Type 2 Diabetes Mellitus Drugs Research Articles

Exendin-4 antagonizes Aβ1-42-induced suppression of long-term potentiation by regulating intracellular calcium homeostasis in rat hippocampal neurons

An imbalance of intracellular calcium homeostasis induced by amyloid β-protein (Aβ) contributes to the pathogenesis of Alzheimer׳s disease (AD), such as deficits in learning and memory. Therefore, regulation of calcium homeostasis may represent a new strategy for treatment of AD. Growing evidence suggests that type 2 diabetes mellitus (T2DM) and AD are closely related in pathogenesis. Thus, drugs used in treatment of T2DM may modify the pathogenesis of AD. This study demonstrated that Exendin-4, which is a glucagon-like peptide-1 (GLP-1) analog used as a therapeutic drug for T2DM, significantly antagonized suppression of long-term potentiation (LTP) induced by Aβ1-42 in the rat hippocampal CA1 region in vivo. This neuroprotection may be mediated by regulation of calcium homeostasis. Pretreatment with Exendin-4 suppressed Aβ1-42-induced elevation in intracellular calcium concentration ([Ca2+]i) through L-type voltage-dependent calcium channels (L-VDCCs) and N-methyl-D-aspartate receptors (NMDARs). Furthermore, Exendin-4 antagonized the decrease in p-Ca2+/calmodulin-dependent protein kinase IIα (p-CaMKIIα) induced by Aβ1-42 in the rat hippocampal CA1 region. Thus, the neuroprotective effects of Exendin-4, which likely involve regulation of calcium homeostasis, provide theoretical support for using Exendin-4 to treat and prevent AD in the future.

Assessing Bladder Cancer Risk in Type 2 Diabetes Clinical Trials: the Dapagliflozin Drug Development Program as a 'Case Study'.

IntroductionDapagliflozin, a sodium-glucose co-transporter 2 inhibitor, decreases plasma glucose levels by suppressing renal glucose reabsorption and increasing urinary glucose excretion. Previously published pre-clinical data suggest that dapagliflozin lacks carcinogenic potential. This article reviews data on bladder cancer with dapagliflozin to illustrate the challenges in assessing bladder cancer in drug development programs in patients with type 2 diabetes mellitus (T2DM).MethodsClinical cases of bladder cancer were analyzed in a pooled population of >9000 patients in 21 phase 2b/3 dapagliflozin clinical trials of up to 208 weeks’ duration.ResultsIn the 21-study pool, demographic and baseline characteristics were generally consistent between dapagliflozin and comparator groups. The overall incidence of malignancies was also balanced between the treatment groups, with an incidence rate ratio (IRR) of 1.035 [95% confidence interval (CI): 0.724, 1.481]. Nine of 5936 dapagliflozin-treated patients and 1 of 3403 comparator-treated patients reported bladder cancer, with an IRR of 5.168 (95% CI: 0.677, 233.55). All of these patients had clinical attributes typical of bladder cancer in the general population (≥60-year-old males; 8 of the 10 patients were current/former smokers). All cases of bladder cancer were reported within 2 years of starting study treatment. There was an absence of detailed workup of hematuria prior to randomization, and no hematuria workup data were collected proactively in the dapagliflozin trials, which is typical of clinical practice. Failure to exclude bladder cancer prior to randomization increases the chance of recruiting patients with pre-existing bladder cancer in clinical trials and may delay the final diagnosis. Of the nine dapagliflozin-treated patients with bladder cancer, eight had microscopic hematuria prior to start of treatment or within 6 months of initiating study treatment.ConclusionThe assessment of bladder cancer data illustrates the challenges of characterizing cancer risk in T2DM drug development programs. The totality of evidence to date does not suggest a causal relationship between dapagliflozin and bladder cancer.FundingAstraZeneca.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0128-9) contains supplementary material, which is available to authorized users.

Pediatric drug development programs for type 2 diabetes: A review.

Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)-approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided.

Anorexigenic lipopeptides ameliorate central insulin signaling and attenuate tau phosphorylation in hippocampi of mice with monosodium glutamate-induced obesity.

