Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes.

Introduction: Alpha-glucosidase inhibitors (AGIs) - oral antihyperglycemic drugs, inhibit upper gastrointestinal enzymes that break down complex carbohydrates into glucose. As a result, the absorption of glucose is delayed, postprandial glucose reduced, and glycemic control improved.Areas covered: In this review, the authors describe the current recommendations on the use of the three major approved AGIs (acarbose, miglitol, voglibose). Efficacy and safety parameters together with ethnic considerations have been highlighted throughout the manuscript. The article also discusses potential diabetes prevention and cardiovascular effects of these medications.Expert opinion: The overall safety and efficacy of this class of drug appears to be high: AGIs do not increase the risk of hypoglycemia, do not cause weight gain; they also significantly improve postprandial hyperglycemia, have been associated with the reduction in risk factors for cardiovascular disease and may also delay the progression of prediabetes to T2DM. In general, we continue to believe that acarbose, miglitol, and voglibose should be used as third-line add on treatment options to other anti-hyperglycemic agents. However, this class can have earlier consideration in elderly and/or when metformin is contraindicated.

Oral semaglutide for the treatment of type 2 diabetes.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists are highly potent antihyperglycemic drugs that impose low risk of hypoglycemia and also result in body weight reduction. Currently, all approved members of the class require administration by injection. Areas covered: This manuscript reviews oral semaglutide-an experimental GLP-1 receptor agonist in phase-3 clinical development. Available pharmacological and clinical data of the drug are reviewed, and important end-points described. Expert opinion: Oral peptide delivery has become possible with the discovery of absorption enhancers. The clinical development program of once-daily oral semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators (sitagliptin, liraglutide, and empagliflozin). Safety and tolerability of oral semaglutide is in line with injectable members of the class. Delayed gastric emptying, local increase in pH, and enhanced absorption do not seem to affect the exposure of a number of other oral drugs that have been tested (metformin, digoxin, oral contraceptive ethinylestradiol/levonorgestrel, lisinopril, warfarin, furosemide and rosuvastatin). Clinical questions for further investigation include the effectiveness and safety of oral semaglutide in cardiovascular indications.

Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver.

INTRODUCTION: Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity. Areas covered: This review will focus on fibrates - PPARα agonists and their implication in causing liver injury. Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.

Subcutaneous semaglutide (NN9535) for the treatment of type 2 diabetes.

INTRODUCTION: It is critical for individuals with type 2 diabetes mellitus (T2DM) to maintain optimal glycemia while avoiding hypoglycemia, control body weight, and reduce cardiovascular risk. The GLP-1 receptor agonists stimulate glucose-dependent insulin release (low risk of hypoglycemia), inhibit glucagon secretion, slow gastric emptying and suppress appetite (weight loss). The new members of the class are available as once daily or weekly injections. Additionally, some members of the class have demonstrated reduced cardiovascular risk. Areas covered: This manuscript describes semaglutide - a new investigational long acting GLP-1 receptor agonist. The key trials from the clinical development process are reviewed and important end-points highlighted. Expert opinion: Once-weekly semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators when used as monotherapy or in combination treatment. In addition, semaglutide improved markers of ß-cell function and have shown cardiovascular risk reduction similar to once daily liraglutide. Although, overall semaglutide safety was comparable to other GLP-1 receptor agonists (low risk of hypoglycemia and high frequency of gastrointestinal side effects), increase in retinopathy complications requires further investigation.

The care of pregestational and gestational diabetes and drug metabolism considerations.

