Low Risk Of Hypoglycemia Research Articles

A comparison of the clinical courses of type 2 diabetic patients whose basal insulin preparation was replaced from insulin glargine 100 units/mL to insulin glargine biosimilar or 300 units/mL: a propensity score-matched observation study

Objective: We compared the clinical course of type 2 diabetic patients whose basal insulin preparations were replaced from insulin glargine (IGlar) 100 units/mL (U100) to IGlar biosimilar or IGlar 300 units/mL (U300).Methods: After propensity score matching, 34 patients whose basal insulin preparation was switched from IGlar U100 to IGlar biosimilar and 102 switched to IGlar U300 were observed for 6 months.Results: The HbA1c level and body weight did not change significantly after the replacement in the IGlar biosimilar or IGlar U300 groups. In the IGlar biosimilar group, the frequency of subjects who experienced hypoglycemia after the replacement (12%) was not different from before (12%). However, the frequency was significantly lower after the replacement (2%) than before (13%) in the IGlar U300 group. The change in the HbA1c level after the replacement showed a significant association with the HbA1c level at the baseline but not with the kind of IGlar. Hypoglycemia was frequently observed in subjects who had experienced hypoglycemia before the replacement.Conclusions: IGlar biosimilar and IGlar U300 induced similar HbA1c and body weight changes among type 2 diabetic patients. IGlar biosimilar is a suitable option for patients with a low risk for hypoglycemia.

Acidosis láctica por metformina. Reporte de dos casos

Metformin is recommended as a first-line treatment for patients with diabetes mellitus type 2; it has a cardiovascular protective effect, and low risk of hypoglycemia. However, a severe but infrequent complication of its use is lactic acidosis, which has high morbidity and mortality rates. The estimated incidence of metformin lactic acidosis is 7,4 cases per 100.000 patients per year. Main risk factors are acute or chronic renal disease, congestive heart failure, hepatic failure, and concomitant use of drugs that affect metformin clearance or energy metabolism. Treatment includes hydration with crystalloids, support measures, and intravenous bicarbonate. Renal replacement therapy has been successful for treating metformin-associated lactic acidosis, but there are still no clear indications for it, because metformin is a partially dialyzable molecule and prolonged hemodialysis is required to reduce its levels sufficiently. Despite current treatment, mortality remains high. Early diagnosis and prompt multidisciplinary support are essential to improve outcome in these patients.

Hospitalisation Due to Heart Failure with Gliptins and Universal Label Change (FDA)-Still Justified? A Meta-Analysis of 5 Cardiovascular Outcomes Trials

Introduction: The addition of gliptins in the management of type 2 diabetes was a welcome addition due to its neutral impact on weight and lower risk of hypoglycemia in addition to moderate anti-hyperglycemic effects. They were also the first anti-hyperglycemic group exposed to the scrutiny of cardiovascular safety assessed through cardiovascular outcomes trial. The disparate signals emanating from the different CVOTs along with recent FDA label change (hospitalisation due to heart failure), prompted us in performing this meta-analysis.Materials and methods: After conducting an extensive database search, we selected 5 CVOTs for this metaanalysis based on a pre-specified set of inclusion criteria. Sufficient caution was exercised in analyzing data heterogeneity and detecting publication bias.Results: The meta-analysis of the 5 CVOTs with respect to hospitalization due to heart failure resulted in a risk ratio of 1.013 with a 95% CI of 0.857-1.197. The effect size analysed with the random effect model was statistically non-significant (P=0.879).Conclusion: This meta-analysis did not find a statistically significant increased risk for hHF in patients with high cardiovascular risk while on a gliptin.

