Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study.

BACKGROUND: No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups. METHODS: We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). RESULTS: We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex. CONCLUSIONS: The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes.

Hyperkalemia is a common adverse event in patients with chronic kidney disease (CKD) and type 2 diabetes and limits the use of guideline-recommended therapies such as renin-angiotensin system inhibitors. Here, we evaluated the comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of hyperkalemia. We conducted a population-based active-comparator, new-user cohort study using claims data from Medicare and two large United States commercial insurance databases (April 2013-April 2022). People with CKD stages 3-4 and type 2 diabetes who newly initiated SGLT-2i vs. DPP-4i (141671 patients), GLP-1RA vs. DPP-4i (159545 patients) and SGLT-2i vs. GLP-1RA (93033 patients) were included. The primary outcome was hyperkalemia diagnosed in inpatient or outpatient settings. Secondary outcomes included hyperkalemia diagnosed in inpatient or emergency department setting, and serum potassium levels of 5.5 mmol/L or more. Pooled hazard ratios and rate differences were estimated after propensity score matching to adjust for over 140 potential confounders. Initiation of SGLT-2i was associated with a lower risk of hyperkalemia compared with DPP-4i (hazard ratio 0.74; 95% confidence interval 0.68-0.80) and contrasted to GLP-1RA (0.92; 0.86-0.99). Compared with DPP-4i, GLP-1RA were also associated with a lower risk of hyperkalemia (0.80; 0.75-0.86). Corresponding absolute rate differences/1000 person-years were -24.8 (95% confidence interval -31.8 to -17.7), -5.0 (-10.9 to 0.8), and -17.7 (-23.4 to -12.1), respectively. Similar findings were observed for the secondary outcomes, among subgroups, and across single agents within the SGLT-2i and GLP-1RA classes. Thus, SGLT-2i and GLP-1RA are associated with a lower risk of hyperkalemia than DPP-4i in patients with CKD and type 2 diabetes, further supporting the use of these drugs in this population.

Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes.

OBJECTIVE: To evaluate the comparative cardiovascular effectiveness and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in older adults with type 2 diabetes (T2D) across different frailty strata. RESEARCH DESIGN AND METHODS: We performed three 1:1 propensity score-matched cohort studies, each stratified by three frailty strata, using data from Medicare beneficiaries (2013-2019) with T2D who initiated SGLT-2is, GLP-1RAs, or DPP-4is. In time-to-event analyses, we assessed the primary cardiovascular effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, and all-cause mortality. The primary safety outcome was a composite of severe adverse events that have been linked to SGLT-2i or GLP-1RA use. RESULTS: Compared with DPP-4is, the overall hazard ratio (HR) for the primary effectiveness outcome associated with SGLT-2is (n = 120,202 matched pairs) was 0.72 (95% CI 0.69-0.75), corresponding to an incidence rate difference (IRD) of -13.35 (95% CI -15.06 to -11.64). IRD ranged from -6.74 (95% CI -8.61 to -4.87) in nonfrail to -27.24 (95% CI -41.64 to -12.84) in frail people (P for interaction < 0.01). Consistent benefits were observed for GLP-1RAs compared with DPP-4is (n = 113,864), with an overall HR of 0.74 (95% CI 0.71-0.77) and an IRD of -15.49 (95% CI -17.46 to -13.52). IRD in the lowest frailty stratum was -7.02 (95% CI -9.23 to -4.81) and -25.88 (95% CI -38.30 to -13.46) in the highest (P for interaction < 0.01). Results for SGLT-2is versus GLP-1RAs (n = 89,865) were comparable. Severe adverse events were not more frequent with SGLT-2is or GLP-1RAs than DPP-4is. CONCLUSIONS: SGLT-2is and GLP-1RAs safely improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among frail people.

Risk of Severe Hypoglycemia With Newer Second-line Glucose-lowering Medications in Older Adults With Type 2 Diabetes Stratified by Known Indicators of Hypoglycemia Risk.