INTRODUCTION: Normal pregnancy development involves gradual decline in insulin sensitivity, which sometimes requires pharmacotherapy. Insulin is the drug of choice for gestational and pregestational diabetes. Metabolism of traditional insulins results in inadequate onset and duration of action and marked peak activity. These properties increase risk of excessive glucose excursions, which are especially undesirable during pregnancy. Insulin analogs have been emerging as a safer and more effective treatment of diabetes during pregnancy. Areas covered: This manuscript reviews currently used antihyperglycemic agents: fast and long-acting insulins, metformin and glyburide. Trials demonstrating their efficacy and safety during pregnancy are described. Certain drug metabolism considerations (e.g. affinity to IGF-1) are emphasized. Expert opinion: The theories that insulin analogs bind to immunoglobulin and cross placenta have been disproved. Lispro, aspart, glargine and detemir do not transfer across the placenta and do not result in adverse maternal and neonatal outcomes. In addition, favorable pharmacokinetic profiles (rapid onset and 24-hour near peakless activity) substantially reduce blood glucose variability including hypoglycemia. We believe that insulin analogs should be given strong consideration for the treatment of diabetes during pregnancy. Metformin has also proven to be safe and may be considered as an initial single agent for milder gestational diabetes.

Discontinued drug therapies to treat diabetes in 2015.

INTRODUCTION: This manuscript describes 21 drug targets in the area of diabetes and related conditions that were discontinued in 2015. Areas covered: The material for this paper was obtained by contacting biopharmaceutical companies, reviewing their pipelines, press releases and annual reports. Additionally, the authors searched clinicaltrials.gov, PubMed and general Internet search engines. Majority of the compounds were in early stages of the development. Expert opinion: Business reasons for termination of the drug projects emerge more and more frequently over the years. Safety signals usually appear early in the development and are often associated with novel drugs. 2015 medicines with inadequate efficacy were unable to compete with existing approved members of the class they represented.

Acute Effects of Oral Dehydroepiandrosterone on Counterregulatory Responses During Repeated Hypoglycemia in Healthy Humans.

We tested the hypothesis that acute administration of oral dehydroepiandrosterone (DHEA) during episodes of repeated hypoglycemia can prevent the development of hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans. Twenty-seven individuals (16 men, 11 women) participated in two separate randomized, single-blind, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hypoglycemic clamps (2.9 mmol/L) with 800 mg of DHEA or placebo administered before each clamp. Day 2 consisted of a single 2-h hypoglycemic clamp (2.9 mmol/L) following either DHEA (1,600 mg) or placebo. A 3-tritiated glucose was used to determine glucose kinetics during hypoglycemia on day 2. Antecedent hypoglycemia with placebo resulted in significant reductions of epinephrine, norepinephrine, glucagon, growth hormone, cortisol, endogenous glucose production, and lipolytic and symptom responses. During hypoglycemia on day 2, DHEA prevented blunting of all neuroendocrine, autonomic nervous system (ANS), metabolic, and symptom counterregulatory responses following hypoglycemia on day 1. In summary, DHEA can acutely preserve a wide range of key neuroendocrine, ANS, and metabolic counterregulatory homeostatic responses during repeated hypoglycemia. We conclude that DHEA may have acute effects to protect against hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans.

Effects of γ-Aminobutyric Acid A Receptor Activation on Counterregulatory Responses to Subsequent Exercise in Individuals With Type 1 Diabetes.

The effects of γ-aminobutyric acid (GABA) A receptor activation on physiologic responses during next-day exercise in type 1 diabetes are unknown. To test the hypothesis that GABA A activation with the benzodiazepine alprazolam would blunt counterregulatory responses during subsequent exercise, 29 (15 male, 14 female) individuals with type 1 diabetes (HbA1c 7.8 ± 1%) were studied during separate 2-day protocols. Day 1 consisted of morning and afternoon 2-h euglycemic or 2.9 mmol/L hypoglycemic clamps with or without 1 mg alprazolam given 30 min before each clamp. Day 2 consisted of a 90-min euglycemic cycling exercise at 50% VO2max Tritiated glucose was used to measure glucose kinetics. Despite equivalent day 2 insulin (93 ± 6 pmol/L) and glucose levels (5.3 ± 0.1 mmol/L), plasma epinephrine, norepinephrine, glucagon, cortisol, and growth hormone responses were similarly reduced after alprazolam or day 1 hypoglycemia compared with euglycemic control. Endogenous glucose production, lipolysis (glycerol, nonesterified fatty acid), and glycogenolysis (lactate) were also reduced during day 2 exercise after day 1 GABA A activation. We conclude that activation of GABA A receptors with alprazolam can result in widespread neuroendocrine, autonomic nervous system, and metabolic counterregulatory failure during subsequent submaximal exercise and may increase the risk of exercise-associated hypoglycemia in individuals with type 1 diabetes.