CARDIOVASCULAR SAFETY OF GLIPTINS. FOCUS ON ALOGLIPTIN

Type 2 diabetes is a chronic progressive disease the prevalence of which is increasing. The development of new strategies for the treatment of diabetes, among which drugs that modulate the “incretin effect” are worth noting, continues. Dipeptidyl peptidase-4 inhibitors (DPP-4, gliptins) are a group of oral antidiabetic incretin drugs that enhance the glucose-induced activity of β-cells and suppress excessive glucagon secretion by pancreatic α-cells. This group of antidiabetic drugs is widespread due to a number of relevant benefits, such as neutral effect on body weight, low risk of hypoglycaemia, convenient administration scheme and good adherence to treatment. Efficacy and safety of treatment demonstrated by global multicenter trials allow for a wide use of gliptins in clinical practice.

Pharmacokinetic drug evaluation of exenatide for the treatment of type 2 diabetes

ABSTRACTIntroduction: Glucagon-like peptide-1 (GLP-1) receptor analogs are a group of therapeutic agents which mimic endogenous GLP-1, exerting their effect by the stimulation of the GLP-1 receptor with a wide distribution. Its activation increases insulin releasing dependent on blood glucose levels, suppression of glucagon secretion and a reduction of hepatic glucose output. It delays gastric emptying and increases satiety. Exenatide is the synthetic version of exendin-4, a natural peptide with similar properties to human GLP-1. There are two pharmaceutical forms, for subcutaneous injection: twice daily and once weekly.Clinical practice guidelines recommend them because of a high efficacy reducing hyperglycemia, low risk of hypoglycemia and a significative weight loss effect. Gastrointestinal adverse events are the most common beside injection site-related. Their cost is the main limitation to use.Areas covered: We review the recent literature investigating the pharmacokinetics and pharmacodynamics and efficacy-safety studies of exenatide twice daily and once weekly in type 2 diabetesExpert opinion: GLP-1 receptor analogs are now positioned as an effective and safe drug for the treatment of type 2 diabetes. Exenatide significally reduces HbA1c and fasting plasma glucose. Additionally, it produces moderate weight loss and decreases blood pressure. One weekly formulation may improve compliance while cost is still a limitation. EXSCEL trial has shown that, despite cardiovascular safety, exenatide do not exhibits cardiovascular benefits.

Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival.

AimsTo characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose‐lowering regimens with differing risks of hypoglycaemia.MethodsData were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose‐lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all‐cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time‐dependent covariable.ResultsThere were 6646 deaths in a total follow‐up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95‐1.12); sulphonylurea, aHR 1.11 (95% CI 0.99‐1.25); insulin, aHR 1.47 (95% CI 1.25‐1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94‐1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13‐1.35) and including insulin, aHR 1.28 (95% CI 1.18‐1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all‐cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia.ConclusionsThe pattern of mortality risk across the range of HbA1c differed by glucose‐lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.

Major adverse cardiovascular event reduction with GLP-1 and SGLT2 agents: evidence and clinical potential.

Treatment of patients with type 2 diabetes is directed against treating symptoms of hyperglycemia, minimizing the risk of hypoglycemia, and the risk of microvascular and macrovascular complications. The majority of patients with type 2 diabetes die from cardiovascular or cerebrovascular disease. Future therapies should therefore focus on reducing cardiovascular morbidity in this high-risk population. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are two drug classes with proven antihyperglycemic effect in type 2 diabetes. However, these drugs seem to have other effects such as weight reduction, low risk of hypoglycemia, and blood pressure reduction. Emerging evidence suggests pleiotropic effects, which potentially could be important in reducing cardiovascular risk. Prompted by regulatory authorities demanding cardiovascular outcome trials (CVOTs) assessing the cardiovascular safety of new antihyperglycemic drug candidates, many CVOTs are ongoing and a few of these are finalized. Somewhat surprising recent CVOTs in both drug classes have shown promising data on cardiovascular morbidity and mortality in patients with a very high risk of cardiovascular events. It is uncertain whether this is a class effect of the two drug classes, and it is yet unproven whether long-term cardiovascular benefits of these drugs can be extrapolated to populations at lower risk of cardiovascular disease. The aim of the present review is to give an overview of our current knowledge of the GLP-1RA and SGLT2-i classes, with specific focus on mechanisms of action, effects on cardiovascular risk factors and cardiovascular morbidity and mortality from the CVOTs presently available. The clinical potential of these data is discussed.