BACKGROUND: Severe hypoglycemia is associated with adverse clinical outcomes. We evaluated the risk of severe hypoglycemia in older adults initiating newer glucose-lowering medications overall and across strata of known indicators of high hypoglycemia risk. METHODS: We conducted a comparative-effectiveness cohort study of older adults aged >65 years with type 2 diabetes initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA) using Medicare claims (3/2013-12/2018) and Medicare-linked-electronic health records. We identified severe hypoglycemia requiring emergency or inpatient visits using validated algorithms. After 1:1 propensity score matching, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years. Analyses were stratified by baseline insulin, sulfonylurea, cardiovascular disease (CVD), chronic kidney disease (CKD), and frailty. RESULTS: Over a median follow-up of 7 (interquartile range: 4-16) months, SGLT2i was associated with a reduced risk of hypoglycemia versus DPP-4i (HR 0.75 [0.68, 0.83]; RD -3.21 [-4.29, -2.12]), and versus GLP-1RA (HR 0.90 [0.82, 0.98]; RD -1.33 [-2.44, -0.23]). RD for SGLT2i versus DPP-4i was larger in patients using baseline insulin than in those not, although HRs were similar. In patients using baseline sulfonylurea, the risk of hypoglycemia was lower in SGLT2i versus DPP-4i (HR 0.57 [0.49, 0.65], RD -6.80 [-8.43, -5.16]), while the association was near-null in those without baseline sulfonylurea. Results stratified by baseline CVD, CKD and frailty were similar to the overall cohort findings. Findings for the GLP-1RA comparison were similar. CONCLUSIONS: SGLT2i was associated with a lower hypoglycemia risk versus incretin-based medications, with larger associations in patients using baseline insulin or sulfonylurea.

Association of Sodium-Glucose Cotransporter-2 Inhibitors With Incident Atrial Fibrillation in Older Adults With Type 2 Diabetes.

Importance: Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have demonstrated many cardiovascular and kidney function benefits for patients with type 2 diabetes (T2D). However, the results of SGLT-2i use in primary prevention of atrial fibrillation (AF) were inconsistent in clinical trials, and incident AF was not a prespecified end point. Objective: To examine incident AF with initiation of an SGLT-2i compared with initiation of a dipeptidyl peptidase-4 inhibitor (DPP-4i) or a glucagonlike peptide-1 receptor agonist (GLP-1RA) among older adults (aged ≥66 years) with T2D in routine clinical practice. Design, Setting, and Participants: A population-based new-user cohort study included older adults with T2D who had no history of AF and were enrolled in Medicare fee-for-service from April 1, 2013, to December 31, 2018. Data analysis was performed from June 28 to December 1, 2021. Exposures: To control for potential confounding, new users of SGLT-2i were 1:1 propensity score (PS)-matched to new users of DPP-4is or GLP-1RAs in 2 pairwise comparisons based on 138 baseline covariates. Main Outcomes and Measures: The primary outcome was incident AF, defined as an inpatient diagnosis code for AF. Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years, with their 95% CIs, were estimated in the PS-matched groups. Results: New users of SGLT-2is were 1:1 PS-matched to new users of a DPP-4i (n = 74 868) or GLP-1RA (n = 80 475). Overall, the mean (SD) age of study participants was 72 (5) years, and 165 984 were women (53.4%). The risk of incident AF was lower in the SGLT-2i group than the matched DPP-4i group (HR, 0.82; 95% CI, 0.76 to 0.89; RD, -3.7; 95% CI, -5.2 to -2.2 per 1000 person-years) or the matched GLP-1RA group (HR, 0.90; 95% CI, 0.83 to 0.98; RD, -1.8; 95% CI, -3.2 to -0.3 per 1000 person-years). Results were consistent across several sensitivity and subgroup analyses. Conclusions and Relevance: The findings of this study suggest that the initiation of an SGLT-2i was associated with a reduced risk of incident AF compared with a DPP-4i or GLP-1RA. The results may be helpful when weighing the potential risks and benefits of various glucose level-lowering agents in older adults with T2D.

Comparative Effectiveness of Empagliflozin vs Liraglutide or Sitagliptin in Older Adults With Diverse Patient Characteristics.

