independent of other adipose depots and fasting plasma insulin levels.Design: Community-based prospective cohort study with 10- to 11-year follow-up.Setting: King County, Washington.Participants: 300 Japanese Americans with a systolic blood pressure less than 140 mm Hg and a diastolic blood pressure less than 90 mm Hg who were not taking antihypertensive medications, oral hypoglycemic medications, or insulin at study entry.Measurements: Abdominal, thoracic, and thigh fat areas were measured by using computed tomography. Total subcutaneous fat area was calculated as the sum of these fat areas excluding the intra-abdominal fat area. Hypertension during follow-up was defined as having a systolic blood pressure of 140 mm Hg or greater, having a diastolic blood pressure of 90 mm Hg or greater, or taking antihypertensive medications.Results: There were 92 incident cases of hypertension during the follow-up period. The intra-abdominal fat area was associated with an increased risk for hypertension. Multiple-adjusted odds ratios of hypertension for quartiles of intra-abdominal fat area (1 = lowest; 4 = highest) were 5.07 (95% CI, 1.75 to 14.73) for quartile 3 and 3.48 (CI, 1.01 to 11.99) for quartile 4 compared with quartile 1 after adjustment for age, sex, fasting plasma insulin level, 2-hour plasma glucose level, body mass index, systolic blood pressure, alcohol consumption, smoking status, and energy expenditure through exercise (P = 0.003 for quadratic trend). The intra-abdominal fat area remained a significant risk factor for hypertension, even after adjustment for total subcutaneous fat area, abdominal subcutaneous fat area, or waist circumference; however, no measure of these fat areas was associated with risk for hypertension in models that contained the intra-abdominal fat area.Limitations: It is not known whether these results pertain to other ethnic groups.Conclusions: Greater visceral adiposity increases the risk for hypertension in Japanese Americans. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether 1-h oral glucose challenge test (OGCT) or 3-h oral glucose tolerance test (OGTT) results below gestational diabetes mellitus (GDM) criteria are associated with developing diabetes. RESEARCH DESIGN AND METHODS: A retrospective cohort study was performed among women without GDM who had a pregnancy OGCT (n = 24,780) or OGTT (n = 6,222). Subsequent diabetes was ascertained by ICD-9 codes or pharmacy or laboratory data over a median follow-up of 8.8 years. RESULTS: Diabetes risk increased across OGCT quartiles: adjusted hazard ratio (HR) 1.67 (95% CI 1.07-2.61) for 5.4-6.2 mmol/l, 2.13 (1.39-3.25) for 6.3-7.3 mmol/l, and 3.60 (2.41-5.39) for >or=7.4 mmol/l compared with

The Cockcroft-Gault and the Modification of Diet in Renal Disease (MDRD) Study equations have not been validated in Asian Americans with varying degrees of glucose tolerance. We compared both equations to 24-h urinary creatinine clearance, the latter as a standard measurement of glomerular filtration rate (GFR), in 398 Japanese Americans (62.1+/-5.8 years, mean+/-S.D.) who had normal glucose tolerance (NGT) (n=138), impaired glucose tolerance (IGT) (n=136) and diabetes (n=124). Although both the Cockcroft-Gault (r=0.65, P<0.001) and the MDRD (r=0.74, P<0.001) equations correlated well with creatinine clearance, the latter was significantly superior (P=0.013 between r values). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) for the MDRD equation was significantly greater than for the Cockcroft-Gault equation (AUC 0.86 versus 0.80, P=0.015) in classifying subjects as having mildly reduced GFR (<90ml/min per 1.73m(2)). However, both equations overestimated the number of individuals with decreased GFR. We conclude therefore that while the MDRD equation more accurately identifies Asians who are in the early stages of kidney disease, as for other groups, a correction term appears necessary in order to reduce the number of Asian subjects being falsely diagnosed with CKD. [ABSTRACT FROM AUTHOR]

Hyperlipidemia is commonly observed in patients with type 2 diabetes and is also characteristic of the metabolic syndrome. We discuss the lipoprotein abnormalities in type 2 diabetes and the relation of triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol to insulin resistance and diabetes. We also present a case study of a diabetic woman with hyperlipidemia and coronary artery disease. [ABSTRACT FROM AUTHOR]

