Introduction: Sodium glucose cotransporter 2 (SGLT2) inhibitors provide an insulin-independent mechanism for lowering blood glucose level and improving glycemic control via induction of urinary glucose excretion caused by SGLT2 inhibition of renal glucose reabsorption. This study was designed to evaluate the safety and efficacy of canagliflozin monotherapy in patients with type 2 diabetes who were inadequately controlled on diet and exercise alone.
Methods: In this phase 3 trial, 584 patients with type 2 diabetes were randomized to receive either canagliflozin 100 mg or 300 mg, or placebo daily for 26 weeks. The primary endpoint of the stidu was change in hemoglobin A1C level from baseline to week 26. The study included patients with normal renal function as well as with mild or moderate renal impairment.
Results: Both the 100-mg and 300-mg doses of canagliflozin were associated with a significantly reduced A1C level from baseline compared with placebo (-0.77%, -1.03%, and 0.14%; respectively; P<0.001 for both comparisons). Both doses also were linked to significant decreases in fasting blood glucose level (-1.5, -1.9, and 0.5 mmol/L), 2-hour postprandial glucose level (-2.4, -3.3, and 0.3 mmol/L), body weight (-2.8%, -3.9%, and -0.6%), and systolic blood pressure (-3.3, -5.0, and 0.4 mmHg; P<0.001 for all comparisons). In addition, patients in the canagliflozin group showed increased high-density lipoprotein (HDL) cholesterol levels (0, 0.12, and -0.07 mg/dLl) compared with patients in the placebo group (P<0.001).
The canagliflozin group had a higher overall incidence of adverse events (AEs; 61.0% and 59.9% for the 100-mg and 300-mg doses vs 52.6% with placebo), specifically higher rates of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs. The rates of serious AEs (4.1% and 1.0% vs 2.1%) and AE-related discontinuations (3.1% and 2.0% vs 1.0%), as well as hypoglycemia (3.6% and 3.0% vs 2.6%, respectively) were low and similar in all groups.
Conclusion: Treatment with either canagliflozin 100 mg and 300 mg significantly improved glycemic control and was well tolerated in patients with type 2 diabetes who were inadequately controlled with diet and exercise. These improvements were associated with weight loss and a low incidence of hypoglycemia.
Commentary by J. Michael Gonzalez-Campoy MD, PhD, FACE
Type 2 diabetes mellitus is a chronic and progressive disease. For the vast majority of patients, diabetes is a consequence of the development of adiposopathy—adipose tissue dysfunction due to pathological changes that come about with increasing fat mass. Adiposopathy contributes to the development of insulin resistance and insulin insufficiency.
The first line of treatment for type 2 diabetes is the implementation of a meal plan that allows for caloric restriction with a goal to revert adiposopathy. This correlates with the loss of fat mass. Awareness of the effect of foods on the level of glycemia is an important part of the knowledge base that patients with diabetes must gain. Physical activity helps glycemia and weight loss efforts.
It is important to highlight that the words “diet” and “exercise” should be abandoned. The National Diabetes Education Program Guiding Principles for Diabetes Care and the American Association of Clinical Endocrinologists recommend that we use “physical activity” and “healthy eating” or “meal planning” instead.
For most patients with diabetes, pharmacotherapy will eventually be necessary. In this paper by Stenlöf and colleagues, monotherapy with canagliflozin resulted in significant A1C improvements that were on par with what is observed for most other oral agents on the market. Of note, compared to placebo, canagliflozin use led to significant beneficial changes in body weight, systolic blood pressure, and HDL cholesterol. These additional effects of canagliflozin monotherapy reflect an overall improvement in metabolism. Because of its beneficial effects on glycemia, weight, lipids, and blood pressure, the use of SGLT2 inhibitors as first-line monotherapy for diabetes should be strongly considered.