Importance: Limited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk. Objective: To evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD). Design, Setting, and Participants: This retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score-matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score-matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2. Exposures: Empagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2). Main Outcomes and Measures: Primary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching. Results: Among 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, -17.6 [95% CI, -24.9 to -10.4]; HHF: RD, -16.7 [95% CI, -21.7 to -11.9]), HF (modified MACE: RD, -41.1 [95% CI, -59.9 to -22.6]; HHF: RD, -50.4 [95% CI, -67.5 to -33.9]), or CKD (modified MACE: RD, -26.7 [95% CI, -41.3 to -12.3]; HHF: RD, -31.9 [95% CI, -43.5 to -20.8]). Conclusions and Relevance: In this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.

Comparative effectiveness of Empagliflozin in reducing the burden of recurrent cardiovascular hospitalizations among older adults with diabetes in routine clinical care.

BACKGROUND: The effect of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the total (first and recurrent) burden of cardiovascular (CV) hospitalizations, including hospitalization for heart failure, myocardial infarction, and stroke, is poorly understood. OBJECTIVE: To assess the effect of empagliflozin, an SGLT2i, on total CV hospitalizations among older adults with T2D. METHODS: Using data from Medicare fee-for-service (08/2014-09/2017), we identified 1:1 propensity score-matched cohorts of patients with T2D initiating empagliflozin versus sitagliptin or empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA), balancing >140 baseline covariates. We compared the risk of first and recurrent hospitalizations with any CV condition as the primary discharge diagnosis (ICD-9: 390-459; ICD-10: I00-I99), hospitalizations for heart failure (HHF), and myocardial infarctions (MI) or stroke. We estimated treatment effects based on the Ghosh-Lin semiparametric model for recurrent events as primary and joint frailty model as secondary analysis. RESULTS: We included 11,429 matched-pairs of empagliflozin and sitagliptin initiators and 17,502 matched-pairs of empagliflozin and GLP1-RA initiators with an average age of 72 years. Empagliflozin was associated with a reduced risk of total CV hospitalizations (0.80 [0.69-0.93] vs sitagliptin; 0.88 [0.77-1.00] vs GLP-1RA) and total HHF (0.70 [0.51-0.98] vs sitagliptin; 0.76 [0.56-1.03] vs GLP1-RA) over a mean follow up of 6.3 months. No differences between treatments were observed for MI or stroke. Results were consistent for joint frailty models. CONCLUSION: Empagliflozin, compared to sitagliptin or to a lesser extent GLP1-RA, was associated with a reduction in the burden of total CV hospitalizations and HHF in older patients with T2D.

Three Sides to the Story: Adherence Trajectories During the First Year of SGLT2 Inhibitor Therapy Among Medicare Beneficiaries.

OBJECTIVE: We aimed to understand the factors associated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) adherence and longitudinal adherence trajectories in older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using Medicare claims data (April 2013-December 2017), we identified 83,675 new SGLT2i users ≥66 years old with type 2 diabetes. We measured SGLT2i adherence as the proportion of days covered (PDC) during the first year of SGLT2i therapy. We used linear regression to assess the association between baseline covariates and PDC. Then we used group-based trajectory modeling to identify distinct longitudinal SGLT2i adherence groups and used a multivariable logistic regression model to examine the association between baseline covariates and membership in these adherence groups. RESULTS: Unadjusted mean PDC was 63%. Previous adherence to statins had the strongest positive association with PDC (regression coefficient 6.00% [95% CI 5.50, 6.50]), whereas female sex (-5.51% [-6.02, -5.00]), and Black race/ethnicity (-5.06% [-6.03, -4.09]) had the strongest negative association. We identified three adherence trajectory groups: low (23% of patients, mean PDC 17%), moderate (32%, mean PDC 50%), and high (45%, mean PDC 96%) adherence. More patients in the high adherence group were previously adherent to statins (odds ratio 1.43 [95% CI 1.39, 1.48]), and more women (1.28 [1.23, 1.32]) and Black patients (1.31 [1.23, 1.40]) were in the low adherence group. CONCLUSIONS: In a large population of older patients with type 2 diabetes, 45% were highly adherent during the first year of SGLT2i treatment. Female sex and Black race/ethnicity were most strongly associated with low adherence.

Effectiveness and safety of empagliflozin in routine care patients: Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study.