Competing Interests: Funding Support and Author Disclosures This study was funded by Novo Nordisk A/S. Dr Verma has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, and Sanofi. Dr Colhoun holds the AXA Research Fund endowed Chair in Medical Informatics and Epidemiology at the University of Edinburgh. Dr Dicker has received consulting honoraria from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, and AstraZeneca; and has received research grants through his affiliation from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, and Rhythm. Dr Hovingh is an employee of and stakeholder in Novo Nordisk. Dr Kahn has received advisory board/consulting fees from AltPep, Bayer, Boehringer Ingelheim, Casma Therapeutics, Eli Lilly, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer, and Third Rock Ventures. Dr Kautzky-Willer has received speaker honoraria from Boehringer Ingelheim, Novartis, Novo Nordisk, and Merck. Dr Lingvay has received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals Inc, Novo Nordisk, Pfizer, and Sanofi U.S. Services Inc; has served as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals Inc, Biomea, Boehringer Ingelheim, Carmot, Eli Lilly and Company, Intarcia, Intercept Pharmaceuticals, Inc, Janssen Global Services, LLC, Johnson & Johnson Medical Devices & Diagnostics Group–Latin America, LLC, MannKind Corporation, Merck, Novo Nordisk, Pfizer Inc, Sanofi U.S. Services Inc, Shionogi Inc, Structure Therapeutics, Target Pharma, Valeritas, Inc, and Zealand Pharma; and has received travel expenses from Boehringer Ingelheim, Eli Lilly and Company, Johnson & Johnson Medical Devices & Diagnostics Group–Latin America, LLC, Novo Nordisk, Sanofi U.S. Services Inc, and Zealand Pharma A/S. Dr Plutzky has received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Inc, Merck, MJH Life Sciences, Novartis, and Novo Nordisk; has received a grant, paid to his institution, from Boehringer Ingelheim; and holds the position of Director, Preventive Cardiology, at Brigham and Women's Hospital. Drs Rasmussen, Rathor, and Hoff are employees of, and shareholder in, Novo Nordisk. Dr Lincoff has received research grants from AbbVie Inc, AstraZeneca, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Inc, and Novartis, paid to his institution; and has served as a consultant for Akebia Therapeutics Inc, Alnylam Pharmaceuticals Inc, Ardelyx, Eli Lilly and Company, FibroGen, GlaxoSmithKline, Intarcia, Medtronic Vascular, Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk, Provention Bio, Entity, and ReCor Medical.

Background: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established., Methods: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete., Findings: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%])., Interpretation: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available., Funding: Novo Nordisk., Competing Interests: Declaration of interests MNK has served as a consultant for 35Pharma, Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Corcept Therapeutics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Regeneron, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has served on a data monitoring board for Applied Therapeutics; has served on an advisory board for Alnylam, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Eli Lilly, Esperion Therapeutics, Merck (Diabetes and Cardiovascular), Novo Nordisk, and Sanofi; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and has received support for data analyses from AstraZeneca and Vifor. JD has received consulting honoraria from Aegerion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Takeda and research grants from Aegerion, British Heart Foundation, Colgate, UK Medical Research Council, MSD, National Institute for Health and Care Research, Pfizer, Public Health England, and Roche. RP reports speaker fees from Eli Lilly, Lilly USA, and Novo Nordisk; consulting fees from AbbVie, AstraZeneca, Bayer, Bayer HealthCare Pharmaceuticals, Corcept Therapeutics, Dexcom, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Hanmi