Do SGLT2 inhibitors decrease cardiovascular events in patients with diabetes and prior cardiovascular disease? What about patients with heart failure with reduced ejection fraction?

Cardiovascular disease is the leading cause of death in patients with diabetes. Hypoglycemic drugs, through various mechanisms, lower blood glucose and effectively reduce microvascular outcomes including retinopathy, and nephropathy. However, the evidence for improvement in macrovascular events has been less consistent. In fact, it was shown that some hypoglycemic drugs, while effectively lowering blood glucose, actually increase adverse cardiovascular events. For instance the thiazolidinediones were shown to increase the risk of CHF. For this reason, in 2008 the FDA mandated that all new hypoglycemic agents needed to demonstrate cardiovascular safety. The SGLT2 inhibitors are a class of medications that block the reabsorption of glucose at the level of the proximal renal tubule. This results in glycosuria and an effective reduction in A1c. EMPA-REG OUTCOME and CANVAS investigated the cardiovascular safety of these medications, with encouraging results. These encouraging results were, in large part, driven by reductions in hospitalizations for heart failure, a secondary finding that the authors of DAPA-HF studied in patients with heart failure, regardless of diabetes status.

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By the end of this post, you should have a basic understanding of these three trials, and an idea of how you might counsel Carmel and Hartman.

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The Trials

• EMPA-REG OUTCOME (2015)
• CANVAS (2017)
• CREDENCE (2019)

EMPA-REG (2015)

POPULATION (n=7,020)

• Adults w DM2 + cardiovascular disease (MI, multivessel CAD, stroke, PAD)

INTERVENTION

• Empagliflozin 10mg daily
• Empagliflozin 25mg daily
• Placebo

OUTCOME

• Pooled empagliflozin groups had a significant reduction in composite of CV mortality/non-fatal MI/non-fatal stroke compared to placebo after a median of 3.1 years [10.5% vs 12.1%]
• All-cause mortality significantly lower in empagliflozin group (secondary outcome)
• HF hospitalization significantly lower in empagliflozin group (secondary outcome)

CRITICISM

• The individual empagliflozin groups did not meet statistical significance
• Control group received placebo and were not specifically assigned another approved oral hypoglycemic (though physicians were allowed to titrate other DM meds)

OTHER POINTS

• Patients had baseline CV disease, therefore difficult to generalize to healthier population
• Significant increase in genital mycotic infections with empagliflozin 
• Follow-up study showed slower progression of kidney disease with empagliflozin

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CANVAS (2017)

POPULATION (n=10,142)

• Patients older than 30 with DM2 + known cardiovascular disease (MI, multivessel CAD, stroke, PAD) 
• Adults older than 50 with DM2 + 2 additional CV risk factors (ie HLD, HTN, smoking…)

INTERVENTION

• Canagliflozin 300mg 
• Canagliflozin 100mg 
• Placebo

OUTCOME

• Pooled canagliflozin groups had a significant reduction in composite of CV mortality/non-fatal MI/non-fatal stroke compared to placebo after a mean of 3.6 years [26.9 vs 31.5 events per 1000 patient years]
• Progression of albuminuria significantly reduced in canagliflozin group (secondary outcome)
• HF hospitalization significantly lower in canagliflozin group (secondary outcome)

CRITICISM

• The individual canagliflozin groups did not meet statistical significance
• Control group received placebo and were not specifically assigned another approved oral hypoglycemic (though physicians were allowed to titrate other DM meds)

OTHER POINTS

• Compared with EMPA-REG, which only included patients with known CVD, this trial also included patients with CVD risk factors alone (ie without actual CVD)
• Significant increase in genital mycotic infections with canagliflozin
• Significant increase in lower extremity amputations with canagliflozin

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DAPA-HF (2019)

POPULATION

• Adults with NYHA class II, III, or IV heart failure 
• Ejection fraction less than 40% 
• Already on evidence based heart failure medical therapy 
• Patients were both diabetic and non-diabetic

INTERVENTION

• Dapagliflozin 10mg daily
• Placebo daily

OUTCOMES

• Dapagliflozin led to a significant reduction in a composite of worsening heart failure or cardiovascular death compared to placebo after a median of 1.5 years [16.3% vs. 21.2%]
• Decrease in death from a cardiovascular cause in dapaglifozin group (secondary outcome)
• Decrease in overall mortality in dapaglifozin group (secondary outcome)

CRITICISMS

• Baseline heart rate and BP were slightly above goal in both groups
• Most patients had moderate heart failure, so further study in patients with more severe disease is needed
• Background use of neprolysin inhibitor was low

