A look at duodenal mucosal resurfacing: Rationale for targeting the duodenum in type 2 diabetes.

Affecting 5%-10% of the world population, type 2 diabetes (T2DM) is firmly established as one of the major health burdens of modern society. People with T2DM require long-term therapies to reduce blood glucose, an approach that can mitigate the vascular complications. However, fewer than half of those living with T2DM reach their glycaemic targets despite the availability of multiple oral and injectable medications. Adherence and access to medications are major barriers contributing to suboptimal diabetes treatment. The gastrointestinal tract has recently emerged as a target for treating T2DM and altering the underlying disease course. Preclinical and clinical analyses have elucidated changes in the mucosal layer of the duodenum potentially caused by dietary excess and obesity, which seem to be prevalent among individuals with metabolic disease. Supporting these findings, gastric bypass, a surgical procedure which removes the duodenum from the intestinal nutrient flow, has remarkable effects that improve, and often cause remission of, diabetes. From this perspective, we explore the rationale for targeting the duodenum with duodenal mucosal resurfacing (DMR). We examine the underlying physiology of the duodenum and its emerging role in T2DM pathogenesis, the rationale for targeting the duodenum by DMR as a potential treatment for T2DM, and current data surrounding DMR. Importantly, DMR has been demonstrated to change mucosal abnormalities common in those with obesity and diabetes. Given the multifactorial aetiology of T2DM, understanding proximate contributors to disease pathogenesis opens the door to rethinking therapeutic approaches to T2DM, from symptom management toward disease modification.

Greater persistence and adherence to basal insulin therapy is associated with lower healthcare utilization and medical costs in patients with type 2 diabetes: a retrospective database analysis.

INTRODUCTION: We aimed to assess persistence and adherence to basal insulin therapy, their association with all-cause healthcare resource utilization (HCRU) and direct medical costs, and predictors of persistence and adherence in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: A retrospective cohort study was conducted with US adults with type 2 diabetes initiating basal insulin therapy between January 1, 2016, and December 31, 2018, using IQVIA PharMetrics Plus claims data. Persistence and adherence were assessed during 1 year post-initiation per previous definitions. Demographic/clinical characteristics were assessed during the 1 year pre-initiation. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding variables. Post-IPTW, all-cause HCRU and direct medical costs were assessed during the first-year and second-year post-initiation by persistence and adherence status. Multivariable logistic regression was used to identify predictors of persistence and adherence. RESULTS: The final sample comprised 64,953 patients; 56.8% demonstrated persistence and 41.9% demonstrated adherence. Patients demonstrating persistence and adherence were significantly less likely to have a hospitalization than patients demonstrating non-persistence or non-adherence, respectively. In the second-year post-initiation, total mean all-cause direct medical costs per patient were lower for patients demonstrating persistence and significantly lower for patients demonstrating adherence. Prior use of both oral and injectable antidiabetic medication predicted persistence and adherence compared with patients with only prior oral antidiabetic medication use (persistence OR, 1.50 (95% CI, 1.44 to 1.57); adherence OR, 1.48 (95% CI, 1.42 to 1.55)). CONCLUSIONS: Persistence and adherence to basal insulin was associated with fewer hospitalizations and lower direct medical costs.

Risk of Anaphylaxis Among New Users of GLP-1 Receptor Agonists: A Cohort Study.

OBJECTIVE: To assess risk of anaphylaxis among patients with type 2 diabetes mellitus who are initiating therapy with a glucagon-like peptide 1 receptor agonist (GLP-1 RA), with a focus on those starting lixisenatide therapy. RESEARCH DESIGN AND METHODS: A cohort study was conducted in three large, U.S. claims databases (2017-2021). Adult (aged ≥18 years) new users of a GLP-1 RA who had type 2 diabetes mellitus and ≥6 months enrollment in the database before GLP-1 RA initiation (start of follow-up) were included. GLP-1 RAs evaluated were lixisenatide, an insulin glargine/lixisenatide fixed-ratio combination (FRC), exenatide, liraglutide or insulin degludec/liraglutide FRC, dulaglutide, and semaglutide (injectable and oral). The first anaphylaxis event during follow-up was identified using a validated algorithm. Incidence rates (IRs) and 95% CIs were calculated within each medication cohort. The unadjusted IR ratio (IRR) comparing anaphylaxis rates in the lixisenatide cohort with all other GLP-1 RAs combined was analyzed post hoc. RESULTS: There were 696,089 new users with 456,612 person-years of exposure to GLP-1 RAs. Baseline demographics, comorbidities, and use of other prescription medications in the 6 months before the index date were similar across medication cohorts. IRs (95% CIs) per 10,000 person-years were 1.0 (0.0-5.6) for lixisenatide, 6.0 (3.6-9.4) for exenatide, 5.1 (3.7-7.0) for liraglutide, 3.9 (3.1-4.8) for dulaglutide, and 3.6 (2.6-4.9) for semaglutide. The IRR (95% CI) for the anaphylaxis rate for the lixisenatide cohort compared with the pooled other GLP-1 RA cohort was 0.24 (0.01-1.35). CONCLUSIONS: Anaphylaxis is rare with GLP-1 RAs. Lixisenatide is unlikely to confer higher risk of anaphylaxis than other GLP-1 RAs.