Numerous epidemiological and experimental studies have demonstrated that patients who suffer from metabolic disorders, such as type 2 diabetes mellitus (T2DM) or obesity, have higher risks of cognitive dysfunction and of Alzheimer's disease (AD). Impaired insulin signaling in the brain could contribute to the formation of neurofibrillary tangles, which contain an abnormally hyperphosphorylated tau protein. This study aimed to determine whether potential tau hyperphosphorylation could be detected in an obesity-induced pre-diabetes state and whether anorexigenic agents could affect this state. We demonstrated that 6-month-old mice with monosodium glutamate (MSG) obesity, which represent a model of obesity-induced pre-diabetes, had increased tau phosphorylation at Ser396 and Thr231 in the hippocampus compared with the controls, as determined by western blots. Two weeks of subcutaneous treatment with a lipidized analog of prolactin-releasing peptide (palm-PrRP31) or with the T2DM drug liraglutide, which both had a central anorexigenic effect, resulted in increased phosphorylation of the insulin cascade kinases PDK1 (Ser241), Akt (Thr308), and GSK-3β (Ser9). Furthermore, these drugs attenuated phosphorylation at Ser396, Thr231, and Thr212 of tau and of the primary tau kinases in the hippocampi of 6-month-old MSG-obese mice. We identified tau hyperphosphorylation in the obesity-induced pre-diabetes state in MSG-obese mice and demonstrated the beneficial effects of palm-PrRP31 and liraglutide, both of known central anorexigenic effects, on hippocampal insulin signaling and on tau phosphorylation.

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization.

Canagliflozin (INVOKANA™) is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Canagliflozin inhibits renal sodium-glucose co-transporter 2 (SGLT2), thereby, reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Given the mechanism of action of SGLT2 inhibitors, we assessed the interplay between renal function, efficacy (HbA1c reduction), and safety (renal adverse reactions). The focus of this article is to highlight the FDA's quantitative clinical pharmacology analyses that were conducted to support the regulatory decision on dosing in patients with renal impairment (RI). The metrics for assessment of efficacy for T2DM drugs is standard; however, there is no standard method for evaluation of renal effects for diabetes drugs. Therefore, several analyses were conducted to assess the impact of canagliflozin on renal function (as measured by eGFR) based on available data. These analyses provided support for approval of canagliflozin in T2DM patients with baseline eGFR ≥ 45 mL/min/1.73 m(2) , highlighting a data-driven approach to dose optimization. The availability of a relatively rich safety dataset (ie, frequent and early measurements of laboratory markers) in the canagliflozin clinical development program enabled adequate assessment of benefit-risk balance in various patient subgroups based on renal function.

Overview of clinically approved oral antidiabetic agents for the treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and characterized by progressive pancreatic β-cell dysfunction. This articles reviews the application and limitations of currently approved oral drugs for the treatment of T2DM. Data were retrieved from the literature and well-recognized drug-related databases. Although lifestyle modifications and metformin are the cornerstones of the initial management of T2DM, there is an increasing array of second- and third-line pharmacological agents, including sulphonylureas, insulin, thiazolidinediones and glitazones, α-glucosidase inhibitors, glucagon-like peptide-1 agonists, dipeptidyl peptidase 4 inhibitors and the amylin receptor agonist pramlintide. Current T2DM treatment focuses on reducing blood glucose levels via different mechanisms, including nuclear hormone receptors, nucleic acid binding proteins, transcription factors, voltage-gated K(+) channels, glucosidase, G-protein-coupled receptors and non-receptor serine/threonine protein kinase. Extensive efforts are needed to address the pathogenesis of T2DM, which may facilitate the development of new therapies and the identification of new therapeutic targets to overcome the shortcomings of currently available drugs for T2DM and to achieve therapeutic goals.

