Neda Rasouli

Aims/Hypothesis: Atypical forms of diabetes often provide diagnostic challenges and are suboptimally treated. We sought to determine whether type 1 and 2 diabetes polygenic scores (PS) would help improve classification of islet autoantibody-negative (IAb-) atypical diabetes cases. Methods: We implemented type 1 diabetes PS (T1D PS) and type 2 diabetes PS (T2D PS) in 309 IAb-individuals’ genome sequencing from the Rare and Atypical Diabetes Network (RADIANT), the largest and most comprehensively phenotyped collection of unsolved and atypical diabetes cases. We performed regression analyses to assess associations between PS, clinical characteristics, and glycemic measures. Results: Both T1D and T2D PS were significantly higher in RADIANT than in ancestry-matched controls from UK Biobank. Both PS were associated with C-peptide measures throughout participant oral glucose tolerance tests (OGTT), although in opposite directions; T1D PS was associated with lower C-peptide measures, while T2D PS was associated with higher measures. Participants with T1D PS above a previously established optimal PS value for differentiating cases and controls (T1D PS GRS2>12.88) had 13-fold higher odds of both insulin deficiency on OGTT and use of both basal and bolus insulin therapy. Conclusions/Interpretation: Individuals in RADIANT with ambiguous diabetes subtypes displayed genetic enrichment for both type 1 and type 2 diabetes, despite ascertainment to remove standard type 1 and type 2 diabetes. T1D PS identified individuals with an unrecognized “type 1 diabetes- like ” phenotype with insulin deficiency and need for intensive insulin in the absence of islet autoantibodies. PS may help identify individuals with atypical diabetes who will ultimately benefit from insulin therapy.

Context: In the SOUL trial (NCT03914326), oral semaglutide reduced risk of major adverse cardiovascular (CV) events (MACE) by 14%. Whether baseline or changes in HbA1c or BMI are associated with these CV benefits is not known. Objective: We evaluated whether CV benefits of oral semaglutide are associated with baseline or in-trial reductions in HbA1c or BMI. Design: Post hoc analysis of SOUL, a double-blind, placebo-controlled trial (2019-2024). Setting: International, 444 sites. Participants: Adults aged ≥50 years, with type 2 diabetes and atherosclerotic CV disease and/or chronic kidney disease. Intervention(s): Oral semaglutide or placebo. Main outcome measures: Three-point MACE (CV death, nonfatal myocardial infarction, or nonfatal stroke) analyzed by baseline and in-trial changes in HbA1c and BMI (weeks 13; 52). Results: A total of 9650 adults randomized 1:1 to oral semaglutide or placebo were followed for 47.5 months. Median (IQR) age was 66 (61-72) years, mean (±SD) HbA1c 8.0 (1.1)% (63.5 ± 12.5 mmol/mol) and BMI 31.1 (5.8) kg/m2. MACE benefits from oral semaglutide were significantly different across baseline HbA1c categories (P-interaction = .04), suggesting greater risk reduction at higher baseline HbA1c, but were consistent across baseline BMI categories. Greater in-trial HbA1c reductions were associated with larger decreases in MACE risk with oral semaglutide at 13 and 52 weeks (P-interactions = .005 and < .001, respectively), whereas BMI changes showed consistency (P-interactions = .88 and .64, respectively). Conclusions: In SOUL, CV benefits of oral semaglutide appeared more pronounced among participants with higher baseline HbA1c and greater HbA1c reductions, but were consistent across baseline or changes in BMI.

Walking limitation and claudication are defining features of peripheral artery disease (PAD), and common in persons with type 2 diabetes (T2D). Despite this burden, effective therapies for PAD remain scarce. In T2D, assessment of PAD severity is challenging as the multifactorial nature of limb symptoms and the frequent presence of atypical presentations obscure associations with functional outcomes.¹

OBJECTIVE: To determine the longitudinal effects on α-cell function of four classes of glucose-lowering agents added to metformin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000–2,000 mg metformin daily, HbA1c 6.8%–8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin. In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]). Whether these measures and those of β-cell function (fasting C-peptide and C-peptide index [CPI]) were related to the primary metabolic outcome (HbA1c ≥7.0%) was examined. RESULTS: Baseline fasting glucagon and GGI were not associated with the primary metabolic outcome (2 df; P = 0.55), whereas the β-cell measures were (2 df; P = 0.04). Treatment-associated changes in fasting glucagon, GGI, and fasting C-peptide were not associated with the primary metabolic outcome, while changes in CPI were, in models unadjusted (P < 0.05) or adjusted (P < 0.001) for α-cell function. A 1-SD increase in CPI was associated with a 17% reduction in the risk of the primary metabolic outcome. There were no clear differential effects of the medications on glucagon responses. CONCLUSIONS: There were different patterns of effects of the four glucose-lowering medications on the α-cell, with no relationship of α-cell function with worsening glycemia. Thus, in treating type 2 diabetes, for choice of medication(s) the focus should primarily be on their impact on β-cell function.