AIM: To investigate effectiveness and safety outcomes among patients with type 2 diabetes (T2D) initiating empagliflozin versus dipeptidyl peptidase-4 (DPP-4) inhibitor treatment across the broad spectrum of cardiovascular risk. METHODS: In a population-based cohort study we identified 39 072 pairs of 1:1 propensity score-matched adult patients with T2D initiating empagliflozin or DPP-4 inhibitors, using data from 2 US commercial insurance databases and Medicare between August 2014 and September 2017. The primary outcomes were a composite of myocardial infarction (MI)/stroke, and hospitalization for heart failure (HHF). Safety outcomes were bone fractures, lower-limb amputations (LLAs), diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for more than 140 baseline covariates. RESULTS: Study participants had a mean age of 60 years and only 28% had established cardiovascular disease. Compared to DPP-4 inhibitors, empagliflozin was associated with similar risk of MI/stroke (HR 0.99 [95% CI 0.81-1.21]), and lower risk of HHF (HR 0.48 [95% CI 0.35-0.67] and 0.63 [95% CI 0.54-0.74], based on a primary and any heart failure discharge diagnosis, respectively). The HR was 0.52 (95% CI 0.38-0.72) for all-cause mortality (ACM) and 0.83 (95% CI 0.70-0.98) for a composite of MI/stroke/ACM. Empagliflozin was associated with a similar risk of LLA and fractures, an increased risk of DKA (HR 1.71 [95% CI 1.08-2.71]) and a decreased risk of AKI (HR 0.60 [95% CI 0.43-0.85]). CONCLUSIONS: In clinical practice, the initiation of empagliflozin versus a DPP-4 inhibitor was associated with a lower risk of HHF, ACM and MI/stroke/ACM, a similar risk of MI/stroke, and a safety profile consistent with documented information.

SGLT2 Inhibitors and the Risk of Acute Kidney Injury in Older Adults With Type 2 Diabetes.

RATIONALE & OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to have many benefits for patients with type 2 diabetes. However, whether SGLT2 inhibitors increase the risk of acute kidney injury (AKI) remains unknown. We examined the association of AKI hospitalization with prior initiation of an SGLT2 inhibitor compared with initiation of a dipeptidyl peptidase 4 (DPP-4) inhibitor or a glucagon-like peptide 1 receptor agonist (GLP-1RA) among older adults with type 2 diabetes in routine practice. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: Older adults aged at least 66 years with type 2 diabetes enrolled in Medicare fee-for-service and who were new users of SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1RA agents in the interval from March 2013 to December 2017. EXPOSURES: New use of an SGLT2 inhibitor versus new use of a DPP-4 inhibitor or GLP-1RA. OUTCOME: The primary outcome was hospitalization for AKI, defined as a discharge diagnosis of AKI in the primary or secondary position. ANALYTICAL APPROACH: New users of SGLT2 inhibitors were matched at a 1:1 ratio to new users of DPP-4 inhibitors or GLP-1RAs using propensity scores in 2 pairwise comparisons. Cox proportional hazards regression models generated hazard ratios (HRs) with 95% CIs in propensity score-matched groups. RESULTS: Totals of 68,130 and 71,477 new users of SGLT2 inhibitors were matched to new users of DPP-4 inhibitors or GLP-1RAs, respectively. Overall, the mean age of study participants was 72 years. The risk of AKI was lower in the SGLT2 inhibitor group than in the DPP-4 inhibitor group (HR, 0.71 [95% CI, 0.65-0.76]) or the GLP-1RA group (HR, 0.81 [95% CI, 0.75-0.87]). LIMITATIONS: Residual confounding and lack of laboratory data. CONCLUSIONS: Among older adults with type 2 diabetes, initiation of an SGLT2 inhibitor was associated with a reduced risk of AKI compared with initiation of a DPP-4 inhibitor or a GLP-1RA.

Sodium-Glucose Cotransporter-2 Inhibitors Versus Glucagon-like Peptide-1 Receptor Agonists and the Risk for Cardiovascular Outcomes in Routine Care Patients With Diabetes Across Categories of Cardiovascular Disease.

