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1.
Efficacy of ipragliflozin as monotherapy or as add-on therapy with other oral antidiabetic medications for treating type 2 diabetes in Japanese patients with inadequate glycemic control: A subgroup analysis based on patient characteristics.
Osonoi, T, Nakamoto, S, Saito, M, Tamasawa, A, Ishida, H, Osonoi, Y
Journal of diabetes investigation. 2018;(2):341-353
Abstract
AIMS/INTRODUCTION The aim of the present study was to evaluate the efficacy and safety of ipragliflozin in treating Japanese type 2 diabetes patients with inadequate glycemic control by investigating diurnal variations of blood glucose and body composition. MATERIALS AND METHODS This was an investigator-initiated, multicenter, prospective study with a 6-month treatment period. The primary outcome investigated was change in hemoglobin A1c levels from baseline. Secondary outcomes included changes in fasting plasma glucose, insulin resistance, variations in 24-h glucose levels detected by continuous glucose monitoring, bodyweight, body composition, waist circumference and serum lipids. Adverse events were evaluated throughout the study. RESULTS A total of 98 patients completed the study. Over the 6-month period, ipragliflozin-treated patients showed reduction in hemoglobin A1c levels by 0.3%, fasting plasma glucose levels by 13.0 mg/dL, bodyweight by 2.1 kg, body fat mass by 1.5 kg and extracellular water by 0.3 kg, as well as a decrease in systolic/diastolic blood pressures. Significant reductions from baseline in mean amplitude of glucose excursions and standard deviation, and the reduced frequency of hyperglycemia were confirmed. High-density lipoprotein cholesterol was also significantly improved. Notably, the subgroup analysis of hemoglobin A1c levels, bodyweight, waist circumference, and body composition based on age, sex and body mass index showed similar reductions within each subgroup. The incidences of adverse events and adverse drug reactions were 20.0% and 1.0%, respectively, over the 6-month period. CONCLUSIONS Ipragliflozin is a useful oral antidiabetic medication for patients with a wide range of background characteristics.
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2.
Multinational Consensus: Insulin Initiation with Insulin Degludec/Aspart (IDegAsp).
Kalra, S, Atkin, S, Cervera, A, Das, AK, Demir, O, Demir, T, Fariduddin, M, Vo, KT, Ku, BJ, Kumar, A, et al
Advances in therapy. 2018;(7):928-936
Abstract
Insulin degludec/aspart (IDegAsp) is the first soluble insulin co-formulation, combining a long-acting insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp). In type 2 diabetes patients with oral antidiabetes agent (OAD) inadequacy, insulin initiation with IDegAsp once daily provides superior long-term glycemic control compared to insulin glargine, with similar fasting plasma glucose (FPG) and insulin doses, and numerically lower rates of overall and nocturnal hypoglycemia. Furthermore, in patients with uncontrolled type 2 diabetes previously treated with insulins, IDegAsp twice daily effectively improves glycated hemoglobin and FPG, with fewer hypoglycemic episodes versus premix insulins and basal bolus therapy. In patients with type 1 diabetes mellitus, IDegAsp once daily with two doses of IAsp is a convenient, yet effective, regimen as compared to the conventional 4-5 injection-based basal bolus therapy. IDegAsp is an appropriate and reasonable option for initiation of insulin therapy in both type 1 and type 2 diabetes.
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3.
Ertugliflozin: First Global Approval.
Markham, A
Drugs. 2018;(4):513-519
Abstract
Ertugliflozin (Steglatro™) is an orally active sodium glucose co-transporter type 2 inhibitor being developed by Merck and Pfizer as a treatment for type 2 diabetes mellitus (T2DM). Ertugliflozin as monotherapy and in combination with various other antidiabetic drugs was associated with improvements in glycaemic control and secondary outcome measures in the VERTIS phase III clinical trial program. Ertugliflozin and fixed-dose combinations of ertugliflozin and metformin (Segluromet™) and ertugliflozin and sitagliptin (Steglujan™) have recently been approved by the US FDA as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. These products have also received a positive opinion from the EU Committee for Medicinal Products for Human Use (CHMP). This article summarizes the milestones in the development of ertugliflozin leading to its first approval for T2DM.