Gastric Contractility Modulation - a novel method for the treatment of type 2 diabetes mellitus and obesity.

Because the majority of antidiabetic medications are of limited efficacy and patient compliance with treatment is usually poor, new therapies are still being searched for. In the review a newly developed system for treatment of subjects with type 2 diabetes and concomitant overweight/obesity is described. The system consists of an implantable pulse generator that delivers electrical stimuli through leads implanted in the sero-muscular layer of the stomach. The device recognises and automatically modulates natural electrical activity of the stomach during meals, strengthening gastric contractility. This increase in the force of contractions enhances vagal afferent activity. Modulated signals are transmitted to the regulatory centres in the brain in order to provoke an early response of the gut typical of a full meal. Clinical trials performed to date show that the system improves glycaemic control with minimal patient compliance needed and with added benefits of body weight loss, a decrease in blood pressure, and favourable changes in the lipid profile. The system is safe, well-tolerated, with a low risk of hypoglycaemia, and will probably become an alternative to the use of incretins or to bariatric surgery in obese patients who are unwilling to undergo a major and anatomically irreversible operation.

Observational Registry of Basal Insulin Treatment in Patients with Type 2 Diabetes in China: Safety and Hypoglycemia Predictors.

The Observational Registry of Basal Insulin Treatment (ORBIT) study evaluated the safety of basal insulin (BI) in real-world settings in China. We analyzed 9002 patients with type 2 diabetes (T2D) inadequately controlled with oral hypoglycemic agents from 8 geographic regions and 2 hospital tiers in China who initiated and maintained BI treatment. Body weight and hypoglycemic episodes were recorded at baseline and 3 and 6 months. Serious adverse events (SAEs) were recorded at 3 and 6 months. Age, gender, inpatient/outpatient status, body mass index, glycated hemoglobin (HbA1c) at baseline and at the end of study, T2D duration, microvascular complications, BI type, combination with insulin secretagogues, self-monitoring of blood glucose frequency, and insulin dosage, all predicted hypoglycemia. BI use generally did not induce significant weight gain (0.02 kg); weight gain with insulin detemir (-0.30 kg) was less than that with neutral protamine Hagedorn (NPH) insulin (0.20 kg) or insulin glargine (0.05 kg). Overall, general hypoglycemia incidence (5.6% vs. 7.7%) and annual event rate (1.6 vs. 1.8) were similar before and after BI initiation, whereas a slight decrease was noted in severe hypoglycemia incidence (0.6%-0.3%) and frequency (0.05-0.03 events/patient-year). The general hypoglycemia rate was lowest with insulin glargine, whereas there was no significant difference in severe hypoglycemia among the three BI groups. Overall, 3.5% of patients had at least one SAE during the study. Most SAEs were found to be unrelated to BI treatment. Real-world BI use, particularly insulin detemir and glargine, was associated with only slight weight gain and low hypoglycemia risk in patients with T2D in China.