Glycaemic control and macrovascular and microvascular outcomes in type 2 diabetes: Systematic review and meta-analysis of cardiovascular outcome trials of novel glucose-lowering agents.

AIM: Using a systematic review and meta-analysis of placebo-controlled cardiovascular outcome trials (CVOTs) of newer glucose-lowering agents [sodium-glucose cotransporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes. MATERIALS AND METHODS: Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study-specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta-regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions. RESULTS: Twenty unique CVOTs (six SGLT-2is, nine GLP-1RAs, five DPP-4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT-2is, GLP-1RAs and DPP-4is with placebo, the hazard ratios (95% CIs) for 3-point major adverse cardiovascular events were 0.88 (0.82-0.94), 0.85 (0.79-0.92) and 1.00 (0.94-1.06), respectively. SGLT-2is and GLP-1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP-4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3-point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67-1.06; p = .14; R2 = 14.2%), which was driven by the component of non-fatal stroke (R2 = 100.0%; p = .094). There were non-significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes. CONCLUSIONS: SGLT-2is and GLP-1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT-2is and GLP-1RAs in patients with T2D extend beyond mere glycaemic control.

Glycaemic control and macrovascular and microvascular outcomes: A systematic review and meta-analysis of trials investigating intensive glucose-lowering strategies in people with type 2 diabetes.

AIM: We aimed to determine the macrovascular and microvascular outcomes of intensive versus standard glucose-lowering strategies in type 2 diabetes (T2D) and investigate the relationships between these outcomes and trial arm glycated haemoglobin (HbA1c) reduction. MATERIALS AND METHODS: In this systematic review and meta-analysis, we identified relevant trials from MEDLINE, Embase, the Cochrane Library, and bibliographies up to August 2023. Macrovascular and microvascular outcomes, along with safety outcomes, were evaluated. Pooled study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and meta-regression was employed to analyse the relationships between outcomes and HbA1c reduction. RESULTS: We included 11 unique RCTs involving 51 469 patients with T2D (intensive therapy, N = 26 691; standard therapy, N = 24 778). Intensive versus standard therapy reduced the risk of non-fatal myocardial infarction (MI) (HR 0.84; 95% CI 0.75-0.94) with no difference in the risk of major adverse cardiovascular events (HR 0.97; 95% CI 0.92-1.03) and other adverse cardiovascular outcomes. Intensive versus standard therapy reduced the risk of retinopathy (HR 0.85; 0.78-0.93), nephropathy (HR 0.71; 0.58-0.87) and composite microvascular outcomes (HR 0.88; 0.77-1.00). Meta-regression analyses showed modest evidence of inverse linear relationships between HbA1c reduction and the outcomes of major adverse cardiovascular events, non-fatal MI, stroke and retinopathy, but these were not statistically significant. CONCLUSIONS: In people with T2D, intensive glucose control was associated with a reduced risk of non-fatal MI and several microvascular outcomes, particularly retinopathy and nephropathy. The lack of an effect of intensive glucose-lowering on most macrovascular outcomes calls for a more comprehensive approach to managing cardiovascular risk factors alongside glycaemic control.

Contemporary Clinical Perspectives on Targeting Remission of Type 2 Diabetes.

