Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE–TIMI 58 trial

Abstract

Aims We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). Methods and results DECLARE–TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: −1.9 to −2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. Conclusions In DECLARE–TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. Clinical trial registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.

Quételet (body mass) index and effects of dapagliflozin in chronic kidney disease

“…Relative benefits of dapagliflozin were observed across the spectrum of BMI, and within BMI strata, among women and men and participants with and without diabetes. Absolute benefits of dapagliflozin on the composite cardiovascular endpoint were highest in participants with grade 2/3 obesity, confirming findings recently published by Oyama et al from the DECLARE‐TIMI 58 trial 29 . We observed similar results across other, exploratory composite endpoints, including the traditional major adverse cardiovascular event (MACE) endpoint of cardiovascular death or non‐fatal myocardial infarction or stroke.…”

“…Absolute benefits of dapagliflozin on the composite cardiovascular endpoint were highest in participants with grade 2/3 obesity, confirming findings recently published by Oyama et al from the DECLARE-TIMI 58 trial. 29 We observed similar results across other, exploratory composite endpoints, including the traditional major adverse cardiovascular event (MACE) endpoint of cardiovascular death or non-fatal myocardial infarction or stroke. Serious adverse events were seen more frequently among obese participants, although rates were numerically lower in participants randomized to dapagliflozin within each BMI category.…”

Sodium‐Glucose Cotransporter 2 Inhibitor Canagliflozin Antagonizes Salt‐Sensitive Hypertension Through Modifying Transient Receptor Potential Channels 3 Mediated Vascular Calcium Handling

“…In recent years, several large clinical trials showed that SGLT2i displayed excellent cardiorenal protective effects in patients with and without diabetes. 7 , 8 , 9 , 10 Because SGLT2 mainly locates in the proximal tubules, its lowering BP and cardiorenal protective effect is thought to depend on its role in promoting urinary sodium and glucose excretion and weight loss. 44 , 45 , 46 In this study, canagliflozin significantly reduced BP in SS with hypertension but not in SS‐19 BN .…”

“…Recently, a new series of antidiabetic drugs, SGLT2 (sodium‐glucose cotransporter 2) inhibitors (SGLT2i), including canagliflozin, dapagliflozin, and empagliflozin, display impressive renal and cardiovascular benefits and reduce all‐cause and cardiovascular death in patients with and without diabetes from several large‐scale clinical trials. 7 , 8 , 9 , 10 The potential mechanisms that account for the cardio‐beneficial effect of SGLT2i might include lowering plasma volume, lowering blood glucose, increasing urinary sodium excretion, and reducing renin‐angiotensin system activation, all of which might help to lower BP. 11 However, it remains elusive whether SGLT2i might directly act on vascular function and BP.…”

Moving the Needle on Atherosclerotic Cardiovascular Disease and Heart Failure with Influenza Vaccination

“…The investigators did not find a significant difference between the strategies in reducing all-cause mortality or cardiopulmonary hospitalizations in this high-risk group. The possible reasons for this are multifactorial, notwithstanding the wider strain coverage conferred by the standard-dose quadrivalent vaccine [ 59 , 60 ••].…”