Empagliflozin and metformin combination therapy in Type 2 diabetes mellitus

Diabetes mellitus (DM) is a spectrum of metabolic disorder characterized by chronic hyperglycemia either due to an absolute or a relative insulin deficiency. The prevalence of diabetes varies between various countries and ethnic groups and of late, it has reached epidemic proportions in both the developed as well as in the developing countries. There is an intense need for new and effective therapies for Type 2 DM (T2DM) with improved safety and tolerability profiles to reduce the outcome of the acute and chronic complications of this condition. Empagliflozin is a new class of selective sodium glucose cotransporter-2 inhibitor approved for the treatment of T2DM in 2014. It has a novel and a unique mechanism of action in that it inhibits the reabsorption of glucose in the kidneys, promotes excessive glucose excretion through a non-insulin dependent mechanism and induces glycosuria. Metformin is the only biguanide which is currently the widely accepted first-line drug for T2DM. It is effective as monotherapy and as combination therapy and has proven beneficial effects on microvascular and macrovascular complications of DM. Recently, the US Food and Drug Administration has approved the fixed dose combination of empagliflozin with metformin hydrochloride during August 2015. The combination of empagliflozin/metformin hydrochloride can be used as an adjunctive therapy to diet and exercise in patients those who are not adequately controlled with monotherapy of either empagliflozin or metformin. This drug update focuses on the insulin-independent unique mechanism of action of empagliflozin and its beneficial effects alone and in combination with metformin in patients with T2DM.

Patient profiling in diabetes and role of canagliflozin

Patient profiling in diabetes and role of canagliflozin Ambika Amblee1,2 1Division of Endocrinology, John H Stroger Jr Hospital of Cook County, 2Rush University Medical Center, Chicago, IL, USA Background: Physicians attempt to achieve glycemic goals in patients with type 2 diabetes mellitus (T2DM) through various means, including glucose-lowering medications. There is interindividual variability in response to medications, which can be partially explained by the presence of genetic polymorphisms that affect drug metabolism. Pharmacogenomics studies the hereditary basis of interpatient variations in drug response and aims to identify subgroups of patients whose drug management could be tailored accordingly. The aim of this review is to explore patient profiling in the management of T2DM with a focus on the sodium glucose transporter inhibitor canagliflozin. Methods: The PubMed database was searched using the terms “pharmacogenomics” and “diabetes” through May 31, 2014. Published articles and abstracts presented at national/international meetings were considered. Results and conclusion: Genome-wide association studies have opened the door for patient profiling and research into genetic variants in multifactorial T2DM. Clinically, it may be possible to tailor the type of medication used based on the presence or absence of the various genetic variants. However, the polymorphisms studied may only explain some of the variability in response to T2DM drugs and needs further validation to ensure its authenticity. There are still unidentified factors which appear to play a role in the interindividual variability seen in clinical practice. The potential exists for pharmacogenomics to promote efficacious, safe, and cost-effective individualized diabetes management. Pharmacogenomics is still in its early stages, and the idea of defining patients genetically to predict individual responses to drugs and obtain safe and effective T2DM management is promising, in spite of existing barriers. Currently, clinical profiling of patients with T2DM and using an individualized approach with most drugs, including canagliflozin, based on comorbid conditions still remains the most accepted approach for the management of T2DM. Keywords: personalized medicine, pharmacogenomics, genetic variants

Network signatures link hepatic effects of anti-diabetic interventions with systemic disease parameters.

BackgroundMultifactorial diseases such as type 2 diabetes mellitus (T2DM), are driven by a complex network of interconnected mechanisms that translate to a diverse range of complications at the physiological level. To optimally treat T2DM, pharmacological interventions should, ideally, target key nodes in this network that act as determinants of disease progression.ResultsWe set out to discover key nodes in molecular networks based on the hepatic transcriptome dataset from a preclinical study in obese LDLR-/- mice recently published by Radonjic et al. Here, we focus on comparing efficacy of anti-diabetic dietary (DLI) and two drug treatments, namely PPARA agonist fenofibrate and LXR agonist T0901317. By combining knowledge-based and data-driven networks with a random walks based algorithm, we extracted network signatures that link the DLI and two drug interventions to dyslipidemia-related disease parameters.ConclusionsThis study identified specific and prioritized sets of key nodes in hepatic molecular networks underlying T2DM, uncovering pathways that are to be modulated by targeted T2DM drug interventions in order to modulate the complex disease phenotype.