BACKGROUND: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in placebo-controlled trials of patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). OBJECTIVE: To evaluate whether SGLT2 inhibitors and GLP-1 RAs are associated with differential cardiovascular benefit among T2D patients with and without CVD. DESIGN: Population-based cohort study. SETTING: Medicare and 2 U.S. commercial claims data sets (April 2013 to December 2017). PARTICIPANTS: 1:1 propensity score-matched adult T2D patients with and without CVD (52 901 and 133 139 matched pairs) initiating SGLT2 inhibitor versus GLP-1 RA therapy. MEASUREMENTS: Primary outcomes were myocardial infarction (MI) or stroke hospitalization and hospitalization for heart failure (HHF). Pooled hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, with 95% CIs, controlling for 138 preexposure covariates. RESULTS: The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with a slightly lower risk for MI or stroke in patients with CVD (HR, 0.90 [95% CI, 0.82 to 0.98]; RD, -2.47 [CI, -4.45 to -0.50]) but similar risk in those without CVD (HR, 1.07 [CI, 0.97 to 1.18]; RD, 0.38 [CI, -0.30 to 1.07]). The initiation of SGLT2 inhibitor versus GLP-1 RA therapy was associated with reductions in HHF risk regardless of baseline CVD in patients with CVD (HR, 0.71 [CI, 0.64 to 0.79]; RD, -4.97 [CI, -6.55 to -3.39]) and in those without CVD (HR, 0.69 [CI, 0.56 to 0.85]; RD, -0.58 [CI, -0.91 to -0.25]). LIMITATION: Treatment selection was not randomized. CONCLUSION: Use of SGLT2 inhibitors versus GLP-1 RAs was associated with consistent reductions in HHF risk among T2D patients with and without CVD, although the absolute benefit was greater in patients with CVD. There were no large differences in risk for MI or stroke among T2D patients with and without CVD. PRIMARY FUNDING SOURCE: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.

Comparative Effectiveness and Safety of Sodium-Glucose Cotransporter 2 Inhibitors Versus Glucagon-Like Peptide 1 Receptor Agonists in Older Adults.

OBJECTIVE: Both sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) demonstrated cardiovascular benefits in randomized controlled trials of patients with type 2 diabetes (T2D) generally <65 years old and mostly with cardiovascular disease. We aimed to evaluate the comparative effectiveness and safety of SGLT2i and GLP-1RA among real-world older adults. RESEARCH DESIGN AND METHODS: Using Medicare data (April 2013-December 2016), we identified 90,094 propensity score-matched (1:1) T2D patients ≥66 years old initiating SGLT2i or GLP-1RA. Primary outcomes were major adverse cardiovascular events (MACE) (i.e., myocardial infarction, stroke, or cardiovascular death) and hospitalization for heart failure (HHF). Other outcomes included diabetic ketoacidosis (DKA), genital infections, fractures, lower-limb amputations (LLA), acute kidney injury (AKI), severe urinary tract infections, and overall mortality. We estimated hazard ratios (HRs) and rate differences (RDs) per 1,000 person-years, controlling for 140 baseline covariates. RESULTS: Compared with GLP-1RA, SGLT2i initiators had similar MACE risk (HR 0.98 [95% CI 0.87, 1.10]; RD -0.38 [95% CI -2.48, 1.72]) and reduced HHF risk (HR 0.68 [95% CI 0.57, 0.80]; RD -3.23 [95% CI -4.68, -1.77]), over a median follow-up of ∼6 months. They also had 0.7 more DKA events (RD 0.72 [95% CI 0.02, 1.41]), 0.9 more LLA (RD 0.90 [95% CI 0.10, 1.70]), 57.1 more genital infections (RD 57.08 [95% CI 53.45, 60.70]), and 7.1 fewer AKI events (RD -7.05 [95% CI -10.27, -3.83]) per 1,000 person-years. CONCLUSIONS: Among older adults, those taking SGLT2i had similar MACE risk, decreased HHF risk, and increased risk of DKA, LLA, and genital infections versus those taking GLP-1RA.

Incremental Risk of Developing Severe COVID-19 Among Mexican Patients With Diabetes Attributed to Social and Health Care Access Disadvantages.

