Effectiveness of glucose-lowering medications on cardiovascular outcomes in patients with type 2 diabetes at moderate cardiovascular risk.

Cardiovascular disease (CVD) is the leading cause of death among people with type 2 diabetes1-5, most of whom are at moderate CVD risk6, yet there is limited evidence on the preferred choice of glucose-lowering medication for CVD risk reduction in this population. Here, we report the results of a retrospective cohort study where data for US adults with type 2 diabetes and moderate risk for CVD are used to compare the risks of experiencing a major adverse cardiovascular event with initiation of glucagon-like peptide-1 receptor agonists (GLP-1RA; n = 44,188), sodium-glucose cotransporter 2 inhibitors (SGLT2i; n = 47,094), dipeptidyl peptidase-4 inhibitors (DPP4i; n = 84,315) and sulfonylureas (n = 210,679). Compared to DPP4i, GLP-1RA (hazard ratio (HR) 0.87; 95% confidence interval (CI) 0.82-0.93) and SGLT2i (HR 0.85; 95% CI 0.81-0.90) were associated with a lower risk of a major adverse cardiovascular event, whereas sulfonylureas were associated with a higher risk (HR 1.19; 95% CI 1.16-1.22). Thus, GLP-1RA and SGLT2i may be the preferred glucose-lowering agents for cardiovascular risk reduction in patients at moderate baseline risk for CVD. ClinicalTrials.gov registration: NCT05214573.

Derivation of an Annualized Claims-Based Major Adverse Cardiovascular Event Estimator in Type 2 Diabetes.

Background: Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction. Objectives: The purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes. Methods: Using medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications. Results: The study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%). Conclusions: ACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data.

Comparative Effectiveness of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter 2 Inhibitors, Dipeptidyl Peptidase-4 Inhibitors, and Sulfonylureas for Sight-Threatening Diabetic Retinopathy.

OBJECTIVE: To investigate whether the choice of glucose-lowering agent for type 2 diabetes (T2D) impacts a patient's risk of developing sight-threatening diabetic retinopathy complications. DESIGN: Retrospective observational database study emulating an idealized target trial. SUBJECTS: Adult (≥21 years) enrollees in United States commercial, Medicare Advantage, and Medicare fee-for-service plans from January 1, 2014, to December 31, 2021, with T2D and moderate cardiovascular disease (CVD) risk who had no baseline history of advanced diabetic retinal complications, initiating treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sulfonylureas. METHODS: We used inverse propensity scoring weights in time-to-event Cox proportional hazards models. MAIN OUTCOME MEASURES: Treatment for either diabetic macular edema or proliferative diabetic retinopathy. RESULTS: The final study population included 371 698 patients, of whom 42 265 initiated GLP-1 RA, 53 476 initiated SGLT2i, 78 444 initiated DPP-4i, and 197 513 initiated sulfonylurea agents. The probability of treatment for sight-threatening retinopathy within 2 and 5 years was 0.3% and 0.7% for patients initiating SGLT2i (median follow-up 830 [interquartile range (IQR), 343-1401] days), 0.4% and 1.0% for GLP-1 RA (669 [IQR, 256-1167] days), 0.4% and 0.9% for DPP-4i (1263 [IQR, 688-1938] days), and 0.5% and 1.2% for sulfonylurea (1223 [IQR, 662-1879] days). Sodium-glucose cotransporter 2 inhibitors use was associated with a lower risk of treatment for sight-threatening retinopathy compared with all other medication classes, including GLP-1 RA (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.97), DPP-4i (HR, 0.79; 95% CI, 0.64-0.97), and sulfonylurea (HR, 0.61; 95% CI, 0.50-0.74). Glucagon-like peptide-1 receptor agonists use was associated with a similar risk of sight-threatening retinopathy as DPP-4i (HR, 1.07; 95% CI, 0.85-1.35) and sulfonylurea (HR, 0.83; 95% CI, 0.67-1.03). CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors use was associated with a lower risk of sight-threatening diabetic retinopathy among adults with T2D and moderate CVD risk compared with other glucose-lowering therapies. Glucagon-like peptide-1 receptor agonists do not confer increased retinal risk, relative to DPP-4i and sulfonylurea medications. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Disparities in Acute and Chronic Complications of Diabetes Along the U.S. Rural-Urban Continuum.

OBJECTIVE: To determine the relative hazards of acute and chronic diabetes complications among people with diabetes across the U.S. rural-urban continuum. RESEARCH DESIGN AND METHODS: This retrospective cohort study used the OptumLabs Data Warehouse, a deidentified data set of U.S. commercial and Medicare Advantage beneficiaries, to follow 2,901,563 adults (age ≥18 years) with diabetes between 1 January 2012 and 31 December 2021. We compared adjusted hazard ratios (HRs) of diabetes complications in remote areas (population <2,500), small towns (population 2,500-50,000), and cities (population >50,000). RESULTS: Compared with residents of cities, residents of remote areas had greater hazards of myocardial infarction (HR 1.06 [95% CI 1.02-1.10]) and revascularization (HR 1.04 [1.02-1.06]) but lower hazards of hyperglycemia (HR 0.90 [0.83-0.98]) and stroke (HR 0.91 [0.88-0.95]). Compared with cities, residents of small towns had greater hazards of hyperglycemia (HR 1.06 [1.02-1.10]), hypoglycemia (HR 1.15 [1.12-1.18]), end-stage kidney disease (HR 1.04 [1.03-1.06]), myocardial infarction (HR 1.10 [1.08-1.12]), heart failure (HR 1.05 [1.03-1.06]), amputation (HR 1.05 [1.02-1.09]), other lower-extremity complications (HR 1.02 [1.01-1.03]), and revascularization (HR 1.05 [1.04-1.06]) but a smaller hazard of stroke (HR 0.95 [0.94-0.97]). Compared with small towns, residents of remote areas had lower hazards of hyperglycemia (HR 0.85 [0.78-0.93]), hypoglycemia (HR 0.92 [0.87-0.97]), and heart failure (HR 0.94 [0.91-0.97]). Hazards of retinopathy and atrial fibrillation/flutter did not vary geographically. CONCLUSIONS: Adults in small towns are disproportionately impacted by complications of diabetes. Future studies should probe for the reasons underlying these disparities.