The role of empagliflozin in the management of type 2 diabetes by patient profile.

Current recommendations for the management of type 2 diabetes mellitus (T2DM) include patient-centered approach, ie, targeting glycemic control based on patient and disease characteristics. Ten different classes of oral and injectable anti-hyperglycemic agents have been developed for T2DM, including the newest class - sodium-glucose cotransporter 2 (SGLT2) inhibitors. Four members of the class with comparable glycemic efficacy and side effects have gained approval in the US and the rest of the world. This review covers empagliflozin - third approved SGLT2 inhibitor in the US. The drug has shown rapid absorption reaching peak levels in ~2 hours and an elimination half-life of ~13 hours. Empagliflozin is a highly selective SGLT2 inhibitor with 2600-fold higher affinity for SGLT2 compared with SGLT1. Oral administration results in a dose-dependent inhibition of the transporters with increased urinary glucose excretion and resultant reduction in plasma glucose. Its efficacy and safety have been shown in a number of studies conducted in many countries. Across the trials, significant improvements in primary and secondary efficacy end points have been demonstrated, including reductions in HbA1c (~-0.8%), fasting plasma glucose (~-2 mmol/L), body weight (~-2 kg), and blood pressure (systolic -4 mmHg and diastolic -2 mmHg). Similar to other SGLT2 inhibitors, empagliflozin does not increase the risk for hypoglycemia, and the most commonly reported side effects are urinary and genital tract infections. Although empagliflozin can be used as the first-line monotherapy, its current place in the treatment of T2DM appears to be as an add-on to other oral anti-hyperglycemic agent(s) or insulin at any stage of the disease.

Sexual Dimorphism in Glucose and Lipid Metabolism during Fasting, Hypoglycemia, and Exercise.

Sexually dimorphic physiologic responses occur during fasting, hypoglycemia, and exercise. The areas covered in this mini review include studies that have used isotopic tracer methods and/or euglycemic clamp studies to investigate substrate metabolism during the above common physiologic stress. Women have greater reliance on lipid metabolism during fasting, hypoglycemia, and exercise while men exhibit preference of carbohydrate utilization. Plasma glucose concentrations were shown to be lower, while free fatty acids (FFA) and lipolysis higher in women compared to men after fasting. Hypoglycemia resulted in significantly reduced epinephrine, norepinephrine, glucagon, growth hormone, pancreatic polypeptide, and hepatic glucose production responses in females as compared to males. Sexual dimorphism during exercise was demonstrated by higher glycerol and FFA responses in women compared to men and higher carbohydrate oxidation rate in men. Mechanisms that can increase lipolytic rates in women include higher total fat mass, enhanced lipolytic sensitivity to epinephrine, and increased activation of ß adrenergic receptors.

Effects of Antecedent GABA A Receptor Activation on Counterregulatory Responses to Exercise in Healthy Man.

The aim of this study was to determine whether antecedent stimulation of γ-aminobutyric acid (GABA) A receptors with the benzodiazepine alprazolam can blunt physiologic responses during next-day moderate (90 min) exercise in healthy man. Thirty-one healthy individuals (16 male/15 female aged 28 ± 1 year, BMI 23 ± 3 kg/m(2)) were studied during separate, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic-euglycemic or hypoglycemic clamps with or without 1 mg alprazolam given 30 min before a clamp. Day 2 consisted of 90-min euglycemic cycling exercise at 50% VO2max. Despite similar euglycemia (5.3 ± 0.1 mmol/L) and insulinemia (46 ± 6 pmol/L) during day 2 exercise studies, GABA A activation with alprazolam during day 1 euglycemia resulted in significant blunting of plasma epinephrine, norepinephrine, glucagon, cortisol, and growth hormone responses. Lipolysis (glycerol, nonesterified fatty acids) and endogenous glucose production during exercise were also reduced, and glucose infusion rates were increased following prior euglycemia with alprazolam. Prior hypoglycemia with alprazolam resulted in further reduction of glucagon and cortisol responses during exercise. We conclude that prior activation of GABA A pathways can play a significant role in blunting key autonomous nervous system, neuroendocrine, and metabolic physiologic responses during next-day exercise in healthy man.

