Body Weight Related to Beneficial Effects of SGLT-2 Inhibitors in Patients with Type 2 Diabetes in New Analysis

Results from a meta-regression analysis suggest that the beneficial effects of sodium glucose cotransporter-2 inhibitors (SGLT-2is) in reducing cardiovascular (CV) death and hospitalization due to heart failure (hHF) in patients with type 2 diabetes (T2D) are related to body weight.

Previous CV outcome trials with SGLT-2is have shown a positive impact on microvascular and macrovascular complications of T2D, and most “analyses suggest that these benefits are independent of achieving metabolic control,” wrote first author Samit Ghosal, MD, MSc, endocrinologist, Nightingale Hospital, Kolkata, India, and colleagues in the journal ESC Heart Failure.

“It could be hypothesized,” the authors continued, “that the positive impact of SGLT-2is on CV health or hospitalization due to heart failure (hHF) endpoints in T2D are not exclusively because of these drugs on the heart but because of their known salutary effects on blood glucose, weight, and blood pressure control.”

Researchers conducted the current analysis to examine the association between metabolic components positively influenced by SGLT-2is and a reduction in CV death or hHF. Ghosal and colleagues did a database search using the Cochrane Library and identified 5 relevant CV outcomes studies to include: EMPA-REG, CANVAS, DECLARE TIMI-58, CREDENCE, and VERTIS CV. Heterogeneity was quantified using Q statistics, according to investigators.

A pooled population of 46 969 patients from the 5 studies were included for analysis, of whom 26 765 were in the SGLT-2i group and 20 204 in the placebo group. The mean age of participants ranged from 62.9 to 64.4 years, and the duration of follow-up ranged from 2.62 to 4.2 years. The mean baseline HbA1c ranged from 8.07% to 8.3%, and mean baseline body mass index and systolic blood pressure (SBP) ranged from 30.6 kg/m2 to 32.1 kg/m2 and 133 mmHg to 139 mmHg, respectively.


Result showed that there was a significant 23% reduction in CV deaths or hHFs in the SGLT-2i arm compared with the placebo arm (hazard ratio [HR] 0.77, 95% CI 0.70-0.85). However, the research team noted that the Q statistics (8.06) and the associated P-value (.09) indicated that the effect size of CV death or hHF varied significantly across the 5 studies. Investigators therefore identified 3 covariates that could have been predictive of positive outcomes among participants who received SGLT2is compared with placebo: HbA1c, SBP, and weight.

Each covariate was assessed separately. The model using the difference in HbA1c (P=.17) between the SGLT-2i and placebo group or difference in SBP (P=.86) did not explain the variance in the observed effect size. The difference in weight, however, between the 2 cohorts, correlated significantly with the variance in CV death or hHF effect size (95% CI 0.05-0.32, P<.01).

Moreover, an R2 of 1.00 “strongly supported” the weight differential explaining the variance between the observed and true effect size, ruling out sampling error. Also, the coefficient of the weight moderator was 0.18, “indicating a positive correlation between the weight differential and the HR for CV death or hHF,” wrote Ghosal and colleagues.

“It appears that the salutary effects of SGLT-2is in reducing CV death and HF are related to their effect on body weight. This hypothesis, however, needs further study,” concluded investigators.

Reference: Ghosal S, Sinha B, Mukherjee R. Heterogeneity in cardiovascular death or hospitalization for heart failure benefits with flozins is linked to weight. ESC Heart Fail. Published online January 27, 2023. doi:10.1002/ehf2.14296.

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