OBJECTIVE: The Semaglutide and Walking Capacity in People with Symptomatic Peripheral Artery Disease and Type 2 Diabetes (STRIDE) trial (NCT04560998) showed that once-weekly subcutaneous semaglutide 1.0 mg significantly improved functional outcomes, symptoms, and quality of life in individuals with symptomatic peripheral artery disease (PAD) and type 2 diabetes. Whether these benefits are consistent across diabetes-related characteristics remains unclear. RESEARCH DESIGN AND METHODS: The primary outcome was the ratio to baseline (ETR) in maximum walking distance (MWD), with pain-free walking distance (PFWD) as a key secondary end point. Both were measured at 52 weeks using a constant load treadmill. Subgroup analyses were performed by diabetes duration, BMI, HbA1c, and diabetes medications. A mixed model for repeated measurements was used, incorporating treatment, region, and subgroup as fixed factors, and baseline value as covariate, along with the treatment-by-subgroup interaction. RESULTS: Among 792 participants (median diabetes duration 12.2 years, HbA1c 7.1%, and BMI 28.7 kg/m2), 35.1% used sodium–glucose cotransporter 2 inhibitors and 31.7% used insulin. Semaglutide significantly improved MWD regardless of diabetes duration (ETR of 1.15 vs. 1.13 for <10 vs. ≥10 years, P = 0.80), BMI (1.12 vs. 1.16 for <30 vs. ≥30 kg/m2, P = 0.58), HbA1c (1.13 for 0.1 for all interactions). BMI reduction correlated weakly with MWD improvements and was more pronounced in the control individuals with higher baseline BMI. Safety outcomes were consistent across subgroups. CONCLUSIONS: Semaglutide improved walking function in people with PAD and type 2 diabetes, including individuals without obesity and those with well-controlled HbA1c. Benefits were consistent across BMI and HbA1c categories, supporting effectiveness beyond weight or glycemic changes.

OBJECTIVE: To evaluate how model-based parameters of β-cell function change with glucose-lowering treatment and associate with glycemic deterioration in adults with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), β-cell function parameters derived from mathematical modeling of oral glucose tolerance tests were assessed at baseline (N = 4,712) and 1, 3, and 5 years following randomization to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin. Parameters included insulin secretion rate (ISR), glucose sensitivity (insulin response to glucose), rate sensitivity (early insulin response), and potentiation. Linear mixed-effects models were used to compare changes across treatments. With Cox proportional hazards and Classification And Regression Tree (CART) analyses we evaluated associations between model parameters and glycemic failure (A1C >7.5%; 58.5 mmol/mol). RESULTS: β-Cell function parameters increased variably at year 1 across treatments but subsequently declined for all treatments. Statistically significant changes were noted. Liraglutide led to the greatest increases in ISR, glucose sensitivity and potentiation, remaining above baseline at study end. Sitagliptin improved glucose sensitivity, with modest effects on other parameters. Glimepiride temporarily increased ISR and rate sensitivity but minimally increased glucose sensitivity or potentiation. Rate sensitivity increased most with glargine. Higher β-cell function parameters were protective against glycemic deterioration, but treatment did not alter the relationship between these parameters and glycemic outcomes. CONCLUSIONS: Common glucose-lowering medications impact different physiologic components of β-cell function in T2D. Regardless of treatment modality, lower β-cell function associated with early glycemic failure, and β-cell function progressively declined after initial improvement.

Historically, an elevated level of 2-hour plasma glucose (2hPG) during a 75-gram oral glucose tolerance test (OGTT) was the hallmark of pre-diabetes. This measurement served as a primary criterion in pivotal diabetes prevention clinical trials, including the Diabetes Prevention Program.1 However, with the American Diabetes Association (ADA) expanding its diagnostic criteria for pre-diabetes in 2010 to include hemoglobin A1c (HbA1c),2 clinical practice has shifted from measuring 2hPG to relying primarily on fasting plasma glucose (FPG) and HbA1c.3 This transition raises questions about the current role of 2hPG in assessing pre-diabetes risk in contemporary clinical settings.