OTHER POINTS

• Magnitude of benefit of the above outcomes was similar regardless of presence or absence of diabetes
• Patients with a GFR less than 30 were excluded 
• No increase in adverse events including DKA, volume depletion, renal adverse events, amputation, Fournier’s gangrene

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The Bottom Line

In conclusion, we now have excellent data in the form of three large, well designed, randomized controlled trials that show SGLT2 inhibitors effectively lower the HbA1C and reduce cardiovascular risk. Furthermore, there appears to be a role for these agents as primary heart failure medications in patients with reduced ejection fraction heart failure. A shift towards more widespread use in patients with diabetes and underlying cardiovascular disease, as well as HFrEF patients with or without diabetes seems warranted. Future editions of “The Evidence” will also touch on the renal protective effects noted in these trials. 

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Experts’ Opinions

Jane Weinreb, MD

Chief, Division of Endocrinology, Diabetes and Metabolism
VA Greater Los Angeles Healthcare System
Clinical Professor of Medicine
David Geffen School of Medicine at UCLA

Recent cardiovascular outcome studies with new anti-hyperglycemic medications have provided an opportunity to look beyond simply improved glycemic control in diabetes management. The relatively brief duration and minimal A1C separation seen in the SGLT2 inhibitor trials noted above indicate that these agents act via a nonglycemic mechanism to decrease CV events and progression of renal disease. Potential mechanisms include osmotic diuresis, reduced intraglomerular pressure, weight reduction, and reduction in blood pressure. Empagliflozin now carries an FDA indication “for reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease.” Renal benefits have also been demonstrated with empagliflozin, canagliflozin and dapagliflozin, despite a background of renin-angiotensin-aldosterone blockade, making this the first class of agents in many years to display an impact on diabetic nephropathy. In light of the aforementioned data, the American Diabetes Association has positioned the SGLT2 inhibitors as second line therapy, after metformin, for treatment of type 2 diabetes in patients with ASCVD, CKD or CHF. As noted above, these drugs have imposing side effects as well, and it is prudent for us to discuss with our patients the balance of noted benefits against the increased risk of Fournier’s gangrene, amputation, euglycemic DKA, genital mycotic infections and orthostatic hypotension.

My clinical take on this: I routinely consider addition of empagliflozin (our VA formulary SGLT2 inhibitor) as second line therapy (after metformin) in type 2 diabetic patients with known CAD, CHF, or CKD with an eGFR of >45 ml/minute who are not at glycemic goal on metformin alone; I tend to avoid it in men who are uncircumcised and hence at high risk of ballinitis, patients with a large pannus with underlying moisture, patients with marginal blood pressure, and patients with insulin deficiency.

No conflicts of interest.

Gregg C. Fonarow, MD, FACC, FAHA, FHFSA

Eliot Corday Professor of Cardiovascular Medicine and Science
Director, Ahmanson-UCLA Cardiomyopathy Center
Chief (Interim), UCLA Division of Cardiology
Co-Director, UCLA Preventative Cardiology Program

I believe that the DAPA-HF trial now establishes SGLT2 inhibitors as a heart failure-protective, cardiovascular and all-cause mortality-reducing therapy for heart failure with reduced ejection fraction. SGLT2 inhibitors joins other classes of drugs, like angiotensin-receptor neprilysin inhibitors (ARNI), beta-blockers and aldosterone antagonists as part of comprehensive disease modifying medical therapy for heart failure with reduced ejection fraction. The benefits of treatment outweighed the risks without significant heterogeneity across clinically relevant subgroups. This new trial now establishes a new standard of care of “quadruple” therapy for heart failure with reduced ejection fraction: ARNI, beta blocker, aldosterone antagonist, and SGLT2 inhibitor. When used together in eligible heart failure patients these therapies together can lower the relative risk of all-cause mortality by 73%, with a number needed to treat (NNT) to save a life over 24 months of 3.9. Compared to an ACE inhibitor + beta blocker therapy, quadruple therapy extends median survival by over 6 years.

These new findings are practice changing and make it clear that all physicians involved in the care of patients with heart failure with reduced ejection fraction should be prescribing these medications to eligible patients without contraindications.

There is also substantial promise that this class of medications may also benefit patients with heart failure with preserved ejection fraction, with or without diabetes. However, that remains to be demonstrated in a series of ongoing randomized clinical trials.

Dr. Fonarow reports research funding from the NIH and serving as a consultant for Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, Merck, and Novartis.

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