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Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and is associated with poor clinical outcomes, including an increased risk of all-cause and cardiovascular mortality, as well as adverse economic and social effects. Slowing the development and progression of CKD remains an unmet clinical need in patients with T2DM. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are widely used for the management of T2DM and have effects beyond glucose lowering that include cardiovascular benefits and potential renoprotective effects. Although the glucose-lowering efficacy of these agents is dependent on renal function, the cardiovascular and renal benefits of SGLT2 inhibition appear to be maintained to estimated glomerular filtration levels as low as 30 mL/min/1.73 m 2 . Clinical evidence has indicated that these agents can reduce the risk of development or worsening of albuminuria, a marker of renal damage, through a range of mechanisms. These include blood pressure lowering, reduction of intraglomerular pressure and hyperfiltration, modification of inflammatory processes, reduction of ischemia-related renal injury, and increases in glucagon levels. The blood pressure-lowering effect of SGLT2 inhibitors is maintained in people with CKD and could further contribute to reduced renal burden, as well as potentially offering synergistic effects with antihypertensive therapies in these patients. Several cardiovascular outcomes trials (CVOTs) have included renal endpoints, adding to the growing evidence of the potential renoprotective effects of these agents in patients with T2DM. Several ongoing dedicated renal outcomes trials will provide further guidance on the potential clinical role of SGLT2 inhibitors in slowing the development and progression of renal impairment in individuals with T2DM.

Objective: to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin., Methods: Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA 1c ) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator., Results: At baseline in the Latino/Hispanic subpopulation, the mean HbA 1c was 8.3%, mean age was 53 years, mean body mass index was 32 kg/m 2 , and mean duration of T2DM was 8.0 years. The primary endpoint of mean HbA 1c difference (albiglutide - placebo) was -0.94% for the Latino/Hispanic subpopulation and -0.86% (p < 0.001) for the overall phase III population. Changes in fasting plasma glucose mirrored those of HbA 1c . Weight loss with albiglutide was numerically greater than with OADs and insulin in both populations, but it was smaller than with liraglutide. Within the Latino/Hispanic subpopulation, more injection-site reactions were reported with albiglutide vs all comparators, while gastrointestinal and hypoglycemic adverse events were comparable between the two groups, and the latter was uncommon when used without insulin and/or a sulfonylurea., Conclusions: In the Latino/Hispanic population, albiglutide resulted in effective lowering of glucose and modest weight loss, and it was generally well tolerated.

Objectives: To evaluate the proportion of patients with type 2 diabetes mellitus (T2DM) achieving reductions in both glycated hemoglobin (HbA1c) and body weight with canagliflozin, a sodium glucose co-transporter 2 inhibitor, versus sitagliptin over 52 weeks., Methods: Data were pooled from two, randomized, Phase 3 studies of canagliflozin 100 and 300 mg versus sitagliptin 100 mg as add-on to metformin, and canagliflozin 300 mg versus sitagliptin 100 mg as add-on to metformin plus sulfonylurea (N = 1856). The composite end points of change from baseline in both HbA1c <0% and body weight <0 kg, and attainment of HbA1c <7.0% and body weight reduction ≥5% at Week 52 were evaluated. Safety was assessed based on adverse event reports., Results: Canagliflozin provided reductions in HbA1c and body weight over 52 weeks versus sitagliptin. A greater proportion of patients had both HbA1c and body weight reductions with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (67.7%, 72.6%, and 44.1%, respectively). Among patients with HbA1c and body weight reductions, more patients achieved the composite end point of HbA1c <7.0% and body weight reduction ≥5% with canagliflozin 100 and 300 mg versus sitagliptin 100 mg (18.9%, 18.3%, and 5.7%, respectively). Canagliflozin was generally well tolerated., Conclusions: A greater proportion of patients with T2DM achieved reductions in both HbA1c and body weight, and more patients with HbA1c and body weight reductions achieved HbA1c <7.0% and body weight reduction ≥5% with canagliflozin versus sitagliptin over 52 weeks., Clinical Trial Registration: www.ClinicalTrials.gov identifiers are NCT01106677; NCT01137812.