OBJECTIVE: Diabetes is an important risk factor for severe coronavirus disease 2019 (COVID-19), but little is known about the marginal effect of additional risk factors for severe COVID-19 among individuals with diabetes. We tested the hypothesis that sociodemographic, access to health care, and presentation to care characteristics among individuals with diabetes in Mexico confer an additional risk of hospitalization with COVID-19. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional study using public data from the General Directorate of Epidemiology of the Mexican Ministry of Health. We included individuals with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 between 1 March and 31 July 2020. The primary outcome was the predicted probability of hospitalization, inclusive of 8.5% of patients who required intensive care unit admission. RESULTS: Among 373,963 adults with COVID-19, 16.1% (95% CI 16.0-16.3) self-reported diabetes. The predicted probability of hospitalization was 38.4% (37.6-39.2) for patients with diabetes only and 42.9% (42.2-43.7) for patients with diabetes and one or more comorbidities (obesity, hypertension, cardiovascular disease, and chronic kidney disease). High municipality-level of social deprivation and low state-level health care resources were associated with a 9.5% (6.3-12.7) and 17.5% (14.5-20.4) increased probability of hospitalization among patients with diabetes, respectively. In age-, sex-, and comorbidity-adjusted models, living in a context of high social vulnerability and low health care resources was associated with the highest predicted probability of hospitalization. CONCLUSIONS: Social vulnerability contributes considerably to the probability of hospitalization among individuals with COVID-19 and diabetes with associated comorbidities. These findings can inform mitigation strategies for populations at the highest risk of severe COVID-19.

Geospatial Analysis of Individual and Community-Level Socioeconomic Factors Impacting SARS-CoV-2 Prevalence and Outcomes.

Background: The SARS-CoV-2 pandemic has disproportionately affected racial and ethnic minority communities across the United States. We sought to disentangle individual and census tract-level sociodemographic and economic factors associated with these disparities. Methods and Findings: All adults tested for SARS-CoV-2 between February 1 and June 21, 2020 were geocoded to a census tract based on their address; hospital employees and individuals with invalid addresses were excluded. Individual (age, sex, race/ethnicity, preferred language, insurance) and census tract-level (demographics, insurance, income, education, employment, occupation, household crowding and occupancy, built home environment, and transportation) variables were analyzed using linear mixed models predicting infection, hospitalization, and death from SARS-CoV-2.Among 57,865 individuals, per capita testing rates, individual (older age, male sex, non-White race, non-English preferred language, and non-private insurance), and census tract-level (increased population density, higher household occupancy, and lower education) measures were associated with likelihood of infection. Among those infected, individual age, sex, race, language, and insurance, and census tract-level measures of lower education, more multi-family homes, and extreme household crowding were associated with increased likelihood of hospitalization, while higher per capita testing rates were associated with decreased likelihood. Only individual-level variables (older age, male sex, Medicare insurance) were associated with increased mortality among those hospitalized. Conclusions: This study of the first wave of the SARS-CoV-2 pandemic in a major U.S. city presents the cascade of outcomes following SARS-CoV-2 infection within a large, multi-ethnic cohort. SARS-CoV-2 infection and hospitalization rates, but not death rates among those hospitalized, are related to census tract-level socioeconomic characteristics including lower educational attainment and higher household crowding and occupancy, but not neighborhood measures of race, independent of individual factors.

Social Factors and Patient Perceptions Associated With Preventable Hospital Readmissions.

BACKGROUND: Preventable hospital readmissions are costly and erode the quality of care delivery. Few efforts to incorporate the patient perspectives and social factors associated with readmission preventability exist. OBJECTIVE: To identify patient perceptions and social barriers to care related to readmission. METHODS: Prospective cohort study of 202 respondents readmitted within 30 days of hospital discharge from 2 inpatient adult medicine units at Massachusetts General Hospital, Boston, Massachusetts between January 2012 and January 2016. RESULTS: Few participants indicated that their readmission was due to unattainable health care after discharge. Almost half indicated that they needed more general assistance to stay well outside the hospital. Those reporting a barrier related to at least 2 measures of social determinants of health were more likely to have preventable readmissions (34% vs 17%, P = .006). Participants with a history of homelessness or substance use disorder were more likely to have preventable readmissions (44% vs 20%, P = .04 and 32% vs 18%, P = .03, respectively). CONCLUSION: Strengthening nonmedical support systems and general social policy may be required to reduce preventable readmissions.

Diabetes Prevalence and Its Relationship With Education, Wealth, and BMI in 29 Low- and Middle-Income Countries.