Pharmaceutical, Hengrui (USA), Intas Pharmaceuticals, Eli Lilly, Lilly USA, Merck, Novo Nordisk, Pfizer, Rivus Pharmaceuticals, Scholar Rock, and Sun Pharmaceutical Industries; and grants from Biomea Fusion, Carmot Therapeutics, Dompe, Endogenex, Fractyl, Eli Lilly, Novo Nordisk, and Sanofi. All grants are directed to RP's institution. Up to Dec 31, 2023, payment for RP's consultant and speaker services was made directly to his employer, AdventHealth, a nonprofit entity; as of Jan 1, 2024, payment was directed to RP personally. BAB receives research support from the US National Institutes of Health and the US Department of Defense, as well as research grant funding from AstraZeneca, Axon Therapies, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics; he has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, NGM, Novo Nordisk, NXT, and VADovations; and is named inventor (US patent number 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. JB is a consultant to Abbott, American Regent, Amgen, Applied Therapeutics, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, CardioCell, Cardior, CSL Behring, CVRx, Cytokinetics, Daxor, Edwards Lifesciences, Element Science, Faraday, Foundry, G3P, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Levator, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, PharmaIN, Prolaio, Pulnovo, Regeneron, Renibus, Roche, Salamandra, Salubris, Sanofi, scPharmaceuticals, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. MJD has acted as a consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi; an advisory board member for AstraZeneca, Carmot/Roche, Medtronic, Pfizer, and Zealand Pharma; and a speaker for Amgen and AstraZeneca; and has received grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi-Aventis. SSE has received consulting fees from Amylyx, AstraZeneca, Avillion, Ayala, Bayer, BeiGene, Boehringer Ingelheim, 89 Bio, BioAge, BioAtla, Bristol Meyer Squibb, BridgeBio, Daiichi Sankyo, Denovo, Fore Therapeutics, GlaxoSmithKline, Inovio, Insmed, Ipsen, Karuna, Lilly, Lundbeck, Mirati, Moderna, Novartis, Novavax, Novo Nordisk, National Surgical Adjuvant Breast and Bowel Project, Pfizer, Principia, Reata, Rebiotx, Roche, Sanofi, solvd, Sutro Biopharma, and TG Therapeutics. SEK received consulting fees from Casma Therapeutics, Oramed, and Third Rock Ventures; and served on an advisory board for AltPep, Anji Pharmaceuticals, Bayer, Boehringer Ingelheim, Eli Lilly, Intarcia, Merck, and Novo Nordisk. He has received stock options from AltPep. DK was supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and US National Institutes of Health grants U01AG076928, R01AG078153, R01AG045551, R01AG18915, P30AG021332, U24AG059624, and U01HL160272; and received honoraria as a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Corvia Medical, Ketyo, Novartis, Novo Nordisk, Pfizer, and Rivus; grant funding from AstraZeneca, Bayer, Novartis, Novo Nordisk, Pfizer, and Rivus; and has stock ownership in Gilead Sciences. IL has received research grants from Boehringer Ingelheim, Merck, Mylan Pharmaceuticals, Novo Nordisk, Pfizer, and Sanofi; served as a consultant for AstraZeneca, Bayer Healthcare Pharmaceuticals, Biomea, Boehringer Ingelheim, Carmot, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, Johnson & Johnson Medical Devices & Diagnostics Group—Latin America, MannKind, Merck, Novo Nordisk, Pfizer, Sanofi, Shionogi, Structure Therapeutics, Target Pharma, Valeritas, and Zealand Pharma; and received travel expenses from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson Medical Devices & Diagnostics Group—Latin America, Novo Nordisk, Sanofi, and Zealand Pharma. KWM has received grants from AHA, Apple, Bayer, California Institute for Regenerative Medicine, CSL Behring, Eidos, Ferring, Gilead, Google, Idorsia, Johnson & Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; and consulting fees from Applied Therapeutics, Bayer, BMS, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson & Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, and Theravance; and holds stock options for Human, Medeloop, Precordior, and Regencor. MCP was supported by the British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; has received research funding