Canagliflozin and Cardiovascular disease- results of the CANVAS trial.

Canagliflozin is a new novel oral antidiabetic agent belonging to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors, inhibiting glucose reabsorption in the proximal tubule, leading to increased urinary glucose excretion and subsequently to reduction in plasma glucose concentration, in individuals with hyperglycemia. Before the approval of canagliflozin by the Food and Drug Administration (FDA) in 2013, a pair-wise meta-analyses of trials involving canagliflozin did not differ from control in terms of all-cause mortality, cardiovascular death, myocardial infarction, and stroke. However, no large, randomized-controlled trials were available for comparison until the results of the CANVAS (Canagliflozin Cardiovascular Assessment Study) trial were published. The CANVAS Trial was designed to assess the cardiovascular safety and efficacy of canagliflozin. Recently, results of the completed CANVAS Trial were released which showed patients with type 2 diabetes and established cardiovascular disease or at high risk for cardiovascular events who were treated with canagliflozin had significantly lower rates of the primary cardiovascular outcome than patients assigned to placebo. All three components of the primary outcome - death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke - showed point estimates of effect that suggested benefit .These results may represent a significant additional therapeutic tool in the clinical prevention and management of cardiovascular mortality and morbidity. However, data on the long-term efficacy on the use of Canagliflozin is still incomplete and their use in patients with type 2 diabetes should be carefully considered.

By 2030, it is estimated that diabetes will affect 440 million people [1]. Currently, 90% of the population is affected by type 2 variant of diabetes which is associated with higher morbidity rate given that the risk for developing cardiovascular disease is twofold in diabetic patients [2]. Newer novel agents have been around the market to control glucose levels to acceptable range. Canaglifozin, a sodium–glucose co-transporter 2 (SGLT2) inhibitor, is one of the newer novel agents [3]. It inhibits glucose reabsorption in the kidneys via the proximal tubules and subsequently leads to reduction in plasma glucose concentration [4]. In addition, the mechanism of action of SGLT2 inhibitors is complementary and not alternative to the mechanisms of other antidiabetic agents. Thus, SGLT2 inhibitors are suitable for use in a combination of approaches.

Before the approval of canagliflozin by the Food and Drug Administration (FDA) in 2013, a pair-wise meta-analyses of trials involving canagliflozin did not differ significantly from control in terms of all-cause mortality and myocardial infarction while results were similar in sensitivity analyses including only placebo-controlled trials [5]. Furthermore, no significant risk reduction was seen in cardiovascular death and non-fatal infarctions as compared to other agents [6]. However, no large, randomized-controlled trials were available for comparison until the results of the CANVAS (Canagliflozin Cardiovascular Assessment Study) trial were published.

The CANVAS Trial, comprising 10,142 participants, was designed to assess the cardiovascular safety and efficacy of canagliflozin. CANVAS trial was initiated in 2009 with the goal to evaluate cardiovascular safety, however, the first approval from the Food and Drug Administration (FDA) was not available until 2013. Owing to the inclusion of unmasked interim cardiovascular outcome data in the regulatory filing documents, a planned expansion of the sample size to enable a test of cardiovascular protection was not undertaken.

Recently, results of the completed CANVAS Trial were released. These results are encouraging–patients with type 2 diabetes and established cardiovascular disease or at high risk for cardiovascular events who were treated with canagliflozin had significantly lower rates of the primary cardiovascular outcome than patients assigned to placebo [7]. All the components of the primary outcome including death from cardiovascular causes and nonfatal myocardial infarction showed point estimates of effect that suggested [7]. The results also showed that patients treated with canagliflozin had a lower risk of hospitalization for heart failure than patients who received placebo [7].

Robust long-term cardiovascular evidence for canagliflozin from the CANVAS trial showed a significant benefit of the use of the drug in cardiovascular patients. The study benefits from the large size of the combined trials, the long duration of the trials, the randomized design, the breadth of included participants, and the high standard to which the conduct of the trials was held. They may represent a significant additional therapeutic tool in the clinical prevention and management of cardiovascular mortality and morbidity. However, data on the long-term efficacy on the use of Canagliflozin is still incomplete, as the drug is relatively new, and their use in patients with type 2 diabetes should be carefully considered. However, while advances in technologies have helped elucidate many aspects of these diseases, many mysteries still remain. With continued research, we can expect more cost- effective and patient-friendly drug therapies to be developed in the near future. Besides, side effects of particular newer novel drugs in post-marketing surveillance should be highlighted and well documented, especially in regions where these protocols are routinely followed. It is anticipated that the results of the CANVAS trial will soon be implemented in international guidelines.