SGLT2 inhibitors benefit patients with type 2 diabetes, regardless of glycemic control

SGLT2 inhibitors were associated with a lower risk for major adverse cardiovascular events and heart failure hospitalization compared with DPP-4 inhibitors among patients with type 2 diabetes, regardless of baseline HbA1c levels, data show

Elvira D’Andrea, MD, PhD, a researcher at Brigham and Women’s Hospital and Harvard Medical School, and colleagues noted that SGLT2 inhibitors have demonstrated “a cardiorenal protective effect” in patients with type 2 diabetes and cardiovascular or kidney conditions.

However, the researchers reported that associations between the performance of SGLT2 inhibitors and varying levels of HbA1c remained unclear. Additionally, evidence suggests that SGLT2 inhibitors may increase the risk for adverse events in patients with lower glycemic control.

“Since [SGLT2 inhibitors] induce a glycosuric response by reducing kidney tubular glucose reabsorption, those medications can have a more pronounced effect on hyperglycemia in patients with poor glycemic control due to the increased amount of filtered glucose,” they wrote.

D’Andrea and colleagues compared the effects of SGLT2 inhibitors vs. DPP-4 inhibitors on two adverse outcomes: modified major adverse cardiovascular events (MACE), “a composite cardiovascular end point of myocardial infarction, ischemic or hemorrhagic stroke and all-cause death,” as well as hospitalization heart failure (HHF).

The study cohort consisted of 144,614 participants aged 18 years or older who had started treatment with SGLT2 (n = 60,523) or DPP-4 (n = 84,091) inhibitors between April 1, 2013, and June 30, 2021.The participants had a mean age of 62 years and 54% were men.

Of the total study group, 87,274 patients were propensity score-matched in a 1:1 ratio:

• 24,052 had controlled HbA1c;
• 32,290 had above-target HbA1c; and
• 30,932 had elevated baseline HbA1c.

The researchers found that the incident rates per 1,000 in-person years for modified MACE were 17.13 among patients who received SGLT2 inhibitors vs. 20.18 among those who received DPP-4 inhibitors. Overall, new SGLT2 inhibitor users had a 15% reduced risk for modified MACE compared with DPP-4 users (HR = 0.85; 95% CI, 0.75-0.95), with about three fewer events per 1,000 person-years.

For HHF, there were 3.68 events per 1,000 person-years in the SGLT2 inhibitor group vs. 8.08 events per 1,000 person-years in the DPP-4 inhibitor group. The risk for HHF was reduced by 54% in the SGLT2 inhibitor group vs. DPP-4 inhibitor group (HR = 0.46; 95% CI, 0.35-0.57), with approximately four fewer cases per 1,000 person-years.

Compared with DPP-4 inhibitor users, SGLT2 inhibitor users had a 2.7-fold increased risk for genital infections and a 1.7-fold increased risk for diabetic ketoacidosis. However, SGLT2 inhibitor users had a 27% decreased risk for acute kidney injury compared with DPP-4 users (HR = 0.73; 95% CI, 0.66-0.81).

“Similar results were obtained in subgroup analyses by HbA1c, with no evidence of treatment effect heterogeneity by HbA1c,” D’Andrea and colleagues wrote.

The study had several limitations, which included potential confounding, the stratification of HbA1c levels — which reduced the precision of some subgroup outcomes — and a short mean follow-up time, according to the researchers.

D’Andrea and colleagues concluded that the study complements prior evidence “by showing that patients with [type 2 diabetes] can benefit from the use of [SGLT2 inhibitors] regardless of glycemic control, with no additional increase in the risk of adverse effects in patients with above-target or elevated HbA1c levels, compared with [DPP-4 inhibitor] initiators with similar glycemic control.”