National Kidney Foundation Spring Clinical Meetings 2018

The National Kidney Foundation's Spring Clinical Meetings took place in Austin (TX, USA) from 10 to 14 April 2018. There, Janssen (Beerse, Belgium) presented a new post hoc analysis of the Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) trial. The sodium–glucose cotransporter 2 (SGLT-2) inhibitor Invokana (canagliflozin) was found to confer significant renal benefit in patients with and without baseline kidney disease (defined as estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73m²). For the composite outcome of a 40% decline in eGFR, end-stage renal disease, or renal death, canagliflozin reduced risk by 47% compared with placebo in the cohort with preserved eGFR (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.39–0.73) and lowered risk by 24% in the cohort with reduced eGFR (HR 0.76; 95% CI 0.49–1.17). The P-value for interaction was not significant at 0.28, implying that there was no significant difference in renal protection with canagliflozin across these subgroups. In the CANVAS study population overall, canagliflozin was associated with a 40% relative risk reduction for this renal composite endpoint (HR 0.60; 95% CI 0.47–0.77). The post hoc analysis did find a significant interaction between baseline kidney disease and the urinary albumin to creatinine ratio (UACR), with an amplified benefit in patients with reduced eGFR. With canagliflozin therapy, UACR dropped by a mean 17% among participants with preserved eGFR and by a mean 23% among those with reduced eGFR (P = 0.01 for heterogeneity). Across the entire CANVAS study population, canagliflozin was associated with a mean 18% decline in UACR.

Asia Pacific Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension

The 6th Asia Pacific Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension took place in Shanghai (China) on 11–12 May 2018. Several speakers highlighted recent data on SGLT-2 inhibitors, cardiovascular protection, and class effects, especially in Asian populations. In the meeting's closing keynote, Dr Itamar Raz (Hadassah Medical Center, Jerusalem, Israel) highlighted the benefit of SGLT-2 inhibitors on heart failure, explaining that the US Food and Drug Administration (FDA) initially did not approve coprimary endpoints for the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE) cardiovascular outcomes trial of AstraZeneca's (Cambridge, UK) SGLT-2 inhibitor Farxiga (dapagliflozin). However, after the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial showed a 35% relative risk reduction for heart failure hospitalization (HR 0.65; 95% CI 0.50–0.85; P = 0.002) with Eli Lilly (Indianapolis, IN, USA) and Boehringer Ingelheim's (Ingelheim am Rhein, Germany) Jardiance (empagliflozin),1 the FDA recognized the “huge burden” of heart failure within the diabetes patient population and the potential value of SGLT-2 inhibitors on this front. In addition to the classic three-point major adverse cardiac events (MACE; i.e. non-fatal myocardial infarction (MI), non-fatal stroke, cardiovascular death), DECLARE now has a second composite primary endpoint, consisting of hospitalization for heart failure and cardiovascular death. The DECLARE study is expected to complete in July 2018, with public disclosure of results anticipated in the second half of 2018.

Dr Mikhail Kosiborod (Saint Luke's Health System, Kansas City, MO, USA) positioned heart failure as a key cardiovascular complication of diabetes, proposing that the most promise for treating heart failure with preserved ejection fraction (HFpEF) lies in the cardiometabolic rather than the cardiovascular, with weight loss and SGLT-2 inhibitors rather than traditional heart failure drugs. Dr Kosiborod explained that HFpEF does not respond to the traditional myocardium-targeting heart failure drugs, adding that HFpEF has become the predominant type of heart failure seen in the hospital over the past decade, which he attributed directly to the obesity epidemic. Dr Kosiborod lamented that no randomized controlled trial has examined weight loss as a treatment for HFpEF, but he also highlighted SGLT-2 inhibitors as a beacon of hope, addressing hypertension, diabetes, and obesity. Dr Kosiborod also mentioned the DECLARE trial as the first SGLT-2 inhibitor outcomes trial to collect baseline data on ejection fraction and heart failure type, and to offer more granularity on which type of heart failure is affected with SGLT-2 inhibitor therapy.

Finally, Dr Antonio Ceriello spoke in favor of cardioprotection as a class effect of SGLT-2 inhibitors, citing the observational Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) 2 study2 as the most compelling evidence for a class effect. Because the study included a majority of patients from Asian countries, including South Korea (n = 336 644), Japan (n = 67 780), and Singapore (n = 2726), it covered some less common SGLT-2 inhibitor molecules, including ipragliflozin (8% of participants), tofogliflozin (3%), and luseogliflozin (1%), in addition to the three major SGLT-2 inhibitors on the market (canagliflozin, dapagliflozin, and empagliflozin). In CVD-REAL 2, patients who were initiated on an SGLT-2 inhibitor experienced a significant risk reduction for heart failure hospitalization (HR 0.64; 95% CI 0.50–0.82; P = 0.001 vs other glucose-lowering drugs) and for all-cause death (HR 0.51; 95% CI 0.37–0.70; P < 0.001 vs other glucose-lowering drugs). Dr Ceriello particularly noted the stroke benefit in CVD-REAL 2, where SGLT-2 inhibitors were associated with a 32% relative risk reduction (HR 0.68; 95% CI 0.55–0.84; P < 0.001 vs other glucose-lowering drugs). Stroke events trended in the wrong direction in EMPA-REG OUTCOME, favoring placebo over empagliflozin, so Dr Ceriello suggested that this result is reassuring, especially because stroke is the most prevalent cardiovascular complication in Asia.