Sodium-glucose cotransporter 2 inhibitors associated with reduced mortality compared with sulfonylureas in patients with type 2 diabetes

1. In patients with type 2 diabetes, use of sodium-glucose cotransporter 2 inhibitors was associated with reduced risk of all-cause mortality compared with sulfonylureas, regardless of cardiovascular disease status, estimated glomerular filtration rate category, and albuminuria status.

2. The addition of SGLT2 inhibitor as a second-line antihyperglycemic agent with metformin was associated with a reduced risk of all-cause mortality compared to SGLT2 inhibitor monotherapy.

Evidence Rating Level: 2 (Good)

Study Rundown: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antihyperglycemic medication that significantly reduces the risk of adverse cardiovascular and renal events in patients with type 2 diabetes. Despite this, randomized clinical trials on SGLT2 inhibitors have only assessed the effect of SGLT2 inhibitors vs placebo and no trials have offered a direct comparison on the effectiveness of SGLT2 inhibitors vs sulfonylureas – the second most widely used class of antihyperglycemic medication after metformin in diabetes. Thus, this cohort study used the US Department of Veterans Affairs electronic health care databases to evaluate the comparative effectiveness of SGLT2 inhibitors vs sulfonylureas associated with the risk of all-cause mortality in patients with type 2 diabetes receiving metformin therapy. The main measure of the analysis was all-cause mortality among cohorts. Among 128,293 patients with type 2 diabetes receiving metformin, use of SGLT2 inhibitors was associated with a significant reduction in risk of all-cause mortality compared with sulfonylureas, regardless of cardiovascular disease status, estimated glomerular filtration rate category, and albuminuria status. Furthermore, the addition of SGLT2 inhibitor as a second-line antihyperglycemic agent with metformin was associated with a reduced risk of all-cause mortality compared to SGLT2 inhibitor monotherapy. These results provide real-world data on the comparative efficacy of SGLT2 inhibitors vs sulfonylureas, which may help guide clinical decision-making when choosing antihyperglycemic agent(s) in individuals with type 2 diabetes. A limitation of this study was the reliance on observational data from the US Department of Veterans Affairs as this population is largely comprised of older, White, male participants, limiting the generalizability of the study findings.

Click to read the study in JAMA Internal Medicine

Click to read an accompanying editorial in JAMA Internal Medicine

Relevant Reading: Comparative effectiveness of the sodium-glucose cotransporter 2 inhibitor empagliflozin versus other antihyperglycemics on risk of major adverse kidney events

In-Depth [retrospective cohort]: This comparative efficacy study enrolled a total of 128,293 individuals (mean [SD] age, 64.60 [9.84] years; 122,096 [95.17%] men) from the US Department of Veterans Affairs between October 2016 and February 2020 with follow up until January 2021. Predefined variables and covariates identified via a high-dimensional variable selection algorithm were used to build propensity scores in the analysis. The overlap weighting method based on the propensity scores was then used to estimate the intention-to-treat effect sizes of SGLT2 inhibitor vs sulfonylurea therapy. Finally, the inverse probability of the treatment adherence weighting method was used to estimate the per-protocol effect sizes. Among 128,293 enrolled patients, 23,870 received SGLT2 inhibitors and 104,423 received sulfonylureas. SGLT2 inhibitors were associated with reduced risk of all-cause mortality (HR, 0.81; 95%CI, 0.75-0.87) compared to sulfonylureas, with an event rate difference of -5.15 (95%CI, -7.16 to -3.02) deaths per 1,000 person-years. SGLT2 inhibitors were also associated with a reduced risk of mortality regardless of cardiovascular disease status, estimated glomerular filtration rate category and albuminuria status. In per-protocol analyses, long-term use of SGLT2 inhibitors was associated with a reduced risk of mortality compared with long-term use of sulfonylureas (HR, 0.66; 95%CI, 0.60-0.74; event rate difference, -10.10; 95%CI, -12.97 to -7.24 deaths per 1,000 person-years). In additional per-protocol analyses, persistent use of SGLT2 inhibitors with metformin was associated with a reduced risk of mortality compared with SGLT2 inhibitor monotherapy (HR, 0.70; 95%CI, 0.50-0.97; event rate difference, -7.62; 95%CI, -17.12 to -0.48 deaths per 1,000 person-years).

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