In T2D, SGLT2s Provide Greater CV Risk Reduction Than DPP-4 Inhibitors

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A new-user comparator study of adults with type 2 diabetes indicates use of SGLT2 inhibitors was associated with a 54% lower risk of hospitalizations for heart failure and a 15% lower risk of a modified MACE outcome compared to use of DPP-4 inhibitors.

New data indicate SGLT2 inhibitors may be a second-line option than DPP-4 inhibitors for long-term prevention of adverse cardiovascular outcomes in people with type 2 diabetes, regardless of baseline HbA1c levels.

A new-user comparative effectiveness and safety study, results of the study, which included data from more than 140,000 commercially insured adults, indicated use of SGLT2 inhibitors was associated with a 15% lower risk of the study’s composite outcome and a more than 50% reduction in risk of heart failure hospitalizations relative to DPP-4 inhibitor use.

“Overall, patients receiving a SGLT2 inhibitor had a 15% lower risk of the composite of myocardial infarction, stroke, or death from all causes (approximately 3 fewer cases per 1000 person-years) and a 54% lower risk of hospitalizations for heart failure (approximately 4 fewer cases per 1000 person-years) than those receiving a DPP-4 inhibitor,” wrote investigators.

The ascent of SGLT2 inhibitors from antihyperglycemic agent to cardiorenal protective agent has been historic. With a proven benefit across the spectrum of ejection fraction2 and multiple phase 3 trials supporting use in chronic kidney disease, SGLT2 inhibitors have dominated discussion among clinicians practicing in cardiometabolic health in recent years. Still, with the relative novelty of the class, questions remain surrounding effects of use in various subgroups of patient populations with and without diabetes. With this in mind, a trio of investigators from Brigham and Women’s Hospital and Massachusetts General Hospital led by Elisabetta Patorno, MD, DrPH, designed the current study with the intent of exploring the effectiveness and safety profiles across different baseline HbA1c groups.1

Using the Optum Clinformatics Data Mart Database, investigators obtained data related to a cohort of 144,614 adults with type 2 diabetes who initiated treatment with an SGLT2 inhibitor or DPP-4 inhibitor between April 2013-June 2021 for inclusion in the current study. Investigators noted DPP-4 inhibitors were selected as a comparator based on use as a second-line therapy and similar out-of-pocket costs as SGLT2 inhibitors.

The study was designed with a pair of primary effectiveness outcomes of interest. The first was defined a composite cardiovascular end point of myocardial infarction, ischemic or hemorrhagic stroke, and all-cause death. The second was hospitalization for heart failure. Safety outcomes of interest included incidence of hypovolemia, nonvertebral fractures, falls, genital infections, diabetic ketoacidosis (DKA), acute kidney injury (AKI), and lower-limb amputations. Investigators noted incidence rates (IR), hazard ratios (HR), and risk difference (RD) were estimated with control for 128 covariates.

The overall study cohort had a mean age of 62 (SD, 12.4) years and 54% were male. Of the 144,614 adults included in the study, 60,523 had received treatment with a SGLT2 inhibitor and 84,091 had received treatment with a DPP-4 inhibitor. Among the overall cohort, 44,099 had an HbA1c at baselineof less than 7.5%, 52,986 had an HbA1c at baseline between 7.5% and 9%, and 47,529 had an HbA1c at baseline greater than 9%. From the cohort, investigators were able to identify 1:1 propensity score-matched pairs in each baseline HbA1c category, with 24,052 pairs with an HbA1c less than 7.5%, 32,290 pairs with an HbA1c between 7.5% and 9%, and 30,932 pairs with an HbA1c greater than 9%.

Upon analysis, results indicated initiation of SGLT2 inhibitors was associated with a reduction in risk for both the composite outcome (IR per 1000 person-years 17.13 vs 20.18; HR, 0.85 [95% CI, 0.75 to 0.95]; RD, -3.02 [95% CI, -5.23 to -0.80]) and hospitalization for heart failure (IR per 1000 person-years 3.68 vs 8.08, respectively; HR, 0.46 [95% CI, 0.35 to 0.57]; RD -4.37 [95% CI, -5.62 to -3.12]) over a mean follow-up of 8 months compared to initiation of DPP-4i inhibitors, with no evidence of treatment effect heterogeneity across HbA1c levels. Analysis of safety outcomes indicated treatment with SGLT2 inhibitors was associated with an increased risk of genital infections (RD, 37.53 [95% CI, 33.98 to 41.09]; HR, 2.17 [95% CI, 1.98 to 2.36]) and DKA (RD, 0.45 [95% CI, -0.09 to 0.98]; HR, 1.73 [95% CI, 1.06 to 2.43]), but a decreased risk of AKI (RD, -7.60 [95% CI, -10.15 to -5.04]; HR, 0.73 [95% CI, 0.66 to 0.81]) relative to DPP inhibitor use. Investigators pointed out these findings were consistent by HbA1c levels, except for a more pronounced risk of genital infections associated with SGLT2i for HbA1c levels of 7.5% to 9% (IR per 1000 person-years 68.5 vs 22.8, respectively; HR, 3.10 [95% CI, 2.68 to 3.58]; RD, 46.22 [95% CI, 40.54 to 51.90]).1

“This study complements the evidence provided by [cardiovascular outcomes trials] by showing that patients with T2D can benefit from the use of SGLT2i regardless of glycemic control, with no additional increase in the risk of adverse effects in patients with above-target or elevatedHbA1c levels, compared with DPP-4i initiators with similar glycemic control,” wrote investigators.1


  1. D’Andrea E, Wexler DJ, Kim SC, Paik JM, Alt E, Patorno E. Comparing Effectiveness and Safety of SGLT2 Inhibitors vs DPP-4 Inhibitors in Patients With Type 2 Diabetes and Varying Baseline HbA1c Levels. JAMA Intern Med. Published online February 06, 2023. doi:10.1001/jamainternmed.2022.6664
  2. Iapoce C. Meta-analysis indicates SGLT2 inhibitors optimal for heart failure treatment. HCP Live. Published September 23, 2022. Accessed February 6, 2023.