OBJECTIVE: Diabetes is a rapidly growing health problem in low- and middle-income countries (LMICs), but empirical data on its prevalence and relationship to socioeconomic status are scarce. We estimated diabetes prevalence and the subset with undiagnosed diabetes in 29 LMICs and evaluated the relationship of education, household wealth, and BMI with diabetes risk. RESEARCH DESIGN AND METHODS: We pooled individual-level data from 29 nationally representative surveys conducted between 2008 and 2016, totaling 588,574 participants aged ≥25 years. Diabetes prevalence and the subset with undiagnosed diabetes was calculated overall and by country, World Bank income group (WBIG), and geographic region. Multivariable Poisson regression models were used to estimate relative risk (RR). RESULTS: Overall, prevalence of diabetes in 29 LMICs was 7.5% (95% CI 7.1-8.0) and of undiagnosed diabetes 4.9% (4.6-5.3). Diabetes prevalence increased with increasing WBIG: countries with low-income economies (LICs) 6.7% (5.5-8.1), lower-middle-income economies (LMIs) 7.1% (6.6-7.6), and upper-middle-income economies (UMIs) 8.2% (7.5-9.0). Compared with no formal education, greater educational attainment was associated with an increased risk of diabetes across WBIGs, after adjusting for BMI (LICs RR 1.47 [95% CI 1.22-1.78], LMIs 1.14 [1.06-1.23], and UMIs 1.28 [1.02-1.61]). CONCLUSIONS: Among 29 LMICs, diabetes prevalence was substantial and increased with increasing WBIG. In contrast to the association seen in high-income countries, diabetes risk was highest among those with greater educational attainment, independent of BMI. LMICs included in this analysis may be at an advanced stage in the nutrition transition but with no reversal in the socioeconomic gradient of diabetes risk.

Design and participant characteristics of a primary care adaptation of the Look AHEAD Lifestyle Intervention for weight loss in type 2 diabetes: The REAL HEALTH-diabetes study.

BACKGROUND/AIMS: The REAL HEALTH -Diabetes Study is a practice-based clinical trial that adapted the Look AHEAD lifestyle intervention for implementation in primary care settings. The trial will compare the effectiveness and cost-effectiveness of in-person group lifestyle intervention, telephone group lifestyle intervention, and individual medical nutrition therapy (MNT), the current recommended standard of care in type 2 diabetes. The primary outcome is percent weight loss at 6 months with outcomes also measured at 12, 18, 24 (intervention completion), and 36 months. Here, we describe the adaptation, trial design, implementation strategies, and baseline characteristics of enrolled participants. METHODS: The study is a three-arm, patient-level, randomized trial conducted in three community health centers (CHCs) and one diabetes practice affiliated with one academic medical center. RESULTS: The study used existing clinical infrastructure to recruit participants from study sites. Strategies for successful conduct of the trial included partnering with health-center based co-investigator clinicians, engaging primary care providers, and accommodating clinical workflows. Of 248 eligible patients who attended a screening visit, 211 enrolled, with 70 randomly assigned to in-person group lifestyle intervention, 72 to telephone group lifestyle intervention, and 69 to MNT. The cohort was 55% female, 29% non-white, with mean age 62 years and mean BMI 35 kg/m2. Enrollment rates were higher at CHC sites. CONCLUSIONS: A practice-based randomized trial of a complex behavioral lifestyle intervention for type 2 diabetes can be implemented in community health and usual clinical settings. Participant and provider engagement was higher at local CHC sites reflecting the study implementation focus. CLINICAL TRIAL REGISTRATION: NCT02320253.

Food Insecurity, Food "Deserts," and Glycemic Control in Patients With Diabetes: A Longitudinal Analysis.