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4.
Sodium-glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis; from Pathophysiology to Clinical Practice.
Patoulias, D, Manafis, A, Mitas, C, Avranas, K, Lales, G, Zografou, I, Sambanis, C, Karagiannis, A
Cardiovascular & hematological disorders drug targets. 2018;(2):139-146
Abstract
BACKGROUND SGLT-2 inhibitors are a novel class of antidiabetic drugs, recently approved for the treatment of patients with T2DM. Their cardioprotective and renoprotective action, along with their beneficial effects on metabolic parameters, makes them an attractive therapeutic option. Since 2015, when the US FDA issued warning regarding the increased risk of euDKA in the setting of SGLT-2 inhibitors administration, a vivid discussion upon the direct connection between this novel class and the major metabolic complication of diabetes mellitus is still ongoing. OBJECTIVES To present the underlying pathophysiology, associating SGLT-2 inhibitors and euDKA, and clinical data both in T1DM and in T2DM patients, in order to understand the clinical background which favors the development of euDKA. METHOD We conducted a comprehensive research of the relevant literature regarding the association between SGLT-2 inhibitors in clinical practice and the events of diabetic ketoacidosis, mainly euglycemic. RESULTS Randomized controlled trials, meta-analyses, case series and case reports shed light on this possible connection, the background that favors euDKA, and the mediating pathophysiologic mechanisms. Many of those euDKA events developed in patients with T1DM, due to off-label use of SGLT-2 inhibitors, or in patients previously misdiagnosed as having T2DM, who in fact suffered from LADA. CONCLUSION SGLT-2 inhibitors certainly predispose to euDKA, but it is unclear if, as certain precipitating factors are usually recognized on the background, DKA would also occur in the absence of an SGLT-2 inhibitor. Further investigation is required in order to establish or not SGLT- 2 inhibitors as causative factors of euDKA.
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5.
Comparison between sodium-glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta-analysis.
Cho, YK, Kim, YJ, Kang, YM, Lee, SE, Park, JY, Lee, WJ, Jung, CH
Journal of diabetes investigation. 2018;(4):882-892
Abstract
AIMS/INTRODUCTION We aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus. MATERIALS AND METHODS We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly. RESULTS A total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] -0.01% [-0.1 mmol/mol], 95% confidence interval [CI] -0.25 to 0.22% [-2.7 to -2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD -0.90 mg/dL, 95% CI: -15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c <7.0% (<53.0 mmol/mol; relative risk 0.98, 95% CI: 0.73 to 1.33; P = 0.917) as compared with the PIO/INS group, with greater weight reduction (WMD -4.54 kg, 95% CI: -5.67 to -3.41 kg; P < 0.001). PIO/INS showed non-significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin doses (WMD -2.45 IU/day, 95% CI: -7.30 to 2.40 IU/day; P = 0.438). CONCLUSIONS Both PIO and SGLT2i are feasible adjunctive oral agents to pre-existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus.
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6.
Effectiveness of a diabetes prevention program for rural women with prior gestational diabetes mellitus: study protocol of a multi-site randomized clinical trial.
