Canagliflozin Helps Heart, Kidneys Even in
'Well-Controlled' Diabetes

Marlene Busko

December 09, 2019

PHILADELPHIA — The SGLT2 inhibitor canagliflozin (Invokana, Janssen) reduced the risk of cardiovascular (CV) and renal events in patients with type 2 diabetes and chronic kidney disease (CKD), even in a subgroup with well-controlled diabetes, concludes a deep dive into the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial.

Christopher P. Cannon, MD, a cardiologist and researcher at Brigham and Women's Hospital, Boston, Massachusetts, presented the study in an oral session at the American Heart Association (AHA) Scientific Sessions 2019 and it was simultaneously published online November 11 in the journal Circulation.

A second study by C. David Mazer, MD, of St. Michael's Hospital, Toronto, Canada, and colleagues, also presented at the scientific sessions and published online in the same issue of Circulation, suggests that SGLT2 inhibitors increase levels of erythropoietin (EPO) secreted by the kidneys, which may partly explain their benefits apart from lowering blood glucose levels.

SGLT2 inhibitors are currently approved for the treatment of type 2 diabetes.

Cannon told theheart.org | Medscape Cardiology in an email that he has already observed a change in prescribing.

"We now are using this more related to patient risk, even we cardiologists, and I know of many nephrologists who are starting to prescribe" an SGLT2 inhibitor, he noted.

It does take collaboration with the primary care physician and endocrinologist, Cannon observed, "but that is all good for patient care — that we all work together."

"I often see patients post-MI [myocardial infarction] on metformin and/or other meds, who have an A1c of 6.8%," he continued, "and these data now show that they too can safely receive SGLT2 inhibitors and get the benefits."  

Asked for his opinion, Subodh Verma, MD, said in an email to theheart.org | Medscape Cardiology: "The paper quite elegantly demonstrates that the benefits of the SGLT2 inhibitor canagliflozin are independent of baseline glycemic control in the context of diabetes.

"I believe these data should help physicians overcome inertia in the treatment of patients with diabetes," added Verma, a cardiac surgeon and researcher at St. Michael's Hospital and professor at the University of Toronto who was not involved with the CREDENCE trial research but was a coauthor of the Mazer et al study investigating SGLT2 inhibitors and their effect on erythropoietin levels.

"If the patient is not on an SGLT2 inhibitor and has diabetes, if there are no contraindications, they should be treated with these agents for renal and cardiac protection."

Study Gives CREDENCE to Benefits Independent of A1c

As previously reported and published in the New England Journal of Medicine, patients in CREDENCE had CKD and type 2 diabetes (A1c  6.5%– 12%), and half also had atherosclerotic cardiovascular disease (ASCVD). Canagliflozin treatment was associated with a lower risk of kidney failure and CV disease after a median follow-up of 2.6 years.

The new analysis shows that canagliflozin reduced the risk of these outcomes to a similar extent in patients with different A1c levels.

This suggests that "treatment of patients with CKD and/or ASCVD is warranted, even if their diabetes is 'well controlled,' " write Cannon and colleagues.

"The practical implication," they advise, "is that clinicians need to evaluate patients' CV and renal risk and consider using SGLT2 inhibitors for their clinical benefit, and not specifically for glycemic or risk factor control, as we currently also do for ACE inhibitors, statins, and antithrombotic therapy in patients with diabetes and/or CV disease."

Recent data for SGLT2 inhibitors "are overwhelming and very consistent," showing "lots of benefit," and "no particular downsides," Cannon added.

Guidelines Based on Trials of Few Patients With A1c <7%

Current 2019 Standards of Medical Care in Diabetes from the American Diabetes Association (ADA) recommend SGLT2 inhibitors — canagliflozin, dapagliflozin (Farxiga, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim) — as add-on therapy for patients with type 2 diabetes whose A1c is not at goal, typically >7%, despite lifestyle changes (diet and exercise) followed by metformin therapy, the researchers write.

Trials with these agents showed they reduce risk of CV death, MI, and heart failure (HF), slow progression of renal dysfunction, and prevent end-stage kidney disease (ESKD), but the trials did not include many patients with A1c <7%.

In this latest analysis, Cannon and colleagues aimed to study outcomes in these patients, using data from CREDENCE.

CREDENCE randomly assigned 4401 patients who had type 2 diabetes, CKD, and albuminuria to receive canagliflozin 100 mg or placebo on top of standard care.

