Aims/hypothesisThe aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin.MethodsThis randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants (N = 1,284) with type 2 diabetes aged ≥18 and ≤80 years who had inadequate glycaemic control (HbA1c ≥7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo (n = 368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA1c at week 26; secondary endpoints included changes in HbA1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study.ResultsAt week 26, canagliflozin 100 mg and 300 mg reduced HbA1c vs placebo (−0.79%, –0.94%, –0.17%, respectively; p < 0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA1c (−0.73%, –0.88%,–0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (−0.12, 0.12) and −0.15% (−0.27, –0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: –3.7%, –4.2%, –1.2%, respectively; p < 0.001) and sitagliptin (week 52: –3.8%, –4.2%, –1.3%, respectively; p < 0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) (p < 0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin.Conclusions/interpretationCanagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin.Clinical trial registryClinicalTrials.gov NCT01106677FundingThis study was supported by Janssen Research & Development, LLC.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-3039-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Our results support the recommendation for assessing insulin resistance and cardiovascular-related features and disorders in all young males with stage III or higher AGA, according to the Hamilton-Norwood classification.

Running title: Glargine initiation in insulin-naïve type 2 diabetes AT.LANTUS: A Trial comparing LANTUS Algorithms to achieve Normal blood glucose Targets in subjects with Uncontrolled blood Sugar 2 ABSTRACT Objective: For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide optimal glycemic control, necessitating insulin therapy. Fear of hypoglycemia is a major barrier to initiating insulin therapy. The AT.LANTUS study investigated optimal methods to initiate and maintain insulin glargine (LANTUS ® ; glargine) therapy using two treatment algorithms. This sub-group analysis investigated the initiation of once-daily glargine therapy in patients sub-optimally controlled on multiple OADs. Research design and methods:This was a 24-week, multinational (59 countries), multicenter (611), randomized study. Algorithm 1 was a clinic-driven titration and Algorithm 2 was a patient-driven titration. Titration was based on target fasting blood glucose ≤100 mg/dL (≤5.5 mmol/L). Algorithms were compared for incidence of severe hypoglycemia (requiring assistance and blood glucose <50 mg/dL [<2.8 mmol/L]) and baseline-to-endpoint change in HbA 1c . Results:Of the 4961 patients enrolled in the study, 865 were included in this sub-group analysis: 340 received glargine plus 1 OAD; 525 received glargine plus >1 OAD. Incidence of severe hypoglycemia was <1%. HbA 1c decreased significantly between baseline and endpoint for patients receiving glargine plus 1 OAD (-1.4%, p<0.001; Algorithm 1 -1.3% vs Algorithm 2 -1.5%; p=0.03) and glargine plus >1 OAD (-1.7%, p<0.001; Algorithm 1 -1.5%vs Algorithm 2 -1.8%; p=0.001). Conclusions:This study shows that initiation of once-daily glargine with OADs results in significant reduction of HbA 1c with a low risk of hypoglycemia. The greater reduction in HbA 1c was seen in patients randomized to the patient-driven algorithm (Algorithm 2) on one or more than one OAD. Following diagnosis, patients are generally advised to make a number of lifestyle changes, focussed on increasing physical activity levels [7] and diet [8]. However, such programs are usually insufficient by this stage of the diabetes [9]. The progressive nature of T2DM, characterized by a decline in β-cell function [10,11] and deterioration in glycemic control [12], means that pharmacologic interventions are usually required [13]. Oral antidiabetic agents (OADs), for example, sulfonylureas, metformin and glitazones are therapeutic interventions used in monotherapy or in combination. However, to achieve and maintain good glycemic control, OADs, even in combination, are insufficient [14] and insulin therapy is often required [13].Both patients and physicians may be reluctant to start insulin therapy [6,15,16]. The fear of hypoglycemia, needle anxiety and weight gain are among the reasons cited that actively discourage insulin therapy. Therefore, it is important that for insulin therapy to be effective in patients with type 2 diabetes, these barriers must be overcome.Insulin glargine (LANTUS ® , glargine) is...

Hereditary type 2 diabetes mellitus is a risk factor for chronic liver disease, and ~30 % of patients with liver cirrhosis develop diabetes. Diabetes mellitus has been associated with cirrhotic and non-cirrhotic hepatitis C virus liver infection, can aggravate the course the liver infection, and can induce a lower sustained response to antiviral treatment. Evidences that HCV may induce metabolic and autoimmune disturbances leading to hypobetalipoproteinemia, steatosis, insulin resistance, impaired glucose tolerance, thyroid disease, and gonadal dysfunction have been found. Prospective studies have demonstrated that diabetes increases the risk of liver complications and death in patients with cirrhosis. However, treatment of diabetes in these patients is complex, as antidiabetic drugs can promote hypoglycemia and lactic acidosis. There have been few therapeutic studies evaluating antidiabetic treatments in patients with liver cirrhosis published to date; thus, the optimal treatment for diabetes and the impact of treatment on morbidity and mortality are not clearly known. As numbers of patients with chronic liver disease and diabetes mellitus are increasing, largely because of the global epidemics of obesity and nonalcoholic fatty liver disease, evaluation of treatment options is becoming more important. This review discusses new concepts on hepatogenous diabetes, the diabetes mellitus–hepatitis C virus association, and clinical implications of diabetes mellitus in patients with chronic liver disease. In addition, the effectiveness and safety of old and new antidiabetic drugs, including incretin-based therapies, will be described.

Diabetes mellitus (DM) that occurs because of chronic liver disease (CLD) is known as hepatogenous diabetes (HD). Although the association of diabetes and liver cirrhosis was described forty years ago, it was scarcely studied for long time. Patients suffering from this condition have low frequency of risk factors of type 2 DM. Its incidence is higher in CLD of viral, alcoholic and cryptogenic etiology. Its pathophysiology relates to liver damage, pancreatic dysfunction, interactions between hepatitis C virus (HCV) and glucose metabolism mechanisms and genetic susceptibility. It associates with increased rate of liver complications and hepatocellular carcinoma, and decreased 5-year survival rate. It reduces sustained virological response in HCV infected patients. In spite of these evidences, the American Diabetes Association does not recognize HD. In addition, the impact of glucose control on clinical outcomes of patients has not been evaluated. Treatment of diabetes may be difficult due to liver insufficiency and hepatotoxicity of antidiabetic drugs. Notwithstanding, no therapeutic guidelines have been implemented up to date. In this editorial, authors discuss the reasons why they think that HD may be a neglected pathological condition and call attention to the necessity for more clinical research on different fields of this disease.