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EASD: SGLT-2 Added to Insulin Effective or Type 2’s with CVD

First results from phase 3 CANVAS trial show canagliflozin as add-on therapy to insulin lowered blood sugar levels in patients with type 2 diabetes at an elevated risk for cardiovascular disease….

Canagliflozin was also shown to be effective and generally well-tolerated in patients with type 2 diabetes aged 55 to 80 in a separate Phase 3 study.

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Janssen announced that use of the investigational medicine canagliflozin substantially lowered blood glucose levels when used as add-on therapy in patients on insulin therapy for type 2 diabetes and who are considered to be at greater risk for cardiovascular disease.

CANVAS (CANagliflozin cardioVascular Assessment Study), also known as DIA3008, is a prospective, double blind, placebo-controlled trial designed to evaluate the efficacy, tolerability and cardiovascular safety of canagliflozin in 4,330 adult patients with type 2 diabetes considered at elevated risk for cardiovascular disease. Cardiovascular disease is the leading cause of death in people with type 2 diabetes, and accounts for over 50% of type 2 diabetes fatalities.

The data presented were from an 18-week sub-study of 1,718 patients enrolled in CANVAS who were receiving insulin for an average of 7.1 years. Patients in this sub-study who were randomized to treatment with daily canagliflozin 100 mg or 300 mg, in addition to their usual insulin regimen, had statistically greater A1C reductions at 18 weeks relative to placebo (percent change from baseline, -0.65 and -0.73%, respectively, p<0.001). The overall incidence of treatment-emergent adverse events (AEs) was generally similar across all treatment arms.

“Adults with type 2 diabetes are two to four times more likely to have heart disease or stroke compared to those who don’t have diabetes,” said David R. Matthews, FRCP, Professor of Diabetes, Oxford Centre for Diabetes, Endocrinology & Metabolism and co-lead investigator of the CANVAS (DIA3008) trial. “Effective management of type 2 diabetes in patients with elevated cardiovascular risk and other comorbidities can be challenging because these patients are often more susceptible to complications of the side effects of antihyperglycemic therapy. The results from this sub-study suggest that canagliflozin could provide an important new treatment option for higher-risk adult patients with type 2 diabetes.”

In secondary efficacy endpoint measures in the CANVAS study, both the canagliflozin 100 mg and 300 mg dose groups provided reductions in body weight relative to placebo (body weight percent change, -1.9 and -2.4%, respectively, p<0.001). Reductions in fasting plasma glucose were consistent with the primary endpoint for canagliflozin 100 mg and 300 mg relative to placebo (-1.25 and -1.61 mmol/L, respectively, p<0.001). The study also met secondary end points including the following (for canagliflozin relative to placebo): reductions in systolic blood pressure with canagliflozin 100 mg and 300 mg (-2.6 and -4.4 mmHg, respectively, p<0.001); reductions in diastolic blood pressure with canagliflozin 100 mg and 300 mg (-1.0 and -1.8 mmHg, respectively); high-density lipoprotein cholesterol (HDL-C) increased with both 100 mg and 300 mg doses of canagliflozin relative to placebo, [percent change, 0.8% (0.02 mmol/L), p=0.46, and 4.7% (0.05 mmol/L), p<0.001, respectively] though the change was not statistically significant for the 100 mg dose; low-density lipoprotein cholesterol (LDL-C) rose with canagliflozin 100 mg and 300 mg [6.3% (0.03 mmol/L) and 6.6% (0.11 mmol/L), respectively); non statistically significant changes in triglycerides with canagliflozin 100 mg and 300 mg [0.2% (0.01 mmol/L), p=0.95, and -2.0% (-0.04 mmol/L), p=0.44, respectively]; and increases in total cholesterol levels with canagliflozin 100 mg and 300 mg [1.0% (0.05 mmol/L) and 3.3% (0.14 mmol/L), respectively]. These efficacy parameters are all important considerations in the disease management of patients with type 2 diabetes.

The incidence of AEs leading to discontinuation was greater with canagliflozin 300 mg (5.3%) compared to canagliflozin 100 mg or placebo (1.9% for both). Most AEs were assessed by the investigator as mild to moderate in intensity and the overall incidence of AEs was balanced across treatment arms. Adverse events of genital mycotic infections in men and women, increased urination (pollakiuria), and hypotension were more common with canagliflozin 100 mg and 300 mg compared to placebo in men and women; these specific adverse events were generally mild or moderate in intensity and infrequently led to discontinuation. A slightly higher incidence of urinary tract infections was seen with canagliflozin 300 mg than 100 mg or placebo. The incidence of hypoglycemia was higher with canagliflozin 100 mg and 300 mg than placebo (49 and 48% vs. 37%, respectively). These data were included in the New Drug Application (NDA) Janssen submitted to the U.S. Food and Drug Administration and the Marketing Authorization Application (MAA) to the European Medicines Agency seeking approval for the use of canagliflozin for the treatment of type 2 diabetes announced on May 31, 2012 and June 26, 2012, respectively.

In a second Phase 3 study also presented at EASD, canagliflozin significantly reduced A1C levels compared to placebo, when added to ongoing antihyperglycemic therapy in older patients with type 2 diabetes not having adequate glycemic control.

In this 26-week randomized, double-blind, placebo-controlled study known as DIA3010, 714 patients with a mean age of 63.6 years were given once-daily doses of canagliflozin (100 mg or 300 mg), or placebo. Patients treated with canagliflozin 100 mg and 300 mg doses had substantial and sustained decreases in A1C levels, and a significantly greater reduction relative to placebo after 26 weeks (-0.57 and -0.70%, respectively, p<0.001). The overall incidence of treatment-emergent AEs was similar with both canagliflozin 100 mg and 300 mg doses and placebo (71.8 and 78.0% vs. 73.4%, respectively).

Presented at the 48th European Association for the Study of Diabetes (EASD) Annual Meeting.