Diabetes Drugs Show Benefit in PAD, but Only Mixed Results in Primary Prevention of CV Events

ANAHEIM, CA—Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, designed for the treatment of diabetes, appear to be effective at reducing MACE in the setting of peripheral artery disease, according to new trial findings. Yet data from another study suggest these agents are less well suited to primary prevention in diabetic patients without prior cardiovascular disease.

Subodh Verma, MD (University of Toronto, Canada), who presented the results of a subanalysis of the EMPA-REG OUTCOME study at the American Heart Association 2017 Scientific Sessions this week, told TCTMD that PAD is one of the most common complications of type 2 diabetes and that patients with suffer from both diseases at once are at a significantly increased risk of death and heart failure.

In their analysis of the EMPA-REG OUTCOME trial, which included more than 7,000 patients with existing CVD and type 2 diabetes, empagliflozin (Jardiance, Boehringer Ingelheim) added to standard care cut the risk of cardiovascular death by 43% and all-cause mortality by 38% in patients who also had peripheral artery disease. Additionally, heart failure hospitalizations and new or worsening nephropathy were reduced by 44% and 46%, respectively.

“Finding treatments that reduce complications in this vulnerable population is imperative,” said Verma. “The fact that empagliflozin reduced mortality by such a profound amount, and with an absolute risk reduction approaching 4%, [has] important implications for patients and physicians with type 2 diabetes and PAD.”

Regarding the risk of lower-limb amputations, an adverse event that has dogged the SGLT-2 inhibitor class, specifically canagliflozin (Invokana; Janssen Pharmaceuticals), 5.5% of PAD patients treated with empagliflozin had an amputation compared with 6.3% of the placebo-treated PAD patients, a nonsignificant difference. The absolute risk of lower-limb amputation was lower in patients without PAD, but there was no signal of harm with empagliflozin in this group either.

As for the risk of amputation with the SGLT-2 inhibitors as a whole, Verma would only comment on the EMPA-REG trial, noting that amputation rates were identical in the overall study and in those patients with a history of PAD. “I can only comment on the data that we have seen in EMPA-REG, since no head to head comparative trials of empagliflozin versus canagliflozin were performed,” he stressed. 

Empagliflozin is currently approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes and to reduce the risk of cardiovascular death in adults with type 2 diabetes and cardiovascular disease.  

Primary vs Secondary Prevention

Like empagliflozin, canagliflozin is approved for glycemic control. It is not approved for the reduction of major adverse cardiovascular events, although the Janssen has submitted a supplemental new drug application to the US Food and Drug Administration (FDA) based on results from CANVAS, a large cardiovascular outcomes study. CANVAS differed from EMPA-REG in that investigators included approximately one-third of patients with diabetes but no history of cardiovascular disease.

In the main CANVAS trial, canagliflozin reduced the risk of cardiovascular death, nonfatal MI, and nonfatal stroke by 14% and reduced the risk of renal decline by 40% among high-risk type 2 diabetes patients.  

Presenting the results of a subanalysis looking at baseline disease status, Kenneth Mahaffey, MD (Stanford University School of Medicine, CA), said that individuals with prior cardiovascular events had higher absolute rates of cardiovascular, renal, and mortality outcomes than those without preexisting cardiovascular disease, but “there was no statistical evidence of heterogeneity of canagliflozin effects across the primary and secondary-prevention participants.”

Despite the lack of heterogeneity, M. Angelyn Bethel, MD (University of Oxford, England), noted that the benefit appears mainly in patients with prior cardiovascular disease. While cautious interpreting the data, especially given that CANVAS was not powered to study clinical outcomes in the smaller subgroups, Bethel said the event curve for the composite endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke is nearly superimposable between canagliflozin versus placebo in the primary-prevention patients.

“If you look at the morphology of the curves, you’ll see that in the secondary-prevention patients, the curve is similar to the primary outcome, with early separation which extends over time and gets gradually larger,” said Bethel, who discussed the trial during the AHA plenary session. “For the primary-prevention patients, there really is no suggestion of any outcome [benefit] over the entire duration of follow-up.”

In contrast, it appears the canagliflozin protects the kidneys of both those with and without prior cardiovascular disease, said Bethel.       

In CANVAS, treatment with canagliflozin was associated with a twofold increase in the risk of amputation. Like the main results, Mahaffey said they observed no heterogeneity between the two groups with respect to lower-limb amputations, with the risk elevated in both populations (P for interaction = 0.63).  

“Further study and large, ongoing cardiovascular outcome trials with longer follow-up and larger populations of primary-prevention patients will provide us with further insight into the effects of canagliflozin as well as other SGLT-2 inhibitors,” said Mahaffey.

Canagliflozin is currently being studied in the CREDENCE trial, a study testing whether the drug protects against adverse cardiovascular and renal events when compared with placebo in patients with diabetes. Empagliflozin will also be studied in approximately 5,000 patients with chronic kidney disease. The TIMI study group is currently assessing whether dapagliflozin (Farxiga, AstraZeneca) reduces cardiovascular events when added to standard medical therapy.

In May 2017, the FDA added a black box to canagliflozin’s label warning of the increased risk of leg and foot amputations. The European Medicines Agency (EMA) also issued a warning about the risk of amputation (mostly toes) with canagliflozin, but extended the directive to all SGLT-2 inhibitors. The EMA believes the mechanism of action resulting in the increased risk of amputation is unclear with canagliflozin and SGLT-2 inhibitors overall, and that existing data are limited.