It has long been known that some patients with type 2 diabetes (T2DM) can experience sustained metabolic improvement to near-normal levels of glycemia either spontaneously or after medical intervention. Now recognized as remission of diabetes, this intriguing state is currently more feasible than ever before due to profound advances in metabolic surgery, pharmacologic therapy, and regimens of lifestyle modification. This enhanced capacity to induce remission has revealed new pathophysiologic insights, including the presence of a reversible component of the pancreatic beta-cell dysfunction that otherwise drives the chronic progressive nature of T2DM. In doing so, it has changed the therapeutic landscape by offering new potential management objectives and considerations for patients and providers. However, the excitement around these developments must also be tempered by the sobering realities of our current understanding of remission, including the recognition that this condition may not be permanent (resulting in glycemic relapse over time) and that beta-cell function may not be normalized in the setting of remission. These limitations highlight both the many gaps in our current understanding of remission and the caution with which clinical discussions must be handled for clear patient-directed communication of the pros and cons of targeting this outcome in practice. In this mini-review, we consider this rapidly growing literature, including its implications and its limitations, and thereby seek to provide objective balanced perspectives on targeting remission of T2DM in current clinical care.

Glycemic and metabolic sub-classification of prediabetes and risk factors for cardiovascular disease in the D2d cohort.

Objectives: Prediabetes represents a spectrum of metabolic abnormalities, including insulin resistance and secretory impairment, that carries increased cardiovascular disease (CVD) risk. It is unclear whether specific glycemic and metabolic sub-classifications are associated with CVD risk. This cross-sectional analysis of 3946 participants from the Vitamin D and Type 2 Diabetes (D2d) study cohort aimed to determine the associations between various baseline CVD risk factors, glycemic sub-classifications of prediabetes (FPG, 2hPG, and HbA1c), and measures of insulin sensitivity and secretion from an OGTT. Methods: The metabolic syndrome and atherosclerotic cardiovascular disease (ASCVD) risk scores were determined for tertiles of insulin sensitivity (HOMA2S) and insulinogenic index (IGI). Unadjusted analyses showed elevated CVD risk factors in the lowest tertile for both IGI and HOMA2S. Results: After adjustment for age, gender, race, obesity, and smoking status, the association remained between HOMA2S and ASCVD score (r = -0.11, p< 0.001) but not for IGI. Those who met at least 2 diagnosic criteria for prediabetes had the largest proportion (> 40%) of participants with high ASCVD risk score >20. A higher percentage of individuals that met all 3 criteria for prediabetes had metabolic syndrome and ASCVD risk score >20 (87.2% and 15.3%, respectively) than those who only met 1 prediabetes criterion (51.6% and 7.1%, respectively). Conclusions: In conclusion, multiple metabolic (HOMA2S, IGI) and glycemic criteria of prediabetes (FPG, 2hPG, & HbA1c) are needed to fully recognize the elevated CVD risk profile that can manifest in prediabetes.

Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes. METHODS: This randomised, double-blind, placebo-controlled, phase 3, superiority trial enrolled adults with a BMI of at least 30 kg/m2, or at least 27 kg/m2 with bodyweight-related complications and comorbidities, without type 2 diabetes. The trial was done at 50 outpatient clinics in nine countries across Asia, Europe, and North America. Participants were randomly allocated (1:1) via an interactive web-response system to oral semaglutide escalated to 50 mg, or visually matching placebo, once per day for 68 weeks, plus lifestyle intervention. Group assignment was masked for participants, investigators, and those assessing outcomes. Coprimary endpoints were the percentage change in bodyweight and whether participants reached a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg versus placebo, assessed regardless of treatment discontinuation or use of other bodyweight-lowering therapies (an intention-to-treat analysis). Safety was assessed in participants who received at least one dose of trial drug. This trial, registered with ClinicalTrials.gov (NCT05035095), is now complete. FINDINGS: From Sept 13 to Nov 22, 2021, 709 participants were screened, of whom 667 were randomly assigned to oral semaglutide 50 mg (n=334) or placebo (n=333). The estimated mean bodyweight change from baseline to week 68 was -15·1% (SE 0·5) with oral semaglutide 50 mg versus -2·4% (0·5) with placebo (estimated treatment difference -12·7 percentage points, 95% CI -14·2 to -11·3; p<0·0001). More participants reached bodyweight reductions of at least 5% (269 [85%] of 317 vs 76 [26%] of 295; odds ratio [OR] 12·6, 95% CI 8·5 to 18·7; p<0·0001), 10% (220 [69%] vs 35 [12%]; OR 14·7, 9·6 to 22·6), 15% (170 [54%] vs 17 [6%]; OR 17·9, 10·4 to 30·7), and 20% (107 [34%] vs 8 [3%]; OR 18·5, 8·8 to 38·9) at week 68 with oral semaglutide 50 mg versus placebo. Adverse events were more frequent with oral semaglutide 50 mg (307 [92%] of 334) than with placebo (285 [86%] of 333). Gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo. INTERPRETATION: In adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo. FUNDING: Novo Nordisk.

Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial.

BACKGROUND: Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes. METHODS: This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0-10·5% (64-91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete. FINDINGS: Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA1c was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA1c at week 52 were -1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, -1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] -0·27, 95% CI -0·42 to -0·12; p=0·0006), and -2·0 percentage points (0·06) with 50 mg (ETD -0·53, -0·68 to -0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related. INTERPRETATION: Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified. FUNDING: Novo Nordisk.

Higher burden of cardiometabolic and socioeconomic risk factors in women with type 2 diabetes: an analysis of the Glycemic Reduction Approaches in Diabetes (GRADE) baseline cohort.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017. RESULTS: Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes. CONCLUSIONS: This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT01794143).

Efficacy and safety of once-weekly efpeglenatide in people with suboptimally controlled type 2 diabetes: The AMPLITUDE-D, AMPLITUDE-L and AMPLITUDE-S randomized controlled trials.

AIM: To evaluate the efficacy and safety of once-weekly (QW) efpeglenatide in people with type 2 diabetes (T2D) suboptimally controlled with oral glucose-lowering drugs and/or basal insulin (BI). MATERIALS AND METHODS: Three phase 3, multicentre, randomized controlled trials compared the efficacy and safety of QW efpeglenatide versus dulaglutide when added to metformin (AMPLITUDE-D), efpeglenatide versus placebo when added to BI ± oral glucose-lowering drugs (AMPLITUDE-L) or metformin ± sulphonylurea (AMPLITUDE-S). All trials were terminated early by the sponsor because of funding rather than safety or efficacy concerns. RESULTS: In AMPLITUDE-D, non-inferiority of efpeglenatide to dulaglutide 1.5 mg was shown in HbA1c reduction from baseline to week 56, least squares mean treatment difference (95% CI): 4 mg, -0.03% (-0.20%, 0.14%)/-0.35 mmol/mol (-2.20, 1.49); 6 mg, -0.08% (-0.25%, 0.09%)/-0.90 mmol/mol (-2.76, 0.96). The reductions in body weight (approximately 3 kg) from baseline to week 56 were similar across all treatment groups. In AMPLITUDE-L and AMPLITUDE-S, numerically greater reduction in HbA1c and body weight were observed at all doses of efpeglenatide than placebo. American Diabetes Association level 2 hypoglycaemia (< 54 mg/dL [< 3.0 mmol/L]) was reported in few participants across all treatment groups (AMPLITUDE-D, ≤ 1%; AMPLITUDE-L, ≤ 10%; and AMPLITUDE-S, ≤ 4%). The adverse events profile was consistent with other glucagon-like peptide-1 receptor agonists (GLP-1 RAs); gastrointestinal adverse events were most frequent in all three studies. CONCLUSIONS: In people with T2D suboptimally controlled with oral glucose-lowering drugs and/or BI, QW efpeglenatide was non-inferior to dulaglutide in terms of HbA1c reduction and showed numerically greater improvements than placebo in glycaemic control and body weight, with safety consistent with the GLP-1 RA class.

Correlation Between Time in Range and HbA1c in People with Type 2 Diabetes on Basal Insulin: Post Hoc Analysis of the SWITCH PRO Study.