Canagliflozin significantly reduced the risk of the primary composite outcome (ESKD, a doubling of serum creatinine, or renal or CV death) as well as other outcomes.   

In this analysis, the researchers divided the patients into three groups, based on baseline A1c levels:

  • 6.5% to <7% (mean 6.6%, n = 650; well-controlled diabetes)

  • 7% to <8% (mean 7.4%, n = 1406)

  • ≥8% to 12% (mean 9.2%, n = 2343)

The patients had a similar mean age (62 to 64 years), mean estimated glomerular filtration rate (54 to 58 mL/min/1.73 m2), and diabetes duration (15 to 16 years), and about half also had ASCVD, but there were fewer women in the well-controlled-diabetes group (27% vs roughly 35%).   

At 13 weeks, the drop in A1c was greater with canagliflozin than with placebo, by 0.18%, 0.23%, and 0.40%, in the three groups (from lower to higher A1c ranges).

Across the three groups, canagliflozin resulted in similar decreases in risk of the primary composite outcome, as well as CV death, hospitalization for HF, and major adverse CV events (MACE, defined as CV death or nonfatal stroke or MI) (all P interaction > .05, nonsignificant).  

There were no significant between-group differences in adverse events or serious adverse events.

The safety concerns with this drug class, Cannon said, are mainly genital infections and the small risk of diabetic ketoacidosis. A previously reported amputation signal "has not been seen in CREDENCE or any other study, so that possible signal in [the] CANVAS [study] was likely a chance finding," he said.

He did acknowledge that the price of these medications "is an issue, but these are highly cost effective given all the benefits — and they cost the same as [dipeptidyl peptidase-4 (DPP-4)] inhibitors that are proven to do nothing."

According to the authors, the current findings support the approach of the 2019 ESC Guidelines on diabetes, prediabetes, and cardiovascular disease, which recommend that the SGLT2 inhibitor drug class should be considered for treatment, based on CV and renal risk, and can be add-on or first-line treatment.

This approach is also supported by results from DAPA-HF, which showed that dapagliflozin provides substantial benefits among patients with chronic HF with reduced ejection fraction (HFrEF) — even among those without diabetes.

A Possible Mechanism of Action

In a separate report, to investigate a possible mechanism of action of another SGLT2 inhibitor, Mazer and colleagues analyzed data from the EMPA-Heart Cardiolink-6 trial (led by Verma), which, as reported earlier, had randomly assigned 97 patients with type 2 diabetes and stable coronary artery disease to empagliflozin 10 mg daily or placebo for 6 months.

That trial showed that empagliflozin was associated with a significant reduction in left ventricular (LV) mass index.

The new deep dive examined changes in blood markers in 82 patients who had complete data for blood test results at baseline, 1 month, and 6 months.

They found that "overall, empagliflozin treatment was associated with an early increase in plasma EPO levels" at 1 month, "accompanied by an increase in hematocrit, reduced ferritin and red blood cell hemoglobin concentration at 6 months, in people with diabetes and CAD," Mazer and colleagues noted.

"At the doses we studied, the rise in EPO levels was modest," Mazer told theheart.org | Medscape Cardiology in an email.

But SGLT2 inhibitors might, or already do, fit the World Anti-Doping Agency (WADA) definition of banned performance-enhancing drugs, which prohibit EPO and agents "including, but not limited to" certain ones that affect erythropoiesis, he added.

"The hematocrit also increased with dapagliflozin in the DAPA-HF trial," Mazer noted, "so it is quite possible that this effect of SGLT2 inhibitors, to increase erythropoietin and stimulate erythropoiesis, is also present in persons without diabetes as well."  

CREDENCE was funded by Janssen, and the study authors received research support and consulting fees from Janssen for their roles on the trial's steering committee. Cannon has received research grants from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Pfizer and consulting fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol-Myers Squibb, Corvidia, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, and Sanofi.

EMPA-Heart Cardiolink-6 was funded by Boehringer Ingelheim. Verma reports receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, and Sun Pharmaceuticals. Mazer has received honoraria from Amgen, Boehringer Ingelheim, and OctaPharma. The disclosures of the other authors are listed with the articles.

Circulation. Published online November 11, 2019.
CREDENCE subanalysis Full text  
EMPA-HEART CardioLink-6 subanalysis Full text

American Heart Association (AHA) Scientific Sessions 2019.
CREDENCE Abstract 287. Presented November 17, 2019.
EMPA-HEART CardioLink-6 Abstract MDP 217. Presented November 16, 2019.

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