Obesity and Diabetes Mellitus

Backgrounds: Generally, a prevalence of obesity increasing constantly represents one of major health care and social problems. Many researchers indicate that obesity has a risk factor for type 2 diabetes mellitus (T2DM), but some persons believe that obesity may occur T2DM. GLP-1 and GIP as incretin hormone are secreted in response to ingestion of nutrients. In the circulation, they are rapidly inactivated by dipeptidyl peptidase-4. We report interesting findings on secretion of incretin after test meal (TM) in Japanese patients with type 1 diabetes mellitus (T1 DM) and T2DM associated with or without obesity. Materials and Methods: In Japan, ≧ 25 kg/m2 in BMI are defined as obesity. After overnight fast, subjects were ingested of TM (550 kcal) comprised of 60% carbohydrate, 23% fat and 17% protein. Based on GLP-1, patients with T1DM (n=10) were treated with multiple daily injections of insulin (MDI) or CSII. Non-obese (n=23) and obese (n=24) patients with T2DM with micro- and macroangiopathy were treated with oral drugs for various disease. Based on GIP, patients with T1DM (n=15) and T2DM (n=29) were treated with MDI or CSII for T1DM and oral drugs for T2DM, respectively. Results: Basal and postprandial levels of plasma active GLP-1 (p-GLP-1) after TM in Japanese patient with T1DM and T2DM are similar to those with control, but basal and postprandial ratio of p-GLP-1/glucose are low compared with controls. AUCs of plasma GIP at early-phase were significant negatively and positively related to BMI in patients with T1DM and T2DM, respectively. Conclusions: Japanese patients with T2DM regards of obesity may have a low secretion of GLP-1, which may be due to genetic factors. However, there is no T2DM in obese persons without low secretion of GLP-1. Therefore, risk factors for DM are important to diagnose T2DM.

Using spatial analysis to predict health care use at the local level: a case study of type 2 diabetes medication use and its association with demographic change and socioeconomic status.

Local health status and health care use may be negatively influenced by low local socio-economic profile, population decline and population ageing. To support the need for targeted local health care, we explored spatial patterns of type 2 diabetes mellitus (T2DM) drug use at local level and determined its association with local demographic, socio-economic and access to care variables. We assessed spatial variability in these associations. We estimated the five-year prevalence of T2DM drug use (2005–2009) in persons aged 45 years and older at four-digit postal code level using the University of Groningen pharmacy database IADB.nl. Statistics Netherlands supplied data on potential predictor variables. We assessed spatial clustering, correlations and estimated a multiple linear regression model and a geographically weighted regression (GWR) model. Prevalence of T2DM medicine use ranged from 2.0% to 25.4%. The regression model included the extent of population ageing, proportion of social welfare/benefits, proportion of low incomes and proportion of pensioners, all significant positive predictors of local T2DM drug use. The GWR model demonstrated considerable spatial variability in the association between T2DM drug use and above predictors and was more accurate. The findings demonstrate the added value of spatial analysis in predicting health care use at local level.

Inhibition of the sodium glucose co‐transporter‐2: its beneficial action and potential combination therapy for type 2 diabetes mellitus

Sodium glucose co-transporter-2 (SGLT2) inhibitors are an emerging class of glucose-lowering drugs in the management of type 2 diabetes mellitus (T2DM). In this context, SGLT2 is a low-affinity, high-capacity transporter that is expressed predominantly in the proximal renal tubules. The rationale for using SGLT2 inhibition as a drug for T2DM is derived from early evidence obtained from individuals with familial renal glycosuria, due to a SGLT2 mutation, which exhibits decreased renal tubular reabsorption of glucose in the absence of hyperglycaemia or any other signs of dysfunction. Thus, reduction of glucose reabsorption by SGLT2 inhibition represents a novel T2DM treatment approach. In light of the emerging role of SGLT2 inhibition in controlling glucose homeostasis, the current review provides a critical appraisal of the rationale, overviews of structural differences between SGLT2 inhibitors and summarizes recent preclinical and clinical studies. The physiological actions of SGLT2 inhibition in relation to insulin sensitivity, islet morphology, inflammation, body weight and blood pressure are reviewed. Finally, the safety and tolerability of SGLT2 inhibitors are also discussed in relation to their potential to provide insulin independence and enhance β-cell function, as well as their potential for synergistic/additive effects if used in combination with other antidiabetic drugs.