SciCombinator

 To assess the risks of amputation, blindness, severe kidney failure, hyperglycaemia, and hypoglycaemia in patients with type 2 diabetes associated with prescribed diabetes drugs, particularly newer agents including gliptins or glitazones (thiazolidinediones).

 To determine whether pioglitazone compared with other antidiabetic drugs is associated with an increased risk of bladder cancer in people with type 2 diabetes.

 To assess associations between risks of cardiovascular disease, heart failure, and all cause mortality and different diabetes drugs in people with type 2 diabetes, particularly newer agents, including gliptins and thiazolidinediones (glitazones).

The management of type 2 diabetes has been challenged by uncertainty about possible cardiovascular effects related to treatment intensity and choice of drug. Although the Food and Drug Administration (FDA) considers a decrease in glycated hemoglobin an approvable end point, very intensive glycemic control is associated with increased cardiovascular and all-cause mortality.(1) The safety of specific drugs for type 2 diabetes - particularly the thiazolidinediones - has also been questioned. After rosiglitazone had been approved in the United States in 1999 and in Europe in 2000, a highly publicized meta-analysis in 2007 reported a 43% increase in myocardial infarction (P=0.03) . . .

Despite half of all type 2 diabetes mellitus (T2DM) patients being over 65 and treatment being complicated by an elevated risk of iatrogenic hypoglycaemia, information about antidiabetic treatment is scarce in this age group. This prospective observational study compares DPP4-inhibitors (DPP4-i) with conventional oral antidiabetic drugs (COAD) in the real-life treatment of elderly patients with T2DM uncontrolled on metformin alone.

OBJECTIVEA 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone.RESEARCH DESIGN AND METHODSA total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500-2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio.RESULTSAfter 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was -0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (-0.91 mg/dL and -7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo.CONCLUSIONSAddition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.

A rapid, simple, and precise RPLC method was developed for the simultaneous determination of the widely used oral antidiabetic, metformin hydrochloride (MTF), with some commonly coadministered oral antidiabetics from different pharmacological classes-glipizide (GPZ), pioglitazone hydrochloride (PGZ), glimepiride (GLM), and repaglinide (RPG)-in bulk, laboratoryprepared mixtures and pharmaceutical formulations in the presence of metformin-reported impurity [1-cyanoguanidine (CNG)]. Chromatographic separation was achieved using isocratic elution mode with a mobile phase of acetonitrile: 0.02 M potassium dihydrogen phosphate (pH 3.17; 50-50, v/v) flowing through a CN Phenomenex column (Phenosphere Next, 250 × 4.6 mm, 5 μm) at a rate of 1.5 mL/min at ambient temperature. UV detection was carried out at 220 nm. The method was validated according to International Conference on Harmonization guidelines. Linearity, accuracy, and precision were satisfactory for concentration ranges: 0.175-350 μg/mL for MTF, 0.0525-105 μg/mL for GPZ, 0.125-250 μg/mL for PGZ, and 0.05-100 μg/mL for GLM and RPG. Correlation coefficients were ˃0.99 for all analytes. LOQs were 0.009 μg/mL for MTF, 0.009 μg/mL for GPZ, 0.04 μg/mL for GLM, 0.124 μg/mL for PGZ, and 0.044 μg/mL for RPG. The developed method is specific, accurate, and suitable for the QC and routine analysis of the cited drugs in their pharmaceutical products.

Loss-of-function mutations inPPARGcause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many cases. Missense mutations inPPARGare present in ∼1:500 people. Whilst mutations are often binarily classified as ‘benign’ or ‘deleterious’, prospective functional classification of all missensePPARGvariants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic ‘endogenous’ (e.g. prostaglandin J2 (PGJ2)) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some PPARγ mutants. Here, we report FPLD3 patients, harbouring two such PPARγ mutations (R308P, A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonistsin vitro, with structural modelling providing a basis for such differential ligand-dependent responsiveness. Concordant with this, dramatic clinical improvement was seen following pioglitazone treatment of the patient with R308P mutant PPARγ. A patient with A261E mutant PPARγ also responded beneficially to rosiglitazone, though cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients withPPARGmutations.

Diabetes is one of the most impactful diseases worldwide. The most commonly prescribed anti-diabetic drug is metformin. In this study, we identified an endosomal Na+/H+ exchanger (NHE) as a new potential target of metformin from an unbiased screen in C. elegans. The same NHE homolog also exists in flies where it too mediates the effects of metformin. Our results suggest that endosomal NHEs could be a metformin target and provide an insight to revealing a novel mechanism of action of metformin on regulating the endocytic cycle.

To analyze the association between cancer incidence and oral diabetes therapy (biguanide, sulfonylurea, thiazolidinedione, meglitinide) in men and women with type 2 diabetes mellitus.