Introduction Newer incretin-based therapies for type 2 diabetes (T2D) have the potential to substantially reduce glycated hemoglobin (HbA1c) and weight with a low associated risk of hypoglycemia. This study aimed to assess the percentage of participants randomized to tirzepatide or comparator who achieved the composite endpoint of HbA1c ≤ 6.5% and weight reduction ≥ 10% without hypoglycemia across prespecified baseline characteristics: T2D duration (≤ 5, > 5–10, or > 10 years), sex, HbA1c (≤ 8.5% or > 8.5%), age (< 65 or ≥ 65 years), and body mass index (< 30, 30 to < 35, or ≥ 35 kg/m²). Methods This post hoc analysis of SURPASS-1 through -5 evaluated adult study participants with T2D treated with tirzepatide 5, 10, or 15 mg versus placebo or active comparator. Missing HbA1c and weight values were imputed from mixed models for repeated measures. Logistic regression was used to compare tirzepatide versus comparators for the percentage of participants reaching the composite endpoint. Results Across subgroups, the composite endpoint was achieved by a median of approximately 30%, 45%, and 54% of participants who received tirzepatide 5, 10, and 15 mg, respectively; this was consistent across baseline subgroups, except that a greater percentage of women than men achieved the composite endpoint. The most common treatment-emergent adverse events were gastrointestinal in nature. Conclusions In this post hoc analysis, tirzepatide achieved the composite outcome of glycemic control and weight loss with no hypoglycemia, irrespective of baseline characteristics. This may help clinicians as they select suitable treatment in diverse populations. Trial Registration ClinicalTrials.gov: NCT03954834, NCT03987919, NCT03882970. NCT03730662, and NCT04039503.

People with lower extremity peripheral artery disease (PAD) suffer from a high burden of symptoms and significant functional impairment. There are few therapies that improve function and reduce symptoms in this population. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control, reduce body weight and reduce the risk of major adverse cardiovascular events, in people with atherosclerotic cardiovascular disease and type 2 diabetes (T2D). STRIDE (NCT04560998) is a randomized, placebo-controlled, double-blind phase 3b trial evaluating 1 mg once-weekly subcutaneous semaglutide (GLP-1 RA) vs. placebo, in people with symptomatic PAD (Fontaine IIa claudication) and T2D. Eligible participants were ≥ 18 years, had hemodynamically stable PAD, had no planned intervention, and were not receiving a GLP-1 RA. The primary endpoint is change in maximum walking distance on a constant-load treadmill (CLT). Secondary endpoints include quality of life and cardiometabolic assessments. A total of 792 participants were randomized in 20 countries. Participants’ median age was 68 and they had T2D for a median of 12 years. Risk factors included 25.6% current smokers, 87.9% with hypertension, and 42.7% with coronary heart disease. The mean BMI was 29.6 kg/m² and mean HbA_1C was 7.3%. Participants exhibited baseline functional impairment with a median maximum walking distance of 186 meters on a CLT. STRIDE has enrolled participants with symptomatic PAD and T2D, frequent risk factors and comorbidities, and functional impairment. The trial will provide evidence for the functional outcomes with semaglutide in people with PAD and T2D.

Introduction: Understanding how race may influence the association between A1c and glycemia can improve diabetes screening. We sought to determine whether, for a given A1c level, glucose levels during an oral glucose tolerance test (OGTT) differed by race. Research design and methods: From data collected at 22 US clinical sites, we conducted a cross-sectional study of concurrently measured A1c and OGTT and observational longitudinal follow-up of the subset with high-risk pre-diabetes. Numerical integration methods were used to calculate area under the glycemic curve (AUC_glu) during OGTT and least squares regression model to estimate A1c for a given AUC_glu by race, controlling for potential confounders. Results: 1016 black, 2658 white, and 193 Asian persons at risk of diabetes were included in cross-sectional analysis. Of these, 2154 with high-risk pre-diabetes were followed for 2.5 years. For a given A1c level, AUC_glu was lower in black versus white participants. After adjustment for potential confounders, A1c levels for a given AUC_glu quintile were 0.15–0.20 and 0.02–0.19 percentage points higher in black and Asian compared with white participants, respectively (p<0.05). In longitudinal analyses, black participants were more likely to be diagnosed with diabetes by A1c than white participants (28% vs 10%, respectively; p<0.01). Black and Asian participants were less likely to be diagnosed by fasting glucose than white participants (16% vs 15% vs 37%, respectively; p<0.05). Black participants with A1c levels in the lower-level quintiles had greater increase in A1c over time compared with white participants. Conclusions: Use of additional testing beyond A1c to screen for diabetes may better stratify diabetes risk in the diverse US population.