In type 2 diabetes mellitus (T2DM), decreased pancreatic beta-cell function and increased insulin resistance contribute to a steady decline in glucose homeostasis. Maintaining levels of glycated hemoglobin ≤7.0% is thought to reduce the microvascular and possibly macrovascular complications that result if T2DM is not properly managed. Recent guidelines have recognized the importance of postprandial glucose (PPG) control in reducing cardiovascular risks, and have recommended a more patient-centered approach. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) mimic the action of the endogenous gastrointestinal hormone GLP-1 to activate the insulin response in pancreatic beta cells in a glucose-dependent manner. Prandial GLP-1 RAs have a short plasma half-life and are particularly effective at targeting PPG elevations, whereas long-acting non-prandial GLP-1 RAs are more effective at reducing fasting plasma glucose. These differences highlight the potential for treatment with these agents to be tailored to the need of individual patients and their glycemic imbalance. All GLP-1 RAs are being evaluated in long-term cardiovascular outcome trials. To date, the only cardiovascular trial that has been completed is the ELIXA trial for lixisenatide, which was found to meet the pre-specified criterion of non-inferiority versus placebo in terms of cardiovascular outcomes.

Most antihyperglycemic agents available for the treatment of type 2 diabetes mellitus (T2DM) have insulin-dependent mechanisms of action; that is, they either stimulate insulin production (sulfonylureas, glinides, incretin mimetics, dipeptidyl peptidase-4 inhibitors), improve insulin sensitivity (thiazolidinediones, biguanides), or directly augment endogenous insulin (basal and prandial insulins). As β-cell function deteriorates, combination therapy is usually needed to effectively control glycemia. Moreover, some antihyperglycemic agents are associated with adverse effects, such as weight gain and hypoglycemia. A novel approach for treating T2DM is to inhibit renal glucose reabsorption through inhibition of sodium glucose co-transporter 2 (SGLT2), which is responsible for the majority of glucose reabsorption in the renal proximal tubule. By reducing the renal capacity to reabsorb filtered glucose, SGLT2 inhibitors increase excretion of excess glucose in urine, thereby decreasing plasma glucose concentration. Thus, although glucosuria is often viewed as an indicator of systemic hyperglycemia, this perception needs to be modified in patients treated with SGLT2 inhibitors where glucosuria is an indicator of the desired treatment effect. Currently, 2 SGLT2 inhibitors, canagliflozin and dapagliflozin, are approved in the United States for the treatment of patients with T2DM; other SGLT2 inhibitors are in various stages of clinical development. Clinical studies in patients with T2DM on a variety of background diabetes treatments have demonstrated the efficacy of canagliflozin and dapagliflozin in improving glycemic control and reducing body weight and blood pressure. Canagliflozin and dapagliflozin are generally well tolerated, with a low risk of hypoglycemia when not used in combination with insulin and/or sulfonylurea. Higher incidences of genital mycotic infections and adverse events related to osmotic diuresis and volume depletion were observed with both agents; they were generally mild or moderate and infrequently led to study discontinuation. Based on current evidence, SGLT2 inhibitors provide an important new treatment option for patients with T2DM.

Type 2 diabetes mellitus is a pandemic, with millions of new diagnoses made each year. In the United States, > 90% of patients with type 2 diabetes mellitus are cared for by primary care physicians who bear the primary responsibility of diagnosing and treating this disease. Building an optimal treatment regimen for a patient from the many choices available depends on many factors, including the ability of a given therapy to safely and effectively lower blood glucose levels, and potential benefits on body weight, cardiovascular risk factors, and hypoglycemia risk. With these considerations at the forefront, this article provides an overview of exenatide once weekly (EQW), a recently available antidiabetes therapy in the glucagon-like peptide-1 receptor agonist class designed to provide continuous glycemic control with once-weekly dosing. We discuss the clinical trials that have demonstrated the ability of EQW to effectively lower blood glucose levels and body weight with a minimal risk of hypoglycemia. In addition, we examine other issues likely to be relevant in a primary care setting, including safety and tolerability profiles, pharmacology and dosing, ease of use, recommended place in treatment, and patient perceptions of EQW.

Initiating insulin therapy for patients who have type 1 or type 2 diabetes mellitus presents a variety of challenges. Knowing when and how to initiate treatment, establishing realistic patient expectations, and being familiar with new approaches and combination therapies will help ensure more effective treatment.