Canagliflozin Results Mixed For Primary, Secondary Prevention in Diabetes, CANVAS Update Finds


on – Kenneth W. Mahaffey, MD

The sodium glucose 
co-transporter 1 inhibitor canagliflozin showed mixed results for cardiovascular prevention in a study presented Monday afternoon at Scientific Sessions.

The agent improved cardiovascular and renal outcomes, but increased risk for lower extremity amputations in patients with diabetes.

Kenneth W. Mahaffey, MD, professor and director of the Stanford Center for Clinical Research at Stanford University in California, presented the update to the CANVAS (Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events in Type 2 Diabetes) trial. Initial results of CANVAS released earlier this year showed a 14 percent reduction in cardiovascular events.

Sixty-six percent of the 10,142 patients in CANVAS had a prior cardiovascular event and were evaluated for secondary prevention. The 34 percent with two or more cardiovascular risk factors were evaluated for primary prevention.

As expected, the secondary prevention arm had a higher cardiovascular burden. These patients also showed greater benefit from canagliflozin — an 18 percent reduction in the risk for cardiovascular death, nonfatal MI or nonfatal stroke. Primary prevention patients had a 2 percent reduction.

Both groups had a similar benefit for hospitalization for heart failure — 32 percent reduction for secondary prevention and 36 percent reduction for primary prevention. Renal outcomes were also similar — 41 percent reduction for secondary prevention and 37 percent reduction for primary prevention.

Adverse events included an expected increase in genital infections, low-trauma fracture and volume depletion events. The risk for lower-extremity amputations doubled in the secondary prevention group compared to placebo.

Larger and longer-term studies already under way will provide additional insight into the effects of canagliflozin and other SGLT2 inhibitors.


The treatment effects of the GLP-1 receptor agonist exenatide don’t vary based on the patient’s baseline cardiovascular risk, according to an update to the Effect of Exenatide Once-Weekly on Clinical Outcomes in Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease (EXSCEL) trial.

The primary EXSCEL trial had more than 14,000 participants with Type 2 diabetes from 35 countries and showed a 15 percent reduction in the risk for all-cause mortality compared to placebo. About 70 percent of the trial population had a prior cardiovascular event.

“The question was whether the magnitude of the treatment benefit depends on a patient’s baseline risk,” said Robert J. Mentz, MD, assistant professor of medicine at Duke University in Durham, North Carolina. “Our hypothesis was that patients who are at increased risk for mortality and MACE have a relatively greater benefit with exenatide than those at lower risk.”

However, data showed no significant difference in treatment benefit based on baseline cardiovascular risk. Instead, the study showed that familiar baseline characteristics — including age, prior cardiovascular events, comorbidity burden and lab values — provide good prognostic value for mortality and MACE.


Patients with diabetes and peripheral artery disease at baseline benefit more from empagliflozin added to standard care compared to patients with diabetes and other types of cardiovascular disease, according to results from a sub-analysis of the Empagliflozin Reduces Mortality and Hospitalization for Heart Failure in Patients with Type 2 Diabetes and Peripheral Artery Disease (EMPA-REG OUTCOME) trial.

Adverse events, including rates of lower limb amputations, were similar in both groups.

PAD is among the most common comorbidities in patients with Type 2 diabetes. Similarly, PAD patients often have diabetes. PAD is a predictor of cardiovascular death and is associated with an increased risk of heart failure.

The primary EMPA-REG OUTCOME trial of empagliflozin in patients with Type 2 diabetes and CVD showed good cardiovascular results. The risk of cardiovascular death was reduced by 38 percent, all-cause mortality by 32 percent, heart failure hospitalization by 35 percent and incident or worsening neuropathy by 39 percent compared to placebo.

The primary analysis didn’t explore the effect of empagliflozin on the 1,461 patients who had PAD.

The trial update compared cardiovascular death, all-cause mortality, MACE, heart failure hospitalization, a composite of heart failure hospitalization or death, neuropathy and adverse events in patients with and without PAD.

The biggest difference in the PAD group was an excess of former and current smokers.

“That’s not surprising,” said Subodh Verma, MD, PhD, FAHA, Professor and Canada Research Chair in Atherosclerosis at the University of Toronto in Ontario. “In patients with PAD, 70 percent are current or former smokers. The presence of PAD identifies a group at higher risk of cardiovascular events and death.”

In EMPA-REG, adding empagliflozin to standard care for patients with PAD reduced the risk of cardiovascular death by 43 percent, all-cause mortality by 38 percent and heart failure hospitalization by 44 percent versus placebo. In patients without PAD, risk reduction was 36 percent for cardiovascular death, 30 percent for all-cause mortality and 32 percent for heart failure hospitalization.

“There’s a profound and precocious separation of curves favoring empagliflozin in patients with PAD,” Verma said. “This is reflective of the higher baseline risk of this population. The substantial risk reductions seen in patients with PAD have important translational implications for clinical practice.”


Serum metabolites could become the next generation of predictors and prognosticators for coronary heart disease, according to the largest study performed on serum metabolites.

Serum Metabolomic Profiles Predict Coronary Heart Disease in the General Population (BiomarCaRE) used the Biomarker for Cardiovascular Risk Assess in Europe database to create a cohort of 10,741 people that included 2,166 patients with coronary heart disease.

“Metabolites are good candidates because they reflect genomic changes in individuals and indicate changes in phenotypes,” said Tanja Zeller, PhD, professor for genomics and systems biology at the University of Hamburg in Germany. “In our cohort of middle-aged individuals, we found four metabolites that are significantly associated with coronary heart disease.”

The four metabolites are phosphatidylcholines and have an inverse relationship to coronary heart disease. Lower metabolite levels increase risk while higher levels are protective. The predictive strength of metabolite markers is similar to classical risk factors such as BMI, systolic blood pressure, diabetes and total cholesterol, Zeller said.

More research and validation are needed before metabolites are ready for clinical use, she said. But the BiomarCaRE study indicates the value of metabolomics to develop novel biomarkers and improve risk stratification.


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