Evolution of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of antidiabetic drugs developed over the past 15 years. GLP-1, a gastrointestinal peptide hormone that contributes to the postprandial incretin effect, stimulates glucose-dependent insulin secretion. The incretin effect is greatly diminished in type 2 diabetes, but can be restored by GLP-1RAs. These drugs also exert other GLP-1 effects, including reducing glucagon secretion, delaying gastric emptying, reducing food intake, improving cardiac ventricular function, and lowering blood pressure. Short-acting GLP-1RAs are administered once daily (lixisenatide) or twice daily (exenatide); long-acting GLP 1RAs are administered once daily (liraglutide) or once weekly (slow-release exenatide, dulaglutide, albiglutide). All GLP-1RAs significantly reduce glycated hemoglobin (HbA1c) in patients with type 2 diabetes whose glycemic control is inadequate with oral antidiabetic drugs. Compared with other antidiabetic medications, GLP-1RAs provide better glycemic control with the additional benefit of weight loss. Within this class, long-acting GLP-1RAs are more efficacious than short-acting GLP-1RAs, with similar or lower risk of hypoglycemia and lower incidence of gastrointestinal adverse effects. Head-to-head trials and a network meta-analysis suggest that once daily liraglutide is the most effective GLP-1RA in reducing HbA1c. Dulaglutide is the only once-weekly GLP 1RA demonstrated to be noninferior to liraglutide. The once-weekly GLP-1RAs offer additional advantages to patients, including fewer injections and easy-to-use, single-dose pen devices. Despite the relatively recent development of GLP-1RAs, international diabetes guidelines recognize the benefits of this class of drugs and recommend them as a treatment option for patients with type 2 diabetes.

Monotherapy in patients with type 2 diabetes mellitus.

In order to improve the quality of life and to prevent chronic complications related to diabetes mellitus, intensive lifestyle modification and proper medication are needed from the early stage of diagnosis of type 2 diabetes mellitus (T2DM). When using the first medication for diabetic patients, the appropriate treatment should be selected considering the clinical characteristics of the patient, efficacy of the drug, side effects, and cost. In general, the use of metformin as the first treatment for oral hypoglycemic monotherapy is recommended because of its excellent blood glucose-lowering effect, relatively low side effects, long-term proven safety, low risk of hypoglycemia, and low weight gain. If metformin is difficult to use as a first-line treatment, other appropriate medications should be selected in view of the clinical situation. If the goal of achieving glycemic control is not achieved by monotherapy, a combination therapy with different mechanisms of action should be initiated promptly.

Effects of exenatide twice daily, exenatide once weekly or insulin in patients with type 2 diabetes and baseline HbA1c ≥10.0%: Two pooled analyses including 20 randomised controlled trials.

Patients with advanced type 2 diabetes (T2D) and high glycated haemoglobin (HbA1c) values can be difficult to treat because of their severe metabolic disease. This pooled analysis examined the treatment effects of exenatide twice daily (BID), exenatide once weekly (QW) and insulin in patients with high baseline HbA1c (≥10.0%). This post hoc analysis used pooled data from 12 and 8 randomised controlled trials of exenatide BID and exenatide QW, respectively. Patients with T2D who completed at least 24weeks of treatment with exenatide BID, exenatide QW or insulin (insulin glargine, insulin detemir or insulin aspart) were categorised by baseline HbA1c. Patients with HbA1c ≥10.0% were included in the analysis. Both exenatide and insulin reduced HbA1c (mean±SE reduction: -2.0%±0.2% [exenatide] and -2.1%±0.2% [insulin] in the exenatide BID studies, and -2.6%±0.1% [exenatide] and -2.1%±0.2% [insulin] in the exenatide QW studies; all P<.001). Body weight decreased with exenatide and increased with insulin. Systolic blood pressure decreased with exenatide QW. Insulin dose increased over the course of treatment. The most common adverse events with exenatide were gastrointestinal. Insulin was associated with some hypoglycaemia risk. Hypoglycaemia events occurred infrequently with exenatide when given without sulphonylureas. For patients with high HbA1c, treatment with exenatide or insulin both improved glycaemic control. Given the associated weight loss and low risk of hypoglycaemia, exenatide may be a suitable alternative to treatment with insulin in certain patients with T2D and high HbA1c.

