SciCombinator

Two large cardiovascular outcome trials of canagliflozin, the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study - Renal (CANVAS-R). Accruing data for the sodium-glucose co-transporter 2 inhibitor (SGLT2i) class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses. These updates will ensure that the data from the CANVAS Program will maximise advances in scientific knowledge and patient care. The specification of the analysis strategy prior to knowledge of the trial results, their design by the independent scientific trial Steering Committee, the detailed a priori definition of the analysis plans and the external review provided by the US Food and Drug Administration, all provide for a maximally efficient and robust utilisation of the data. The CANVAS Program should significantly advance our understanding of the effects of canagliflozin, and the broader SGLT2i class, on a range of important efficacy and safety outcomes.

Lifestyle weight management interventions are recommended in clinical guidelines for patients with type 2 diabetes and obesity, but lack evidence regarding their long term effectiveness.

To characterise survival in relation to achieved HbA1c within alternative glucose-lowering regimens with differing risks of hypoglycaemia.

Outside of the biological arena the term ‘repression’ often has a negative connotation. However, in the pancreatic β-cell a small group of genes, which are abundantly expressed in most if not all other mammalian tissues, are highly selectively repressed, with likely functional consequences. The two ‘founder’ members of this group, lactate dehydrogenase A (Ldha) and monocarboxylate transporter-1 (MCT-1/Slc16a1), are inactivated by multiple mechanisms including histone modifications and microRNA-mediated silencing. Their inactivation ensures that pyruvate and lactate, derived from muscle during exercise, do not stimulate insulin release inappropriately. Correspondingly, activating mutations in the MCT-1 promoter underlie ‘exercise-induced hyperinsulinism’ (EIHI) in man, a condition mimicked by forced over-expression of MCT-1 in the β-cell in mice. Furthermore, LDHA expression in the β-cell is upregulated in both human type 2 diabetes and in rodent models of the disease. Recent work by us and by others has identified a further ∼60 genes which are selectively inactivated in the β-cell, a list which we refine here up to seven by detailed comparison of the two studies. These genes include key regulators of cell proliferation and stimulus-secretion coupling. The present, and our earlier results, thus highlight the probable importance of shutting down a subset of ‘disallowed’ genes for the differentiated function of β-cells, and implicate previously unsuspected signalling pathways in the control of β-cell expansion and insulin secretion. Targeting of deregulated ‘disallowed’ genes in these cells may thus, in the future, provide new therapeutic avenues for type 2 diabetes.

AIMS: Aside from lowering blood glucose, glucagon-like peptide-1 receptor agonists (GLP-1 RA) attract much attention because of their cardioprotective effects. The aim of this study was to assess the blood pressure-lowering effects of the GLP-1 RAs exenatide and liraglutide compared with other common drugs used to treat type 2 diabetes based on randomised controlled trials including data describing complete blood pressure (BP) changes from baseline. METHODS: We searched the major databases for published or unpublished randomised controlled trials (RCTs) that had been performed in patients with type 2 diabetes and compared the effects of exenatide and liraglutide to those of other common drugs used to treat type 2 diabetes. The RCTs that included data describing BP changes between the baseline and the end of the study were selected for further analysis. RESULTS: A total of 16 RCTs that enrolled 3443 patients in the GLP-1 RA treatment group and 2417 subjects in the control group were included in this meta-analysis. The GLP-1 RA exenatide reduced systolic blood pressure (SBP) when compared with both placebo and insulin glargine, with mean differences of -5.24 mmHg and -3.46 mmHg, respectively, and with 95% confidence intervals (CI) of -6.88 to -3.59, P<0.00001, and -3.63 to -3.29, P<0.00001, respectively. Meanwhile, in the exenatide-treated group, diastolic blood pressure (DBP) was reduced by -5.91 mmHg, with a 95% CI of -7.53 to -4.28, P<0.00001 compared with the placebo group, and -0.99 mmHg with a 95% CI of -1.12 to -0.87, P<0.00001 compared with the sitagliptin group. SBP changes in this meta-analysis were assessed in the groups treated with 1.2 mg or 1.8 mg liraglutide per day. In the 1.2 mg-treated group, liraglutide treatment reduced SBP compared with placebo and glimepiride treatment, with mean differences of -5.60 mmHg and -2.38 mmHg, and 95% CIs of -5.84 to -5.36, P<0.00001 and -4.75 to -0.01, P=0.05, respectively. In the 1.8 mg-treated group, liraglutide also reduced SBP compared with placebo and glimepiride treatment with mean differences of -4.49 mmHg and -2.62 mmHg, and a 95% CI of -4.73 to -4.26, P<0.00001, and -2.91 to -2.33, P<0.00001, respectively. CONCLUSION: Treatment with the GLP-1 RAs exenatide and liraglutide reduced SBP and DBP by 1 to 5 mmHg compared with some other anti-diabetic drugs including insulin, glimepiride and placebo for patients with type 2 diabetes. GLP-1 RAs may offer an alternative therapy for these patients and will help provide extra cardiovascular benefits.

To investigate therapy persistence, frequency of hypoglycaemia and macrovascular outcomes among type 2 diabetes patients with dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4) and sulphonylureas (SU).

To compare the effect of replacing diet beverages (DBs) with water or continuing to drink DBs in patients with type 2 diabetes during a 24-week weight loss program. The primary endpoint was the effect of intervention on weight over a 24-week period. The main secondary endpoints included anthropometric measurement and glucose and fat metabolism during the 24-week period.

To validate strategies to prevent exercise-induced hypoglycaemia via insulin-dose adjustment in adult patients with type 1 diabetes on pump therapy.

To use meta-analytic techniques to quantitatively evaluate the efficacy of orlistat and lorcaserin in the treatment of people who are overweight and obese.

The PROactive study investigated pioglitazone for secondary prevention of macrovascular events in type 2 diabetes. Pioglitazone showed a 10% (NS) relative risk reduction for the primary composite endpoint and a significant 16% reduction for the main secondary endpoint (death, MI, stroke) after a mean 34.5 months. There was no difference in cumulative malignancy incidence, but an imbalance in bladder malignancies (pioglitazone 14, placebo 5). We present a pre-specified 6-year interim analysis of a 10-year observational follow-up.