from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, and SQ Innovations; and served on committees or consulted for AbbVie, Akero, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corvia, Eli Lilly, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Siemens, SQ Innovations, Takeda, Teikoku, and Vifor. JP has received consulting fees from Altimmune, Amgen, Esperion Therapeutics, Merck, MJH Life Sciences, Novartis, and Novo Nordisk and received a grant, paid to his institution, from Boehringer Ingelheim. CR, SR, and PEW are employees and SR and PEW are shareholders of Novo Nordisk. SJS has received research grants from AstraZeneca, Corvia, and Pfizer; and consulting fees from Abbott, Alleviant, Amgen, Aria CV, AstraZeneca, Axon Therapies, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Imara, Impulse Dynamics, Intellia, Ionis, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, ReCor, Regeneron, Rivus, Sardocor, Shifamed, Tenax, Tenaya, and Ultromics. SV reports speaking honoraria or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. AML has received research grants from AbbVie, AstraZeneca, CSL Behring, Eli Lilly, Esperion Therapeutics, and Novartis, paid to his institution; and consulting fees from Akebia Therapeutics, Alnylam Pharmaceuticals, Ardelyx, Eli Lilly, FibroGen, GlaxoSmithKline, Intarcia, Medtronic Vascular, Novartis, Novo Nordisk, Provention Bio, Amgen, and ReCor Medical. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aims/hypothesis: Apart from its fibrinolytic activity, the tissue plasminogen activator (tPA)/plasmin system has been reported to cleave the peptide amyloid beta, attenuating brain amyloid deposition in Alzheimer's disease. As aggregation of human islet amyloid polypeptide (hIAPP) is toxic to beta cells, we sought to determine whether activation of the fibrinolytic system can also reduce islet amyloid deposition and its cytotoxic effects, which are both observed in type 2 diabetes., Methods: The expression of Plat (encoding tPA) and plasmin activity were measured in isolated islets from amyloid-prone hIAPP transgenic mice or non-transgenic control islets expressing non-amyloidogenic mouse islet amyloid polypeptide cultured in the absence or presence of the amyloid inhibitor Congo Red. Plat expression was also determined in hIAPP-treated primary islet endothelial cells, bone marrow-derived macrophages (BMDM) and INS-1 cells, in order to determine the islet cell type(s) producing tPA in response to hIAPP aggregation. Cell-free thioflavin-T assays and MS were used to respectively monitor hIAPP aggregation kinetics and investigate plasmin cleavage of hIAPP. Cell viability was assessed in INS-1 beta cells treated with hIAPP with or without plasmin. Finally, to confirm the findings in human samples, PLAT expression was measured in freshly isolated islets from donors with and without type 2 diabetes., Results: In isolated islets from transgenic mice, islet Plat expression and plasmin activity increased significantly with the process of amyloid deposition (p≤0.01, n=5); these effects were not observed in islets from non-transgenic mice and were blocked by Congo Red (p≤0.01, n=4). In response to hIAPP exposure, Plat expression increased in BMDM and INS-1 cells vs vehicle-treated cells (p≤0.05, n=4), but not in islet endothelial cells. Plasmin reduced hIAPP fibril formation in a dose-dependent manner in a cell-free system, and restored hIAPP-induced loss of cell viability in INS-1 beta cells (p≤0.01, n=5). Plasmin cleaved monomeric hIAPP, inducing a rapid decrease in the abundance of full-length hIAPP and the appearance of hIAPP 1-11 and 12-37 fragments. hIAPP 12-37, which contains the critical amyloidogenic region, was not toxic to INS-1 cells. Finally, PLAT expression was significantly increased by 2.4-fold in islets from donors with type 2 diabetes (n=4) vs islets from donors without type 2 diabetes (n=7) (p≤0.05)., Conclusions/interpretation: The fibrinolytic system is upregulated in islets with hIAPP aggregation. Plasmin rapidly degrades hIAPP, limiting its aggregation into amyloid and thus protecting beta cells from hIAPP-induced toxicity. Thus, increasing islet plasmin activity might be a strategy to limit beta cell loss in type 2 diabetes., (© 2024. The Author(s).)