Diabetes injectable therapy: type 2 diabetes management in Danish practice

Most diabetes care is done by GPs in Denmark. This study aimed to identify the barriers for GPs in initiating injectable therapies and reasons for referral to specialists. The web interview conducted included 85 GPs and 30 specialists experienced in type 2 diabetes (T2D). GPs felt more comfortable with initiating the first injectable therapy (defined as a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or basal insulin) than the second (defined as adding a basal insulin in patients treated with a GLP-1 RA (± oral anti-diabetic treatments [OADs]), or adding either a GLP-1 RA or a bolus insulin in patients treated with basal insulin (± OADs). The main barriers to initiating injectables were related to the complexity of available injectable therapies and the lack of comfort with complex patient profiles, namely patients with difficult glycemia control or significant comorbidities, whom GPs would rather refer to specialists. Main attributes that would increase the GPs’ comfort level with initiation of injectables are low risk of hypoglycemia, glycemic control improvement and ease of use of the treatment. An injectable therapy with such attributes could help to overcome barriers to initiating injectable in primary care.

A safety evaluation of empagliflozin plus linagliptin for treating type 2 diabetes

ABSTRACTIntroduction: Dipeptidyl-peptidase-IV inhibitors (DPP-4i) and sodium-glucose-transporter-2 inhibitors (SGLT-2i) are oral antidiabetic drugs that improve glycemic parameters and possess a very low intrinsic hypoglycemia risk and favorable cardiovascular data.Areas covered: An overview on the clinical studies investigating the combination therapy with the DPP-4i linagliptin and the SGLT-2i empagliflozin is given. The clinical evidence for the efficacy and safety of free combinations as well as for their fixed dose combinations is presented. Empagliflozin has recently proved to reduce cardiovascular risk in type 2 diabetes and cardiovascular high risk situations. A fixed dose combination (FDC) of empagliflozin and linagliptin as add on therapy to metformin or as initial treatment lowered the HbA1c by approximately 1.1% and reduced the body weight by 2.0–3.0 kg. The hypoglycemia risk was not significantly increased. The relevant studies were identified by a search in Medline and in clinicaltrials.gov.Expert opinion/commentary: A DPP-4i/SGLT-2i FDC may be especially useful to simplify treatment, to reduce the tablet burden and to increase medication adherence. This FDC may be particularly beneficial for patients where the reduction of body weight, blood pressure and cardiovascular risk are important and in whom hypoglycemia should be avoided.

Cost-Effectiveness Study To Evaluate Insulin Glargine Compared With NPH Insulin In Patients With Type 2 Diabetes Uncontrolled With Oral Anti-Diabetic Agents In Hong Kong

Insulin glargine is superior to neutral protamine Hagedorn (NPH) insulin in reducing blood glucose and has lower risk of hypoglycaemia. Due to higher acquisition costs, use of insulin glargine remains second-line in Hong Kong. We conducted a cost-effectiveness analysis of insulin glargine compared with NPH insulin by applying local patient and cost data to a published diabetes outcome model. The IMS CORE Diabetes Model Version 9.0 was used for projection of complication and economic outcomes. The model was populated with clinical data from the Hong Kong Diabetes Registry. We selected patients with type 2 diabetes, on non-insulin anti-diabetic drugs and were uncontrolled with HbA1c ≥7.5%. Efficacy of intervention with respect to reduction of HbA1c and rates of hypoglycaemia were based on results of Lantus Evaluation in Asian Diabetics study, which compared insulin glargine and NPH insulin in an Asian population. Costs of insulins and diabetes complications were assembled using cost data listed in Hospital Authority Gazette. Costs and outcomes were discounted at 3%/year. A simulation period of 50 years was applied. The simulation cohort had mean age 57.3±13.1years and HbA1c 8.9±1.5%, between 2-8% had established cardiovascular disease, and 23-29% had microvascular complications. Over 50-year simulation, total costs of treating diabetes which included costs related to diabetes complications were modestly higher with insulin glargine (HKD 708,250 [USD 91,142]) than NPH insulin (HKD 707,289 [USD 91,018]). Treatment with insulin glargine led to a gain in life year of 0.017 years/patient and in quality-adjusted life year (QALY) of 0.025 years/patient compared with treatment with NPH insulin. The incremental cost-effectiveness ratio of insulin glargine over NPH insulin was HKD 38,788 (USD 4,991)/QALY, which was below the current gross domestic product per capita in Hong Kong. Applying WHO threshold of cost-effectiveness, insulin glargine was highly cost-effective relative to NPH insulin.