Ipragliflozin , a sodium-glucose cotransporter 2 inhibitor, in the treatment of type 2 diabetes.

INTRODUCTION: Type 2 diabetes is the fastest growing non-communicable chronic disease worldwide. One of the newer treatment options is the class of sodium-glucose cotransporter 2 inhibitors that offer improved glycemia through increased urinary glucose excretion. The class has shown to be effective, safe and well-tolerated in newly diagnosed and long-standing diabetes. Additional benefits of the inhibitors include low risk of hypoglycemia and weight loss. AREAS COVERED: This perspective reviews ipragliflozin - a sodium-glucose cotransporter 2 inhibitor - that has gained approval for clinical use in Type 2 diabetes in Japan. The paper discusses pharmacokinetics (PK), pharmacodynamics, clinical efficacy, safety and tolerability of the drug. EXPERT OPINION: Due to its efficacy (hemoglobin A1c reduction of ≈1%), safety (low risk of hypoglycemia and very low rate of urinary tract infections), favorable PK interaction with other anti-diabetes medications and mechanism of action that is independent from ß-cell function and insulin sensitivity, ipragliflozin can be used as a monotherapy or as an add-on to other agents in any stage of Type 2 diabetes.

Discontinued in 2013: diabetic drugs.

INTRODUCTION: The increasing prevalence of diabetes, with no cure on the horizon, continues to provide biopharmaceutical companies with an incentive to develop novel therapies and improve existing compounds. AREAS COVERED: The following paper provides a summary of the experimental drug projects targeted for diabetes and associated complications that were discontinued in 2013. The discontinued projects, highlighted in this article, were identified via biopharmaceutical company pipelines, annual reports, and press releases. The authors also used other sources including: Google, ClinicalTrials.gov, and PubMed. Compounds were in various stages of development at termination and many of them had been associated with favorable effects in earlier studies. EXPERT OPINION: There were two main reasons for the termination of anti-diabetic compounds that dominated 2013: concerns about safety and efficacy. Attempts to discover a novel mechanism that is both safe and effective in human disease present many challenges, not least is the cost for developing new treatments.

Mechanisms of hypoglycemia and exercise-associated autonomic dysfunction.

It is well established that diabetes can lead to multiple microvascular and macrovascular complications. Several large scale randomized multicenter studies have shown that intensifying glucose control decreases microvascular and, to a certain extent, macrovascular complications of diabetes. However, intensifying glucose control in both type 1 and type 2 diabetes increases the risk of developing hypoglycemia, one of the most feared complications of people with the disease. The mechanisms responsible for intensive therapy causing increased hypoglycemia in patients with diabetes have been extensively investigated. It is now known that a single episode of hypoglycemia can blunt the body's normal counterregulatory defenses against subsequent hypoglycemia or exercise. Similarly, a single bout of exercise can also blunt counterregulatory responses against subsequent hypoglycemia. Both neuroendocrine and autonomic nervous system responses are reduced by prior hypoglycemia and/or exercise. Work from several laboratories has identified multiple physiologic mechanisms involved in the pathogenesis of this hypoglycemia and exercise-associated counterregulatory failure. By continuing to study these mechanisms, some promising approaches to amplify counterregulatory responses to hypoglycemia are being discovered.

Basal insulin treatment in type 2 diabetes.