INTRODUCTION: Use of continuous glucose monitoring (CGM) in people with diabetes may provide a more complete picture of glycemic control than glycated hemoglobin (HbA1c) measurements, which do not capture day-to-day fluctuations in blood glucose levels. The randomized, crossover, phase IV SWITCH PRO study assessed time in range (TIR), derived from CGM, following treatment with insulin degludec or insulin glargine U100 in patients with type 2 diabetes at risk for hypoglycemia. This post hoc analysis evaluated the relationship between TIR and HbA1c, following treatment intensification during the SWITCH PRO study. METHODS: Correlation between absolute values for TIR (assessed over 2-week intervals) and HbA1c, at baseline and at the end of maintenance period 1 (M1; week 18) or maintenance period 2 (M2; week 36), were assessed by linear regression and using the Spearman correlation coefficient (rs). These methods were also used to assess correlation between change in TIR and change in HbA1c from baseline to the end of M1, both in the full cohort and in subgroups stratified by baseline median HbA1c (≥ 7.5% [≥ 58.5 mmol/mol] or < 7.5% [< 58.5 mmol/mol]). RESULTS: A total of 419 participants were included in the analysis. A moderate inverse linear correlation was observed between TIR and HbA1c at baseline (rs -0.54), becoming stronger following treatment intensification during maintenance periods M1 (weeks 17-18: rs -0.59) and M2 (weeks 35-36: rs -0.60). Changes in TIR and HbA1c from baseline to end of M1 were also linearly inversely correlated in the full cohort (rs -0.40) and the subgroup with baseline HbA1c ≥ 7.5% (rs -0.43). This was less apparent in the subgroup with baseline HbA1c < 7.5% (rs -0.17) (p-interaction = 0.07). CONCLUSION: Results from this post hoc analysis of data from SWITCH PRO, one of the first large interventional clinical studies to use TIR as the primary outcome, further support TIR as a valid clinical indicator of glycemic control. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03687827.

Coordinated Care to Optimize Cardiovascular Preventive Therapies in Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Evidence-based therapies to reduce atherosclerotic cardiovascular disease risk in adults with type 2 diabetes are underused in clinical practice. Objective: To assess the effect of a coordinated, multifaceted intervention of assessment, education, and feedback vs usual care on the proportion of adults with type 2 diabetes and atherosclerotic cardiovascular disease prescribed all 3 groups of recommended, evidence-based therapies (high-intensity statins, angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs], and sodium-glucose cotransporter 2 [SGLT2] inhibitors and/or glucagon-like peptide 1 receptor agonists [GLP-1RAs]). Design, Setting, and Participants: Cluster randomized clinical trial with 43 US cardiology clinics recruiting participants from July 2019 through May 2022 and follow-up through December 2022. The participants were adults with type 2 diabetes and atherosclerotic cardiovascular disease not already taking all 3 groups of evidence-based therapies. Interventions: Assessing local barriers, developing care pathways, coordinating care, educating clinicians, reporting data back to the clinics, and providing tools for participants (n = 459) vs usual care per practice guidelines (n = 590). Main Outcomes and Measures: The primary outcome was the proportion of participants prescribed all 3 groups of recommended therapies at 6 to 12 months after enrollment. The secondary outcomes included changes in atherosclerotic cardiovascular disease risk factors and a composite outcome of all-cause death or hospitalization for myocardial infarction, stroke, decompensated heart failure, or urgent revascularization (the trial was not powered to show these differences). Results: Of 1049 participants enrolled (459 at 20 intervention clinics and 590 at 23 usual care clinics), the median age was 70 years and there were 338 women (32.2%), 173 Black participants (16.5%), and 90 Hispanic participants (8.6%). At the last follow-up visit (12 months for 97.3% of participants), those in the intervention group were more likely to be prescribed all 3 therapies (173/457 [37.9%]) vs the usual care group (85/588 [14.5%]), which is a difference of 23.4% (adjusted odds ratio [OR], 4.38 [95% CI, 2.49 to 7.71]; P < .001) and were more likely to be prescribed each of the 3 therapies (change from baseline in high-intensity statins from 66.5% to 70.7% for intervention vs from 58.2% to 56.8% for usual care [adjusted OR, 1.73; 95% CI, 1.06-2.83]; ACEIs or ARBs: from 75.1% to 81.4% for intervention vs from 69.6% to 68.4% for usual care [adjusted OR, 1.82; 95% CI, 1.14-2.91]; SGLT2 inhibitors and/or GLP-1RAs: from 12.3% to 60.4% for intervention vs from 14.5% to 35.5% for usual care [adjusted OR, 3.11; 95% CI, 2.08-4.64]). The intervention was not associated with changes in atherosclerotic cardiovascular disease risk factors. The composite secondary outcome occurred in 23 of 457 participants (5%) in the intervention group vs 40 of 588 participants (6.8%) in the usual care group (adjusted hazard ratio, 0.79 [95% CI, 0.46 to 1.33]). Conclusions and Relevance: A coordinated, multifaceted intervention increased prescription of 3 groups of evidence-based therapies in adults with type 2 diabetes and atherosclerotic cardiovascular disease. Trial Registration: ClinicalTrials.gov Identifier: NCT03936660.