Rationale, Design, and Baseline Characteristics of the Utopia Trial for Preventing Diabetic Atherosclerosis Using an SGLT2 Inhibitor: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study.

IntroductionSodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-diabetic agents that improve glycemic control with a low risk of hypoglycemia and ameliorate a variety of cardiovascular risk factors. The aim of the ongoing study described herein is to investigate the preventive effects of tofogliflozin, a potent and selective SGLT2 inhibitor, on the progression of atherosclerosis in subjects with type 2 diabetes (T2DM) using carotid intima-media thickness (IMT), an established marker of cardiovascular disease (CVD), as a marker.MethodsThe Study of Using Tofogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA) trial is a prospective, randomized, open-label, blinded-endpoint, multicenter, and parallel-group comparative study. The aim was to recruit a total of 340 subjects with T2DM but no history of apparent CVD at 24 clinical sites and randomly allocate these to a tofogliflozin treatment group or a conventional treatment group using drugs other than SGLT2 inhibitors. As primary outcomes, changes in mean and maximum IMT of the common carotid artery during a 104-week treatment period will be measured by carotid echography. Secondary outcomes include changes in glycemic control, parameters related to β-cell function and diabetic nephropathy, the occurrence of CVD and adverse events, and biochemical measurements reflecting vascular function.ConclusionThis is the first study to address the effects of SGLT2 inhibitors on the progression of carotid IMT in subjects with T2DM without a history of CVD. The results will be available in the very near future, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent CVD.FundingKowa Co., Ltd.Clinical Trial RegistrationUMIN000017607.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-017-0292-1) contains supplementary material, which is available to authorized users.

Canagliflozin: A Review in Type 2 Diabetes.

Canagliflozin (Invokana®) is a sodium-glucose co-transporter-2 (SGLT2) inhibitor indicated in various countries worldwide for the once-daily oral treatment of type 2 diabetes (T2D). Canagliflozin lowers blood glucose levels independently of insulin, with the inhibition of SGLT2 reducing renal reabsorption of glucose and increasing excretion of glucose in the urine. In well-designed clinical trials, canagliflozin (as first-line monotherapy or add-on therapy to other antihyperglycaemic agents) improved glycaemic control in adults with T2D, including those of older age and/or at high cardiovascular (CV) risk, and also had beneficial effects on their bodyweight and blood pressure (BP). CV risk reduction, as well as possible renal benefits, were also seen with canagliflozin in T2D patients at high CV risk in the CANVAS Program, an integrated analysis of two large CV outcomes studies. Canagliflozin was generally well tolerated, had a low risk of hypoglycaemia and was most commonly associated with adverse events such as genital and urinary tract infections and increased urination, consistent with its mechanism of action. Although the amputation and fracture risk observed among recipients of the drug require further investigation, canagliflozin is an important option for T2D management in adults.

Discovery of 2,3‐Dihydro‐1H‐indene Derivatives as Novel GPR40 Agonists

GPR40 (G protein‐coupled receptor 40) has become an attractive target for insulin secretagogue via glucose‐dependent mechanism with low risk of hypoglycemia. In order to overcome problems associated with previously developed GPR40 agonists, we recruited the core fragment 2,3‐dihydro‐1H‐indene to GPR40 receptor binding pharmacophore with carboxylic acid moiety, and screened various amine analogs to finally discover several hit compounds displaying GPR40 agonistic activities. Through additional in vitro ADME, pharmacokinetics, and in vivo efficacy evaluations, compound 1e was demonstrated as a potent lead GPR40 agonist.

Empagliflozin for Type 2 Diabetes Mellitus: An Overview of Phase 3 Clinical Trials.