Guo, J, Tang, Y, Wiley, J, Whittemore, R, Chen, JL
BMC public health. 2018;(1):809
Abstract
BACKGROUND In China, about 53.4 million women (11%) have type 2 diabetes (T2DM). Women with prior 2 (GDM) are at a high risk for T2DM. Postpartum lifestyle interventions have been effective in reducing T2DM for this population, but the evidence is limited to interventions provided in urban areas, despite the fact that a higher prevalence of undiagnosed T2DM was found in rural areas in China. The primary purpose of this proposed study is to examine the effect of a postpartum intensive lifestyle modification (ILSM) program on physiological health outcomes (T2DM development, insulin resistance, and weight-related variables), weight-related health behaviors (dietary intake and physical activity), and psychosocial outcomes (self-efficacy, perceived stress, social support, and health-related quality of life) compared to usual care at 3, 6, and 18 months post baseline assessment. The secondary outcomes are to identify potential mediators and moderators on change of physiological health outcomes. METHODS/DESIGN A multi-site randomized clinical trial (RCT) will be conducted to examine the efficacy of an evidence-based Intensive Lifestyle Modification (ILSM) program compared with usual care for women with prior GDM living in rural areas in China. A total sample of 256 participants will be recruited in the study. The intervention consists of six bi-weekly in-person group sessions, five bi-weekly telephone consultation sessions, and three monthly telephone consultations to encourage behavior change. The usual care provided to the control group will utilize current clinical guideline and recommendations for T2DM prevention. Outcome measures include physiological variables (OGTT-2 h, HbA1c, weight, and waist circumference); weight-related health behavioral (dietary intake and physical activities); and psychosocial variables (self-efficacy and social support) at 3-, 6- and 18- month after baseline. We will also assess the potential cost-effectiveness of ILSM (net cost per T2DM case and per DALY averted) compared with usual care. DISCUSSION If successful, this ILSM program can be adapted and used in rural areas as a blueprint for clinical guidelines to decrease T2DM by improving postpartum GDM care in China. Findings of this study are expected to make a significant contribution to public health practice and health policy related to T2DM prevention in China. TRIAL REGISTRATION Chinese Clinical Trial Registry, ChiCTR1800015023 . Registered 1 March 2018 - Retrospectively registered, http://apps.who.int/trialsearch/default.aspx .
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7.
Comparison of non-insulin antidiabetic agents as an add-on drug to insulin therapy in type 2 diabetes: a network meta-analysis.
Yoon, JH, Min, SH, Ahn, CH, Cho, YM, Hahn, S
Scientific reports. 2018;(1):4095
Abstract
We aimed to evaluate the comparative efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2i), or thiazolidinedione (TZD) as an adjunctive treatment in patients with poorly controlled type 2 diabetes mellitus (T2DM) on insulin therapy. We searched Medline, Embase, the Cochrane Library, and ClinicalTrials.gov through April 2016. Bayesian network meta-analyses were performed with covariate adjustment. The primary outcome was the change in glycated hemoglobin A1c (HbA1c) from baseline. Fifty randomized controlled trials covering 15,494 patients were included. GLP-1RA showed the greatest HbA1c-lowering effect compared to the control (-0.84%; 95% credible interval, -1.00% to -0.69%), followed by TZD (-0.73%; -0.93 to -0.52%), SGLT2i (-0.66%; -0.84% to -0.48%), and DPP4i (-0.54%; -0.68% to -0.39%). SGLT2i showed the greatest fasting plasma glucose reduction. GLP-1RA and SGLT2i showed greater body weight reduction, whereas TZD increased body weight. TZD was ranked the highest in terms of insulin dose reduction. The risk of hypoglycemia was increased with TZD or GLP-1RA. The study provides the best available evidence on the comparative efficacy and safety of non-insulin anti-diabetic agents on top of pre-existing insulin therapy for inadequately controlled T2DM patients.
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8.
Cardiovascular effects of antidiabetic drugs.
Sørensen, AM, Christensen, MB
Drugs of today (Barcelona, Spain : 1998). 2018;(9):547-559
Abstract
Type 2 diabetes mellitus is a common and severe chronic metabolic disease, which confers increased risk of cardiovascular disease and mortality. During the last decade a large number of new drugs within the classes dipeptidyl peptidase 4 (DPP-4) inhibitors (DPP-4Is), glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and sodium/glucose cotransporter 2 (SGLT-2) inhibitors (SGLT-2Is) have been developed and tested in nine large-scale cardiovascular outcome trials (CVOTs). Here we review the evidence behind antihyperglycemic treatment of patients with type 2 diabetes with a particular focus on compiling and summarizing the evidence of hard clinical endpoints stemming from these large CVOTs.