Insulin glargine is the first 24-h recombinant DNA insulin analog introduced to the market. Substitution of glycine for asparagine and addition of two arginine residues raise the isoelectric point of insulin glargine and result in microprecipitates, delaying absorption from subcutaneous tissue. This delayed absorption result in fairly flat 24-h insulin concentration profiles with no discernible peak. Large, multicenter, randomized, controlled trials in patients with type 2 diabetes show that although NPH insulin and insulin glargine are equally effective in lowering glycosylated hemoglobin (A1c) and fasting blood glucose, there is a clear advantage of insulin glargine over NPH insulin in reducing nocturnal and overall hypoglycemia. Lower risk of hypoglycemia with glargine was also consistently demonstrated by trials comparing insulin glargine and premixed analog insulins. These studies also showed greater reduction in A1c with twice-daily premixed insulins compared with glargine, when insulin glargine was administered without mealtime insulin coverage. Insulin glargine was also compared with another insulin analog, insulin detemir. Trials showed that both insulin analogs are equally effective in lowering A1c and have comparable risk of hypoglycemia. Trials comparing insulin glargine with glucagon-like peptide-1 agonists showed comparable significant reductions in A1c with both regimens. Insulin glargine is well tolerated, has low immunogenicity, reduced risks for acute myocardial infarction, and a lower risk of hypoglycemia compared with NPH insulin in individuals with type 2 diabetes.

Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals.

OBJECTIVE: Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals. RESEARCH DESIGN AND METHODS: Thirty-five healthy volunteers (19 male and 16 female subjects age 32 +/- 2 years, BMI 26 +/- 2 kg/m(2), A1C 5.1 +/- 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 +/- 3 years, BMI 24 +/- 2 kg/m(2), A1C 7.7 +/- 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic or hypoglycemic (2.9 +/- 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study. RESULTS: Insulin levels were similar (602 +/- 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 +/- 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 +/- 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes. CONCLUSIONS: In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.

Dose-response effects of insulin glargine in type 2 diabetes.

OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 +/- 3 years, with BMI 36 +/- 2 kg/m(2) and A1C 8.3 +/- 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique. RESULTS Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and beta-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 mumol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal. CONCLUSION: A single subcutaneous injection of glargine at a dose of >or=0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.

Effects of antecedent GABAA activation with alprazolam on counterregulatory responses to hypoglycemia in healthy humans.

OBJECTIVE: To date, there are no data investigating the effects of GABA(A) activation on counterregulatory responses during repeated hypoglycemia in humans. The aim of this study was to determine the effects of prior GABA(A) activation using the benzodiazepine alprazolam on the neuroendocrine and autonomic nervous system (ANS) and metabolic counterregulatory responses during next-day hypoglycemia in healthy humans. RESEARCH DESIGN AND METHODS: Twenty-eight healthy individuals (14 male and 14 female, age 27 +/- 6 years, BMI 24 +/- 3 kg/m(2), and A1C 5.2 +/- 0.1%) participated in four randomized, double-blind, 2-day studies. Day 1 consisted of either morning and afternoon 2-h hyperinsulinemic euglycemia or 2-h hyperinsulinemic hypoglycemia (2.9 mmol/l) with either 1 mg alprazolam or placebo administered 30 min before the start of each clamp. Day 2 consisted of a single-step hyperinsulinemic-hypoglycemic clamp of 2.9 mmol/l. RESULTS: Despite similar hypoglycemia (2.9 +/- 1 mmol/l) and insulinemia (672 +/- 108 pmol/l) during day 2 studies, GABA(A) activation with alprazolam during day 1 euglycemia resulted in significant blunting (P < 0.05) of ANS (epinephrine, norepinephrine, muscle sympathetic nerve activity, and pancreatic polypeptide), neuroendocrine (glucagon and growth hormone), and metabolic (glucose kinetics, lipolysis, and glycogenolysis) counterregulatory responses. GABA(A) activation with alprazolam during prior hypoglycemia caused further significant (P < 0.05) decrements in subsequent glucagon, growth hormone, pancreatic polypeptide, and muscle sympathetic nerve activity counterregulatory responses. CONCLUSIONS: Alprazolam activation of GABA(A) pathways during day 1 hypoglycemia can play an important role in regulating a spectrum of key physiologic responses during subsequent (day 2) hypoglycemia in healthy man.