Introduction:Sodium glucose cotransporter 2 (SGLT2) inhibitors have a unique mecha-nism of action leading to excretion of glucose in the urine and subsequent lowering of plasma glu-cose. This mechanism is independent of β-cell function; thus, these agents are effective treatment for type 2 diabetes mellitus (T2DM) at theoretically any disease stage. This class should not confer an additional risk of hypoglycemia (unless combined with insulin or an insulin secretagogue) and has the potential to be combined with other classes of glucose-lowering agents. Empagliflozin is one of three currently approved SGLT2 inhibitors in the United States, and has shown a favorable benefit-risk ratio in phase 3 clinical trials as monotherapy and as add-on to other glucose-lowering therapy in broad patient populations. In addition to its glucose-lowering effects, empagliflozin has been shown to reduce body weight and blood pressure without a compensatory increase in heart rate. Moreover, on top of standard of care, empagliflozin is the first glucose-lowering agent to demonstrate cardiovas-cular risk reduction in patients at high risk of cardiovascular disease in a prospective outcomes trial: a 14% reduction in risk of the 3-point composite endpoint of death from cardiovascular causes, nonfa-tal myocardial infarction, or nonfatal stroke. Like other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital mycotic infections than placebo and has the potential for volume deple-tion–associated events.Conclusion:This review summarizes the empagliflozin phase 3 clinical trials program and its poten-tial significance in the treatment of patients with T2DM. Evidence from these clinical trials show re-ductions in glycated hemoglobin (–0.59 to –0.82%) with a low risk of hypoglycemia except when used with insulin or insulin secretagogues, and moderate reductions in body weight (–2.1 to –2.5 kg) and systolic blood pressure (–2.9 to –5.2 mm Hg), thus supporting the use of empagliflozin as mono-therapy or in addition to other glucose-lowering agents. In addition, evidence from the recent EMPA-REG OUTCOME study, which demonstrated relative risk reductions in major adverse cardiac events (14%), cardiovascular mortality (38%) and all-cause mortality (32%), as well as hospitalization for heart failure (36%), supports use of empagliflozin in patients with T2DM and increased cardiovascu-lar risk.

A novel free fatty acid receptor 1 (GPR40/FFAR1) agonist, MR1704, enhances glucose-dependent insulin secretion and improves glucose homeostasis in rats.

Activation of G protein‐coupled receptor 40/Free fatty acid receptor 1 (GPR40/FFAR1), which is highly expressed in pancreatic β cells, is considered an important pharmacologic target for the treatment of type 2 diabetes mellitus. The aim of this study was to determine the effect of MR1704, a novel GPR40/FFAR1 agonist, on glucose homeostasis in rats. MR1704 is a highly potent and selective, orally bioavailable agonist with similar in vitro potencies among humans, mice, and rats. Treatment of rat islets with MR1704 increased glucose‐dependent insulin secretion. Augmentation of glucose‐dependent insulin secretion was abolished by adding a GPR40/FFAR1 antagonist. In mouse, insulinoma MIN6 cells, palmitic acid induced the activity of caspase 3/7 after a 72‐h exposure, while pharmacologically active concentrations of MR1704 did not. In an oral glucose tolerance test in normal Sprague‐Dawley rats, orally administered MR1704 (1–10 mg·kg−1) reduced plasma glucose excursion and enhanced insulin secretion, but MR1704 did not induce hypoglycemia, even at 300 mg·kg−1, in fasted Sprague‐Dawley rats. In addition, orally administered MR1704 reduced plasma glucose excursion and enhanced insulin secretion in diabetic Goto‐Kakizaki rats. Oral administration of MR1704 once daily to Goto‐Kakizaki rats reduced their blood glucose levels during a 5‐week treatment period without reducing pancreatic insulin content; as a result, hemoglobin A1C levels significantly decreased. These results suggest that MR1704 improves glucose homeostasis through glucose‐dependent insulin secretion with a low risk of hypoglycemia and pancreatic toxicity. MR1704 shows promise as a new, glucose‐lowering drug to treat type 2 diabetes mellitus.