Cardiovascular Protection from SGLT2 Inhibitors

A new meta-analysis has added to accumulating evidence that SGLT2 inhibitors may have a net protective effect against cardiovascular (CV) events and all-cause mortality. The study was published online in the Lancet Diabetes Endocrinology.¹

“The evidence suggests net protection of SGLT2 inhibitors against cardiovascular outcomes and death. Although treatment with SGLT2 inhibitors does cause important adverse effects, protection against vascular events and death will probably override the risk of harm in many patients with type 2 diabetes,” wrote first author Jason Wu, PhD, of the George Institute for Global Health, University of Sydney (Sydney, Australia), and colleagues.

The results come on the heels of other studies pointing to the CV benefits of SGLT2 inhibitors. The CV outcomes trial EMPA-REG recently reported that empagliflozin decreased risk of all-cause mortality, CV death, and hospitalization for heart failure, compared to placebo.² Based on these results, in January 2016 the FDA accepted Eli Lilly’s request for a supplemental new drug application for empagliflozin for lowering CV risk. 

So far, empagliflozin is the only SGLT2 inhibitor for which long-term CV safety data have been reported. However, another metanalysis published in February 2016 in Cardiovascular Diabetology suggested dapagliflozin may also have a beneficial effect on CV risk.³

In the current study, researchers searched Medline, Embase, and the Cochrane Library, as well as US, European, and Japanese regulatory authority websites for randomized controlled trials (RCTs) of SGLT2 inhibitors compared to control (placebo or another active drug) published in any language between January 1950 and September 2015. Data in the analysis came from six regulatory submission (37,525 patients) and 57 published RCTs (33,385 patients), and covered seven different SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and ertugliflozin). The primary outcome was major adverse cardiovascular events (MACE): CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. 

Key Results:

• MACE: 16% decreased risk (relative risk 0.84 [95% CI 0.75–0.95]; P=0.006)

• Cardiovascular death: 37% decreased risk (0.63 [0.51–0.77]; P<0.0001)

• Heart failure: 35% decreased risk (0.65 [0.50–0.85]; P=0.002) (note: data available only for empagliflozin)

• All-cause death: 29% decreased risk (0.71 [0.61–0.83]; P<0.0001)

• Non-fatal myocardial infarction: No significant effect (0.88 [0.72–1.07]; P=0.18)

• Hospital admission for unstable angina: No significant effect (0.95 [0.73–1.23]; P=0.70)

• Non-fatal stroke: 30% increased risk (1.30 [1.00–1.68]; P=0.049)

• No clear evidence that CV outcomes or death varied between different SGLT2 inhibitors

• Other safety outcomes:

♦ Consistently increased risk of genital infections in RCTs and regulatory submission data

♦ Strong evidence suggesting increased risk of urinary tract infections and volume depletion events in regulatory submission data, but not in RCT data

♦ No significant effects on cancer, bone fracture, hypoglycemia, venous thromboembolism, acidosis, and kidney disease

The results suggest a CV protective affect for SGLT2 inhibitors that is greater than expected from glucose lowering alone, according to the authors. They conjectured that the blood pressure lowering effect of SGLT2 inhibitors may drive these results. Consistent evidence has shown that lowering blood pressure can prevent CV events in patients with diabetes. SGLT2 inhibition could also decrease volume expansion, which may explain the beneficial effects on heart failure seen with empagliflozin, and could provide another explanation for the CV benefits of SGLT2 inhibitors.

However, the increased risk of stroke found in this study is surprising, given the beneficial effect of blood pressure lowering on stroke. Hemoconcentration related to SGLT2 inhibition could be one explanation, according to the authors. 

The small number of events for rare safety outcomes like acidosis limit these results. In addition, the CV results were driven largely by outcomes from empagliflozin reported from a single study, the EMPA-REG trial. Results for heart failure were based solely on available data from empagliflozin.

More studies are needed to confirm these findings across the drug class. Data are also needed about possible differences in side effect profiles between drugs of this class, as well as the relative benefits and risks for a wide range of patient groups.  

Nevertheless, the authors concluded: “Although the capacity to draw conclusions about the long-term effects of SGLT2 inhibitors as a class is still limited by the available data, our overview findings suggest that accumulating data will lend support to SGLT2 inhibitors as the first drug class targeting glycaemia to deliver cardiovascular protection and that SGLT2 inhibition will become a mainstay of treatment for patients with type 2 diabetes at high risk of cardiovascular events.”

Take-home Points

• A new meta-analysis has added to accumulating evidence that SGLT2 inhibitors may have a net protective effect against cardiovascular (CV) events and all-cause mortality.

• Results showed that SGLT2 inhibitors significantly decreased MACE, cardiovascular death, and all-cause mortality.

• The risk of heart failure also decreased, but data were available only for empagliflozin.

• SGLT2 inhibitor use was linked to significantly increased risk of non-fatal stroke.

• CV results were driven largely by outcomes from empagliflozin reported from a single study, and more studies are needed to confirm these findings across the drug class.

Dr. Blomster is an employee of AstraZeneca Research and Development. One or more authors reports consulting, personal fees, grants, fellowships, and/or steering committee membership for one or more of the following: Janssen, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck, Abbvie, Astellas, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, Servier, Itrim, Dr Reddy's Laboratories, Merck Schering-Plough, Roche, Abbott, Novartis, National Health and Medical Research Council of Australia Research Fellowships.

References:

1. Wu JH, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016 Mar 18.

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. 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.