Background: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure., Methods: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m 2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597., Findings: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m 2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all p interaction >0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype., Interpretation: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group., Funding: Novo Nordisk., Competing Interests: Declaration of interests JD declares having received consulting honoraria from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer, and research grants from British Heart Foundation, Medical Research Council (UK), National Institute for Health and Care Research, Public Health England, MSD, Pfizer, Aegerion, Colgate, and Roche. BMS declares having received institutional research grants to Brigham and Women's Hospital from Better Therapeutics, Merck, Novo Nordisk, and Pfizer, and consulting fees from Allergan, Boehringer Ingelheim, Better Therapeutics, Elsevier PracticeUpdate Cardiology, Esperion, Hanmi, Lexicon, Novo Nordisk, and equity in health at Scale and Doximity. SV reports speaking honoraria or consulting fees from Abbott, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, and TIMI. DR declares having received consulting honoraria from Altimmune, Amgen, Biohaven, Boehringer Ingelheim, Calibrate, Carmot Therapeutics, CinRx, Eli Lilly, Epitomee, Gila Therapeutics, Ifa Celtic, Novo Nordisk, Pfizer, Rhythm, Scientific Intake, Wondr Health, and Zealand. DR also declares having received stock options from Calibrate, Epitomee, Scientific Intake, and Xeno Bioscience. IL declares having received research funding (paid to institution) from Novo Nordisk, Sanofi, Mylan, and Boehringer Ingelheim. IL received advisory or consulting fees or other support from Altimmune, AstraZeneca, Bayer, Biomea, Boehringer Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/Johnson & Johnson, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Regeneron, Sanofi, Shionogi, Structure Therapeutics, Target RWE, Terns Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma. HMC declares being a stockholder and serving on an advisory panel for Bayer; receiving research grants from Chief Scientist Office, Diabetes UK, European Commission, IQVIA, Juvenile Diabetes Research Foundation, and Medical Research Council; serving on an advisory board and speakers bureau for Novo Nordisk; and holding stock in Roche Pharmaceuticals. SEK declares having received consulting honoraria from Anii Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Oramed and stock options from Altpep. JP declares having received consulting honoraria from Altimmune, Amgen, Esperion Therapeutics, Merck, MJH Life Sciences, Novartis, and Novo Nordisk; he has received a grant, paid to his institution, from Boehringer Ingelheim, and holds the position of Director, Preventive Cardiology, at Brigham and Women's Hospital. MNK declares having served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; holds stocks in Artera Health and Saghmos Therapeutics; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. MNK has also received other research support from AstraZeneca. SSE declares having received consulting honoraria from Amylyx, AstraZeneca, Avillion, Ayala, Bayer, BeiGene, Boehringer Ingelheim, 89 Bio, BioAge, BioAtla, Bristol Myers Squibb, BridgeBio, Daiichi Sankyo, Denovo, Fore Therapeutics, GlaxoSmithKline, Inovio, Insmed, Ipsen, Karuna, Lilly, Lundbeck, Mirati, Moderna, Novartis, Novavax, Novo Nordisk, National Surgical Adjuvant Breast and Bowel Project, Pfizer, Principia, Reata, Rebiotx, Roche, Sanofi, Solvd, Sutro Biopharma, and TG Therapeutics. AG declares having received honoraria from Novo Nordisk, AstraZeneca, Novartis, Boehringer Ingelheim, and Bayer. CCL declares having received consulting and research honoraria from Amarin, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Moderna, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics. MU-T declares having received consulting and research honoraria from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Frosst Laboratories, Johnson and Johnson, Menarini, Novartis, Novo Nordisk, Pfizer, Procaps, Sanofi-Aventis, Servier, and Tecnofarma. MP declares having received honoraria from Novo Nordisk. AML declares having received honoraria from Novo Nordisk, Eli Lilly, Akebia, Amgen, Ardelyx, Becton Dickson, Endologix, Fibrogen, GlaxoSmithkline, Medtronic, Neovasc, Provention Bio, ReCor, Brainstorm Cell, Alnylam, and Intarcia for consulting activities and research funding to his institution from AbbVie, Esperion, AstraZeneca, CSL Behring, Novartis, and Eli Lilly. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms. Associations were tested with general linear models and Cox regression with adjustment for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at 1-year follow-up with adjustment for baseline measures (effect per pPS SD -0.04, P = 9.6 × 10-7, and -8.45 μU/mg, P = 5.6 × 10-6, respectively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver/lipid pPS was associated with reduced 1-year baseline-adjusted triglyceride levels (effect per SD -4.37, P = 0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function., (© 2024 by the American Diabetes Association.)

