HF, Survival Gains From SGLT-2 Inhibitors Seen in Lower-Risk Patients: CVD REAL

Marlene Busko

March 23, 2017

WASHINGTON, DC — In a retrospective study of more than 300,000 patients with type 2 diabetes in clinical practice in the US and Europe, those who were newly prescribed a sodium-glucose cotransporter 2 (SGLT-2) inhibitor — canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga/Forxiga, AstraZeneca), or empagliflozin (Jardiance, Boehringer Ingelheim) — had a lower rate of hospitalization for heart failure and all-cause mortality after up to 4 years than those newly prescribed other glucose-lowering drugs[1].

Dr Mikhail Kosiborod (University of Missouri-Kansas City School of Medicine, Kansas City) presented these results from the Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors (CVD-REAL) trial at the American College of Cardiology (ACC) 2017 Scientific Sessions .

Dr Mikhail Kosiborod

The heart-failure and mortality findings in these patients who mostly had no cardiovascular disease were "remarkably similar" to those seen in the EMPA-REG OUTCOME clinical trial in patients with established cardiovascular disease who were randomized to empagliflozin vs placebo—so the benefits of SGLT-2 inhibitors appear to extend to lower-risk, real-world patients, Kosiborod said.

Moreover, this appears to be a drug-class effect, since "we did not see any significant heterogeneity across countries, despite geographic variations in the use of specific SGLT-2 inhibitor compounds (with predominance of canagliflozin in the United States and dapagliflozin in Europe)," he added.

The consistency across countries "supports the potential benefit," panelist Dr Adrian F Hernandez (Duke Clinical Research Institute, Durham, NC) agreed, speaking to heartwire from Medscape. "We have to see how other [randomized] trials replicate it. Now we see the potential for drugs to actually help with heart failure in patients with diabetes, and not just hurt them, so that's a very positive."

"We need to investigate the impact of these drugs in heart failure, and this gives us a great deal of hope," panelist Dr Mariell Jessup (Leducq Foundation, Boston, MA) echoed to heartwire .

Invited to comment, Dr Silvio E Inzucchi (Yale University School of Medicine, New Haven, CT) who presented the findings from a prespecified secondary analysis of EMPA-REG at the American Heart Association 2015 Scientific Sessions, as well as composite heart-failure outcomes data at this year's ACC meeting[2], noted that CVD-REAL was an observational study but that the upcoming Canagliflozin Cardiovascular Assessment Study (CANVAS) and Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) studies are the actual randomized trials.

A Potential Drug Class Effect in "Real-world" Patients

CVD-REAL aimed to compare the risk of hospitalization for heart failure (the primary end point), death, and combined death and heart failure (the secondary end points) in patients with type 2 diabetes who were newly initiated on an SGLT-2 inhibitor vs another glucose-lowering drug in six countries.

Kosiborod and colleagues analyzed data from well-established registries from when the first SGLT-2 inhibitor was launched in Germany, Sweden, Norway, Denmark, and the UK in November 2012 and when the first SGLT-2 inhibitor (canagliflozin) was launched in the US in March 2013.

Using country-specific propensity scores, the researchers matched 154,523 adults with type 2 diabetes who were new users of SGLT-2 inhibitors with 154,523 others who were new users of other glucose-lowering drugs.

The patients had a mean age of 57, and 44% were women. Only 13% had established cardiovascular disease: acute MI (3%), unstable angina (2%), heart failure (3%), atrial fibrillation (4%), stroke (4%), or peripheral arterial disease (3%). Only 3% had chronic kidney disease.

At baseline, 80% of patients were receiving an antihypertensive medication, two-thirds were receiving a statin, and 80% were receiving metformin.

Overall, about half of the patients who received an SGLT-2 inhibitor received canagliflozin (53%) or dapagliflozin (42%), and few received empagliflozin (5%).

However, prescribing differed in the US vs Europe. In the US, most patients who were given an SGLT-2 inhibitor received canagliflozin (76%), and fewer received dapagliflozin (19%) or empagliflozin (5%).

In Europe, almost all patients given an SGLT-2 inhibitor received dapagliflozin (92%), and few received empagliflozin (6%) or canagliflozin (2%).

Compared with new users of other glucose-lowering drugs, new users of SGLT-2 inhibitors had a 39% lower rate of hospitalization for heart failure (HR 0.61, 95% CI 0.51–0.73; P<0.001).

Similarly, compared with new users of other glucose-lowering drugs, new users of SGLT-2 inhibitors had a 51% lower rate of death from any cause during follow-up (HR 0.49, 95% CI 0.41–0.57; P<0.001). They also had a similar lower risk of the combined end point of death or hospitalization for heart failure.

Waiting for CANVAS, DECLARE . . . 

"Given these results—and there are several trials going on in this area in heart failure—should we just tell people not to enroll in those trials?" Hernandez asked facetiously.

"I think it's important that the question is answered definitively from multiple sources." Kosiborod replied. "I think you need more clinical trials; this class has a really remarkable potential to transform how we manage diabetes and patient outcomes and we need more and more data from other sources."

"We have a little bit of data already that the effect we see in patients with diabetes who develop heart failure with diabetic drugs is different from that in the patients who have heart failure and get a diabetic drug, so I would second your idea that we need to forge ahead and really understand what these drugs are doing in patients with established heart failure," Jessup added.

"What you're really seeing in terms of heart-failure hospitalization is really a heart-failure prevention signal rather than a heart-failure treatment signal," Kosiborod observed.

Invited to put prescribing into perspective, Inzucchi noted the following:

"The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend metformin as initial therapy, and a second therapy such as an SGLT-2 inhibitor can be added if the patient does not reach their HbA1c target at 3 months. However, other drug categories (sulfonylureas, the thiazolidinedione pioglitazone, a [dipeptidyl peptidase-4 ] DPP-4 inhibitor, a [glucagonlike peptide 1] GLP-1 agonist, or basal insulin) could also be used based on various factors—individualizing treatment to the patient is key.

"SGLT-2 inhibitors' benefits include a low risk of hypoglycemia and a modest reduction in blood pressure and weight. But they are expensive and associated with an increase in genitourinary infections.

"In the EMPA-REG trial, therapy with the SGLT-2 inhibitor empagliflozin reduced CV death and heart-failure hospitalization in patients with type 2 diabetes and established CVD.

"The recently presented CVD-REAL study, which was retrospective and observational, suggests that these benefits may indeed be a class effect. However, we must wait for the randomized clinical trials involving canagliflozin (CANVAS) and dapagliflozin (DECLARE) before we know this for sure," he said.

The trial was funded by AstraZeneca. Kosiborod reports receiving consultant fees/honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Glytec, Merck, Novo Nordisk, Sanofi, and ZS Pharma; research grants from AstraZeneca, Boehringer Ingelheim, Gilead, and Sanofi; and being on the speaker's bureau for Amgen. Hernandez reports receiving consultant fees/honoraria from Amgen, Bayer, Boehringer Engelheim, Boston Scientific, Gilead, Merck, Novartis, Pfizer, Pluristem Therapeutics, and Sensible Medical Innovation; and research grants from Abbott Evalve, Aires Pharmaceuticals, Amgen, Amylin, AstraZeneca, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, Portola, Roche and Scios. Jessup reports receiving a salary from the Leducq Foundation. Inzucchi reports receiving consultant fees/honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lexicon, Merck, Poxel, Sanofi, and VTV Therapeutics; being on the data safety monitoring board of Intarcia and Novo Nordisk; and receiving a salary from Elsevier.

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