OBJECTIVE: Both food insecurity (limited food access owing to cost) and living in areas with low physical access to nutritious foods are public health concerns, but their relative contribution to diabetes management is poorly understood. RESEARCH DESIGN AND METHODS: This was a prospective cohort study. A random sample of patients with diabetes in a primary care network completed food insecurity assessment in 2013. Low physical food access at the census tract level was defined as no supermarket within 1 mile in urban areas and 10 miles in rural areas. HbA1c measurements were obtained from electronic health records through November 2016. The relationship among food insecurity, low physical food access, and glycemic control (as defined by HbA1c) was analyzed using hierarchical linear mixed models. RESULTS: Three hundred and ninety-one participants were followed for a mean of 37 months. Twenty percent of respondents reported food insecurity, and 31% resided in an area of low physical food access. In adjusted models, food insecurity was associated with higher HbA1c (difference of 0.6% [6.6 mmol/mol], 95% CI 0.4-0.8 [4.4-8.7], P < 0.0001), which did not improve over time (P = 0.50). Living in an area with low physical food access was not associated with a difference in HbA1c (difference 0.2% [2.2 mmol/mol], 95% CI -0.2 to 0.5 [-2.2 to 5.6], P = 0.33) or with change over time (P = 0.07). CONCLUSIONS: Food insecurity is associated with higher HbA1c, but living in an area with low physical food access is not. Food insecurity screening and interventions may help improve glycemic control for vulnerable patients.

Multidisciplinary coordinated care for Type 2 diabetes: A qualitative analysis of patient perspectives.

AIMS: To explore the patient perspective on coordinated multidisciplinary diabetes team care among a socioeconomically diverse group of adults with type 2 diabetes. METHODS: Qualitative research design using 8 focus groups (n=53). We randomly sampled primary care patients with type 2 diabetes and conducted focus groups at their primary care clinic. Discussion prompts queried current perceptions of team care. Each focus group was audio recorded, transcribed verbatim, and independently coded by three reviewers. Coding used an iterative process. Thematic saturation was achieved. Data were analyzed using content analysis. RESULTS: Most participants believed that coordinated multidisciplinary diabetes team care was a good approach, feeling that diabetes was too complicated for any one care team member to manage. Primary care physicians were seen as too busy to manage diabetes alone, and participants were content to be treated by other care team members, especially if there was a single point of contact and the care was coordinated. Participants suggested that an ideal multidisciplinary approach would additionally include support for exercise and managing socioeconomic challenges, components perceived to be missing from the existing approach to diabetes care. CONCLUSIONS: Coordinated, multidisciplinary diabetes team care is understood by and acceptable to patients with type 2 diabetes.

Hypoglycemia in Diabetes Mellitus as a Coronary Artery Disease Risk Factor in Patients at Elevated Vascular Risk.

CONTEXT: Although clinical trials have shown that hypoglycemia is associated with coronary artery disease (CAD), little is known whether hypoglycemia is a CAD risk factor in primary care. OBJECTIVE: We sought to determine whether previous hypoglycemia was associated with incident CAD, and whether this association differed in patients of different underlying vascular risk. DESIGN, SETTING AND PARTICIPANTS: This is a longitudinal cohort study of diabetes patients without CAD before January 1, 2006 (n = 9173) followed at an academic network of 13 primary care practices from January 1, 2006 to June 30, 2012. Hypoglycemic events before January 1, 2006 were identified via International Classification of Diseases Ninth Revision codes from emergency department, inpatient and outpatient visits. MAIN OUTCOME MEASURE: Patients were followed until incident CAD or June 30, 2012. Cox regression with time interaction was used to determine the association between hypoglycemia and CAD (significance set at P ≤ .05). We then tested the association among high vascular risk patients (age ≥ 55 y, hemoglobin A1c ≥ 7.5%, ≥2 risk factors [dyslipidemia, hypertension or obesity]), a subset of high vascular risk patients aged 65 years or older, and the remaining patients with lower vascular risk. RESULTS: Three percent of patients (n = 285) had previous hypoglycemia. Hypoglycemia was associated with a 2-fold CAD risk (hazard ratio [HR] 2.15; 95% confidence interval [95%CI] 1.24-3.74), adjusting for time interaction and vascular risk factors. Among high vascular risk patients, the risk was 3-fold (HR 3.01 [95%CI 1.15-7.91], n = 1823 [20% of cohort]), and over 4-fold (HR 4.62 [95%CI 1.65-12.9], n = 996) in the subset aged more than or equal to 65 years. No association was found in the remaining 80% of the cohort with lower vascular risk. CONCLUSIONS: Previous hypoglycemia was associated with CAD among high vascular risk patients. Hypoglycemia may not be a CAD risk factor for the majority of primary care patients with lower underlying vascular risk.