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9.
The place of gliclazide MR in the evolving type 2 diabetes landscape: A comparison with other sulfonylureas and newer oral antihyperglycemic agents.
Colagiuri, S, Matthews, D, Leiter, LA, Chan, SP, Sesti, G, Marre, M
Diabetes research and clinical practice. 2018;:1-14
Abstract
The sulfonylureas are effective oral glucose-lowering agents with a long history of clinical use. While all have the same general mechanism of action, their pharmacokinetic properties are influenced by factors such as dosage, rate of absorption, duration of action, route of elimination, tissue specificity, and binding affinity for pancreatic β-cell receptor. The result is a class of agents with similar HbA1c-lowering efficacy, but well-documented differences in terms of effects on hypoglycemia, and cardiovascular and renal safety. This review examines the differences between currently available sulfonylureas with a focus on how gliclazide modified release (MR) differs from other members of this class and from newer oral antihyperglycemic agents in the form of dipeptidyl peptidase-4 (DPP4) and sodium- glucose cotransporter 2 (SGLT2) inhibitors. The first part focuses on major outcome trials that have been conducted with the sulfonylureas and new oral agents. Consideration is then given to factors important for day-to-day prescribing including efficacy and durability, weight changes, hypoglycemia, renal effects and cost. Based on current evidence, third-generation sulfonylureas such as gliclazide MR possess many of the properties desired of a type 2 diabetes drug including high glucose-lowering efficacy, once-daily oral administration, few side effects other than mild hypoglycemia, and cardiovascular safety.
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10.
Effects of testosterone supplementation therapy on lipid metabolism in hypogonadal men with T2DM: a meta-analysis of randomized controlled trials.
Zhang, KS, Zhao, MJ, An, Q, Jia, YF, Fu, LL, Xu, JF, Gu, YQ
Andrology. 2018;(1):37-46
Abstract
Testosterone supplementation may be effective for the treatment of hypogonadism in men with type 2 diabetes mellitus (T2DM), but the evidence from randomized controlled trials (RCTs) is inconclusive. We aimed to systematically summarize results from intervention studies and assess the effects of testosterone supplementation therapy (TST) on lipid metabolism in RCTs of hypogonadal men with T2DM by meta-analysis. PubMed, Embase, and Cochrane Library databases were searched for studies reporting the effect of TST on lipid metabolism in hypogonadal men with T2DM until December 31, 2016. Seven RCTs from 252 trials, enrolling a total of 612 patients in the experimental and control groups with a mean age of 58.5 years, were included in this study. The pooled results of the meta-analysis demonstrated that TST significantly decreased TC and TG levels in hypogonadal men with T2DM compared with the control group, with mean differences (MDs) of -6.44 (95% CI: -11.82 to -1.06; I2 = 28%; p = 0.02) and -27.94 (95% CI: -52.33 to -3.54; I2 = 76%; p = 0.02). Subgroup analyses revealed that the heterogeneity (I2 = 76%) of TG originated from different economic regions, in which economic development, genetic and environmental factors, and dietary habits affect lipid metabolism of human, with a decrease (I2 = 45%) in developed countries. Additionally, subgroup analyses showed that TST increased HDL-C level in developing countries compared with the control group (MD = 2.79; 95% CI: 0.73 to 4.86; I2 = 0%; p = 0.008), but there was no improvement in developed countries (MD = 1.02; 95% CI: -4.55 to 6.60; I2 = 91%; p = 0.72). However, LDL-C levels were not improved consistently. Because the relationship between lipid metabolism and atherosclerosis is unequivocal, TST, which ameliorates lipid metabolism, may decrease the morbidity and mortality of cardiovascular disease in hypogonadal men with T2DM by preventing atherogenesis.