ESR-15-11293 - Saxa/Dapa, Safety and Efficacy Study

Diabetes Mellitus, Type 2

This is a 16-week, single center, randomized, double-blind, active-controlled, parallel-group, Phase 3b efficacy and safety study of simultaneous administration of saxagliptin 5 mg plus dapagliflozin 10 mg once daily (QD) compared with dapagliflozin plus placebo for saxagliptin, and placebo for saxagliptin plus placebo for dapagliflozin in patients with Type 2 diabetes who have inadequate glycemic control on metformin or metformin/sulfonylurea.

The study is intended to demonstrate complimentary action of saxagliptin/dapagliflozin added to metformin versus dapagliflozin added to metformin with regard to EGP. Many medications are approved for the treatment of T2DM; however, the challenge of achieving and maintaining treatment goals within the current sequential therapy approach is linked to shortcomings of older classes of drugs. Metformin is in the biguanide drug class that acts to decrease hepatic glucose output and subsequently, decreases fasting hyperglycemia. Metformin, the oral first-line gold standard agent, is recommended as the initial pharmacological therapy because of its glycemic efficacy, weight neutrality, low risk of hypoglycemia, and beneficial cardiovascular (CV) profile. Current sequential add-on second and third line oral therapy includes oral drugs such as sulfonylureas (SUs) and thiazolidinediones (TZDs). These therapies and insulin are associated with increased risks for weight gain and hypoglycemia; therefore, caution is recommended when using combination therapy with other agents known to cause hypoglycemia. Hypoglycemia is a clinically important issue in optimizing treatment and there is emerging evidence that hypoglycemia is associated with negative CV outcomes. Efforts by patients to lose weight as part of a therapeutic lifestyle program are undermined by therapies that lead to weight gain. The majority of patients with T2DM are overweight or obese, and additional weight gain often results in reduced treatment efficacy. Over the past few years, it has been widely recognized that the management approach for each T2DM patients' needs to be personalized based on his or her clinical characteristics (e.g., the likelihood of weight gain, risk for hypoglycemia, and lifestyle preferences \[e.g., many patients may be reluctant to use injections\]) (Inzucchi et al 2012). Based on data from the National Health and Nutrition Examination Survey in 2007 to 2010, HbA1c is not appropriately controlled in approximately one-third of patients using even less stringent targets (Ali et al 2013). Because of the challenge to achieve glycemic control in patients with T2DM, the progressive nature of the disease, and the limitations of available oral and non-oral therapies, there is a significant medical need for oral combination treatment options and dual add-on therapy in patients with high baseline HbA1c. Expert groups have increasingly suggested making use of combination therapy early after diagnosis to improve glycemic control (Inzucchi et al 2012, Rodbard et al 2009). In a recent study, initiating triple therapy (pathophysiological-based approach) in patients with new onset T2DM versus metformin followed by sequential addition of SUs and basal insulin (treat-to-fail approach) demonstrated a more durable HbA1c reduction over 24 months and less hypoglycemia with initial triple therapy (Abdul-Ghani et al 2014). Initial combination therapy with saxagliptin and dapagliflozin added to metformin may have similar potential for durable glucose lowering in combination with low risk of hypoglycemia. Treatment with saxagliptin and dapagliflozin, both individually and in combination with metformin, have demonstrated a favorable safety and tolerability profile. These drugs had a low propensity for hypoglycemia, therefore addressing a potential key concern when adding 2 glucose lowering agents simultaneously. These drugs have demonstrated weight neutrality (saxagliptin) or moderate weight reduction (dapagliflozin). Dapagliflozin has also been shown to cause a persistent reduction in HbA1c and weight after 2 years of therapy. Dapagliflozin was recently shown to increase EGP, which, in part, may be mediated by increased plasma glucagon (Merovci et al). In contrast, saxagliptin has been demonstrated to reduce glucagon levels, e.g., in response to a meal (Sjöstrand et al 2014) and vildagliptin, also a DPP-4 inhibitor, has been shown to inhibit EGP (Balas et al 2007). A second-line oral dual add-on therapy with saxagliptin co-administered with dapagliflozin could be a new option, as part of a triple therapy combination that includes drugs with complementary mechanisms of action, opposing effects on plasma glucagon concentration, and possibly EGP, low risk of hypoglycemia, and the potential for moderate weight loss, providing a more effective and patient-friendly approach to the treatment of T2DM.

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