ArticlesEffect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial
Introduction
From 2000 to 2010, the estimated prevalence of diabetes increased from 121 million to 285 million people, representing 6·4% of the global adult population.1 Type 2 diabetes, which accounts for more than 90% of all diabetes, is a complex progressive metabolic derangement associated with comorbidities such as obesity, hypertension, and hyperlipidaemia.2 Strategies for selection of antidiabetic agents aim to balance effectiveness, safety, tolerability, and non-glycaemic effects that can reduce long-term complications, notably microvascular and premature macrovascular disease. Despite efforts to intensify management, many adult patients with type 2 diabetes do not achieve glycaemic control.3, 4, 5, 6
Pharmacological treatment usually begins with metformin, which together with lifestyle management is a validated first-step approach.7, 8 Although metformin is often initially effective as monotherapy, the progressive nature of diabetes frequently requires additional therapies.9 As β-cell function deteriorates further, selection of agents and management of their side-effects become increasingly more difficult. For example, sulphonylureas and insulin cause weight gain and hypoglycaemia; thiazolidinediones cause weight gain and are contraindicated in patients with heart failure; and use of α-glucosidase inhibitors is limited by gastrointestinal side-effects. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are not associated with weight gain or hypoglycaemia, but assessment of long-term use is needed. There is also a necessity for additional treatments that avoid side-effects and address some of the broader metabolic issues of diabetes without dependency on β-cell function.10, 11
As part of the quest for new agents, research has expanded into new targets of glycaemic control that are not directly focused on insulin-dependent mechanisms. Sodium-glucose cotransporter 2 (SGLT2), located mainly in segment S1 of the proximal tubule of the kidney nephron, reabsorbs most glucose filtered by the glomerulus.12 Dapagliflozin is a stable and highly selective inhibitor of SGLT2.13, 14 Binding of dapagliflozin to SGLT2 inhibits renal glucose reabsorption, promotes urinary glucose excretion, and thereby lowers hyperglycaemia by an insulin-independent mechanism.15, 16, 17, 18 Since the glucotoxicity caused by chronic hyperglycaemia is a major source of microvascular complications and contributes to macrovascular disease, glycaemia per se is a very legitimate therapeutic target for treatment of type 2 diabetes.
This study assessed the efficacy and safety of dapagliflozin when added to metformin in adult patients with type 2 diabetes who are not adequately controlled with metformin alone. We report the results of 24 weeks of treatment.
Section snippets
Study design and patients
This phase 3, randomised, double-blind, parallel-group, placebo-controlled trial was undertaken at 80 sites (30 in the USA, 21 in Canada, 11 in Argentina, ten in Mexico, and eight in Brazil). Patients were accrued from Sept 18, 2007, to April 10, 2008. The study complied with the Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by institutional review boards and independent ethics committees for participating centres. All participants provided written informed
Results
Figure 1 shows the trial profile. The 24-week data cutoff date was Nov 4, 2008. Table 1 shows demographic and baseline characteristics of study participants. All randomised patients took at least one dose of study medication. 88% of randomised patients completed the trial: the most common reasons for discontinuation during the double-blind period were withdrawal of consent and loss to follow-up (figure 1).
Reductions in HbA1c percentage after 24 weeks were significantly greater in the
Discussion
Dapagliflozin offers a novel insulin-independent approach to lowering hyperglycaemia and improving metabolic control of type 2 diabetes: it reduces renal glucose reabsorption by inhibition of SGLT2 transporters in the proximal tubule of the kidney, resulting in urinary glucose excretion. Since SGLT2 inhibition is independent of β-cell function or insulin sensitivity, this treatment approach could have applications throughout the natural history of diabetes.
Patients in this trial did not have
References (31)
- et al.
Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study)
Diabetes Res Clin Pract
(2005) - et al.
Aglycone exploration of C-arylglucoside inhibitors of renal sodium-dependent glucose transporter SGLT2
Bioorg Med Chem Lett
(2008) - et al.
Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes
Clin Ther
(2005) - et al.
Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations
Am J Obstet Gynecol
(1998) - et al.
Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus
Metabolism
(2008) Foreword to IDF Diabetes Atlas
Metabolic syndrome pandemic
Arterioscler Thromb Vasc Biol
(2008)- et al.
Evaluation of risk factors for development of complications in type II diabetes in Europe
Diabetologia
(2002) - et al.
Treatment approach and HbA1c control among US adults with type 2 diabetes: NHANES 1999–2004
Curr Med Res Opin
(2009) - et al.
Control of type 2 diabetes mellitus among general practitioners in private practice in nine countries of Latin America
Rev Panam Salud Publica
(2007)