Cardiovascular Impact of Dapagliflozin

A new metanalysis has shown no increased risk of major adverse cardiovascular events (MACE: CVD death, MI, stroke) for the SGLT2 inhibitor dapagliflozin compared to control in patients with varying levels of cardiovascular (CV) risk. Results also suggest that dapagliflozin may have a beneficial effect on CV risk.

The article was published online in Cardiovascular Diabetology.

“In this meta-analysis of data from across the dapagliflozin clinical development programme, including high CV risk patients, there was no evidence for increased risk of major adverse CV events with dapagliflozin. The results suggest the potential for a beneficial CV effect by dapagliflozin which is consistent with the multifactorial benefits on CV risk factors associated with SGLT2 inhibitors,” wrote first author Christian Sonesson, PhD, of Astrazeneca, and colleagues.

Other studies have suggested a role for SGLT2 inhibitors in improving CV outcomes. The EMPA-REG trial recently found that empagliflozin decreased risk of all-cause mortality, CV death, and hospitalization for heart failure, compared to placebo.² Based on results of this trial, in January 2016 the FDA accepted a supplemental new drug application for empagliflozin for lowering CV risk.

Dapagliflozin has a similar profile to empagliflozin, but whether or not it has a positive effect on CV outcomes remains under investigation. Like other members of this class, dapagliflozin has low risk for hypoglycemia, and affects various risk factors for cardiovascular disease (CVD), including lowering blood pressure, decreasing weight and waist circumference, and decreasing albuminuria and serum uric acid levels.

The meta-analysis focused on subgroups at increased CV risk in 21 phase2b/3 clinical trials covering 9339 patients (dapagliflozin 2.5-10 mg: 5936 patients; control: 3403 patients). Participants had type 2 diabetes and different levels of CV risk based on age, smoking, history of cardiovascular disease (CVD), hypertension or dyslipidaemia, first degree relative with a history of premature coronary heart disease, and baseline estimated glomerular filtration rate. 

Key results for dapagliflozin vs control suggested:

• No increased CV risk

• Potential CV benefit

♦ Overall population: 23% lower risk of MACE [hazard ratio (HR) 0.77; 95 % CI (0.54, 1.10)]

♦ Patients with history of CVD: 20% lower risk of MACE [HR 0.80 (0.53, 1.22)]

♦ Elderly patients with a history of CVD and hypertension: 8% lower risk of MACE (HR 0.92, 95% CI 0.512-1.640)

♦ Similar findings in patients with different levels of CV risk, including age, number and type of past CVD events, and number of current CV risk factors.

• No increased risk of MACE in patients with past hypoglycaemic events, compared to those without 

These results are consistent with meta-analyses of the CV effect of other SGLT2 inhibitors, according to the authors.

Limitations include those inherent meta-analyses: variability in sample populations, post hoc analyses in some cases, and relative low number of events.

“The CV effects of SGLT2 inhibitors calls for further studies and confirmation,” the authors concluded.

The DECLARE-TIMI, a prospective CV outcomes trial, is underway and is looking at the effect of dapagliflozin on CV outcomes in patients with CVD or multiple risk factors. Enrollment is estimated to be over 17,000, and it is expected to be completed by 2019.

Take-home Points

• Meta-analysis of 21 clinical trials found no increased CV risk, and potential CV benefit with dapagliflozin in the overall population.

• Similar findings resulted from subgroup analyses of patients at increased CV risk.

• There was no increased risk of MACE in patients with past hypoglycaemic events, compared to those without. 

The authors are employees and stock/shareholders of AstraZeneca, the maker of dapagliflozin.

References:

1. Sonesson C, et al. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016 Feb 19;15(1):37.

2. Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 26; 373(22):2117-2128.

3. Langkilde AM, et al. Abstract 11105: cardiovascular safety of the SGLT2 inhibitor dapagliflozin: meta-analysis with >6000 patient-years exposure. Presented at the American Heart Association 2013 Scientific Sessions, Dallas, TX, November 16–20, 2013; 2013.