Objective: To evaluate the cardiovascular effects of semaglutide by baseline glycated hemoglobin (HbA1c) and change in HbA1c in a prespecified analysis of Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT)., Research Design and Methods: In SELECT, people with overweight or obesity and atherosclerotic cardiovascular disease without diabetes were randomized to weekly semaglutide 2.4 mg or placebo. The primary end point of first major adverse cardiovascular event (MACE) (cardiovascular mortality, nonfatal myocardial infarction, or stroke) was reduced by 20% with semaglutide versus placebo. Analysis of outcomes included first MACE, its individual components, expanded MACE (cardiovascular mortality, nonfatal myocardial infarction, or stroke; coronary revascularization; or hospitalization for unstable angina), a heart failure composite (heart failure hospitalization or urgent medical visit or cardiovascular mortality), coronary revascularization, and all-cause mortality by baseline HbA1c subgroup and categories of HbA1c change (<-0.3, -0.3 to 0.3, and >0.3 percentage points) from baseline to 20 weeks using the intention-to-treat principle with Cox proportional hazards., Results: Among 17,604 participants (mean age 61.6 years, 72.3% male), baseline HbA1c was <5.7% for 33.5%, 5.7% to <6.0% for 34.6%, and 6.0% to <6.5% for 31.9%. Cardiovascular risk reduction with semaglutide versus placebo was not shown to be different across baseline HbA1c groups and was consistent with that of the overall study for all end points, except all-cause mortality. Cardiovascular outcomes were also consistent across subgroups of HbA1c change., Conclusions: In people with overweight or obesity and established atherosclerotic cardiovascular disease but not diabetes, semaglutide reduced cardiovascular events irrespective of baseline HbA1c or change in HbA1c. Thus, semaglutide is expected to confer cardiovascular benefits in people with established atherosclerotic cardiovascular disease who are normoglycemic at baseline and/or in those without HbA1c improvements., (© 2024 by the American Diabetes Association.)

Objective: To determine whether semaglutide slows progression of glycemia in people with cardiovascular disease and overweight or obesity but without diabetes., Research Design and Methods: In a multicenter, double-blind trial, participants aged ≥45 years, with BMI ≥27 kg/m2, and with preexisting cardiovascular disease but without diabetes (HbA1c <6.5%) were randomized to receive subcutaneous semaglutide (2.4 mg weekly) or placebo. Major glycemic outcomes were HbA1c and proportions achieving biochemical normoglycemia (HbA1c <5.7%) and progressing to biochemical diabetes (HbA1c ≥6.5%)., Results: Of 17,604 participants, 8,803 were assigned to semaglutide and 8,801 to placebo. Mean ± SD intervention exposure was 152 ± 56 weeks and follow-up 176 ± 40 weeks. In both treatment arms mean nadir HbA1c for participants was at 20 weeks. Thereafter, HbA1c increased similarly in both arms, with a mean difference of -0.32 percentage points (95% CI -0.33 to -0.30; -3.49 mmol/mol [-3.66 to -3.32]) and with the difference favoring semaglutide throughout the study (P < 0.0001). Body weight plateaued at 65 weeks and was 8.9% lower with semaglutide. At week 156, a greater proportion treated with semaglutide were normoglycemic (69.5% vs. 35.8%; P < 0.0001) and a smaller proportion had biochemical diabetes by week 156 (1.5% vs. 6.9%; P < 0.0001). The number needed to treat was 18.5 to prevent a case of diabetes. Both regression and progression were dependent on glycemia at baseline, with the magnitude of weight reduction important in mediating 24.5% of progression and 27.1% of regression., Conclusions: In people with preexisting cardiovascular disease and overweight or obesity but without diabetes, long-term semaglutide increases regression to biochemical normoglycemia and reduces progression to biochemical diabetes but does not slow glycemic progression over time., (© 2024 by the American Diabetes Association.)