Sociodemographic, Clinical, and Treatment-Related Factors Associated With Hyperglycemic Crises Among Adults With Type 1 or Type 2 Diabetes in the US From 2014 to 2020.

Importance: Hyperglycemic crises (ie, diabetic ketoacidosis [DKA] and hyperglycemic hyperosmolar state [HHS]) are life-threatening acute complications of diabetes. Efforts to prevent these events at the population level have been hindered by scarce granular data and difficulty in identifying individuals at highest risk. Objective: To assess sociodemographic, clinical, and treatment-related factors associated with hyperglycemic crises in adults with type 1 or type 2 diabetes in the US from 2014 to 2020. Design, Setting, and Participants: This retrospective cohort study analyzed administrative claims and laboratory results for adults (aged ≥18 years) with type 1 or type 2 diabetes from the OptumLabs Data Warehouse from January 1, 2014, through December 31, 2020. Main Outcomes and Measures: Rates of emergency department or hospital visits with a primary diagnosis of DKA or HHS (adjusted for age, sex, race/ethnicity, and region, and for year when calculating annualized rates) were calculated separately for patients with type 1 diabetes and type 2 diabetes. The associations of sociodemographic factors (age, sex, race/ethnicity, region, and income), clinical factors (comorbidities), and treatment factors (glucose-lowering medications, hemoglobin A1c) with DKA or HHS in patients with type 1 or type 2 diabetes were assessed using negative binomial regression. Results: Among 20 156 adults with type 1 diabetes (mean [SD] age, 46.6 [16.5] years; 51.2% male; 72.6% White race/ethnicity) and 796 382 with type 2 diabetes (mean [SD] age, 65.6 [11.8] years; 50.3% female; 54.4% White race/ethnicity), adjusted rates of hyperglycemic crises were 52.69 per 1000 person-years (95% CI, 48.26-57.12 per 1000 person-years) for type 1 diabetes and 4.04 per 1000 person-years (95% CI, 3.88-4.21 per 1000 person-years) for type 2 diabetes. In both groups, factors associated with the greatest hyperglycemic crisis risk were low income (≥$200 000 vs <$40 000: type 1 diabetes incidence risk ratio [IRR], 0.61 [95% CI, 0.46-0.81]; type 2 diabetes IRR, 0.69 [95% CI, 0.56-0.86]), Black race/ethnicity (vs White race/ethnicity: type 1 diabetes IRR, 1.33 [95% CI, 1.01-1.74]; type 2 diabetes IRR, 1.18 [95% CI, 1.09-1.27]), high hemoglobin A1c level (≥10% vs 6.5%-6.9%: type 1 diabetes IRR, 7.81 [95% CI, 5.78-10.54]; type 2 diabetes IRR, 7.06 [95% CI, 6.26-7.96]), history of hyperglycemic crises (type 1 diabetes IRR, 7.88 [95% CI, 6.06-9.99]; type 2 diabetes IRR, 17.51 [95% CI, 15.07-20.34]), severe hypoglycemia (type 1 diabetes IRR, 2.77 [95% CI, 2.15-3.56]; type 2 diabetes IRR, 4.18 [95% CI, 3.58-4.87]), depression (type 1 diabetes IRR, 1.62 [95% CI, 1.37-1.92]; type 2 diabetes IRR, 1.46 [95% CI, 1.34-1.59]), neuropathy (type 1 diabetes IRR, 1.64 [95% CI, 1.39-1.93]; type 2 diabetes IRR, 1.25 [95% CI, 1.17-1.34]), and nephropathy (type 1 diabetes IRR, 1.22 [95% CI, 1.01-1.48]; type 2 diabetes IRR, 1.23 [95% CI, 1.14-1.33]). Age had a U-shaped association with hyperglycemic crisis risk in patients with type 1 diabetes (compared with patients aged 18-44 years: 45-64 years IRR, 0.72 [95% CI, 0.59-0.87]; 65-74 years IRR, 0.62 [95% CI, 0.47-0.80]; ≥75 years IRR, 0.96 [95% CI, 0.66-1.38]). In type 2 diabetes, risk of hyperglycemic crises decreased progressively with age (45-64 years IRR, 0.57 [95% CI, 0.51-0.63]; 65-74 years IRR, 0.44 [95% CI, .39-0.49]; ≥75 years IRR, 0.41 [95% CI, 0.36-0.47]). In patients with type 2 diabetes, higher risk was associated with sodium-glucose cotransporter 2 inhibitor therapy (IRR, 1.30; 95% CI, 1.14-1.49) and insulin dependency (compared with regimens with bolus insulin: regimens with basal insulin only, IRR, 0.69 [95% CI, 0.63-0.75]; and without any insulin, IRR, 0.36 [95% CI, 0.33-0.40]). Conclusions and Relevance: In this cohort study, younger age, Black race/ethnicity, low income, and poor glycemic control were associated with an increased risk of hyperglycemic crises. The findings suggest that multidisciplinary interventions focusing on groups at high risk for hyperglycemic crises are needed to prevent these dangerous events.