Lisa M. Younk

Pramlintide and the treatment of diabetes: a review of the data since its introduction

Introduction: Postprandial glucose excursions negatively affect glycemic control and markers of cardiovascular health. Pramlintide, an amylinomimetic, is approved for treatment of elevated postprandial glucose levels in type 1 and type 2 diabetes mellitus. Areas covered: A literature search of PubMed was conducted to locate articles (up to January 2011) pertaining to original preclinical and clinical research and reviews of amylin and pramlintide. Additional sources were selected from reference lists within articles obtained through the original literature search and from the internet. This article describes the known effects of endogenous amylin and the pharmacodynamics, pharmacokinetics and clinical efficacy of pramlintide. Drug–drug interactions and safety and tolerability are also reviewed. Expert opinion: Pramlintide significantly reduces hemoglobin A1c and body weight in patients with type 1 and type 2 diabetes mellitus. Newer research is focusing on weight loss effects of pramlintide and pramlintide plus metreleptin in nondiabetic obese individuals. Preliminary results of these studies are discussed.

Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus.

Introduction: Canagliflozin is an orally administered sodium glucose cotransporter 2 inhibitor proposed for the treatment of type 2 diabetes. Canagliflozin improves glycemic control in an insulin-independent fashion through inhibition of glucose reuptake in the kidney. Areas covered: This article reviews the available data on the pharmacodynamics, the pharmacokinetics and metabolism, and the efficacy and safety of canagliflozin. Relevant articles were identified via PubMed using the search term canagliflozin with no date restriction. The authors also discuss the abstracts from canagliflozin studies presented at large diabetes conferences. Expert opinion: Canagliflozin offers a relatively modest reduction in HbA1c, FPG, and PPG. It has a low incidence of hypoglycemia and a reduction in body weight. Dose adjustment may be recommended in the elderly, those on loop diuretics, and those with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 if there are concerns or symptoms of volume-related side effects. Issues remain with observed increases in low-density lipoprotein cholesterol (LDL-C) and the odds of heart attack and stroke. Canagliflozin offers a novel mechanism of action, a modest glycemic control, and a favorable side-effect profile. It was approved by the US Food and Drug Administration in April 2013 and is undergoing evaluation by the European Medicines Agency.

Effects of Acute and Antecedent Hypoglycemia on Endothelial Function and Markers of Atherothrombotic Balance in Healthy Humans

The aim of this study was to determine the effects of single and repeated episodes of clamped hypoglycemia on fibrinolytic balance, proinflammatory biomarkers, proatherothrombotic mechanisms, and endothelial function. Twenty healthy individuals (12 male and 8 female) were studied during separate 2-day randomized protocols. Day 1 consisted of either two 2-h hyperinsulinemic (812 ± 50 pmol/L)-euglycemic (5 ± 0.1 mmol/L) or hyperinsulinemic (812 ± 50 pmol/L)-hypoglycemic (2.9 ± 0.1 mmol/L) clamps. Day 2 consisted of a single 2-h hyperinsulinemic-hypoglycemic clamp. Two-dimensional Doppler ultrasound was used to determine brachial arterial endothelial function. Plasminogen activator inhibitor 1, vascular cell adhesion molecule-1, intracellular adhesion molecule-1, E-selectin, P-selectin, TAT (thrombin/antithrombin complex), tumor necrosis factor-α, and interleukin-6 responses were increased (P < 0.05) during single or repeated hypoglycemia compared with euglycemia. Endogenous and exogenous nitric oxide (NO)-mediated vasodilation were both impaired by repeated hypoglycemia. Neuroendocrine and autonomic nervous system (ANS) responses were also blunted by repeated hypoglycemia (P < 0.05). In summary, acute moderate hypoglycemia impairs fibrinolytic balance; increases proinflammatory responses, platelet activation, and coagulation biomarkers; and reduces NO-mediated endothelial function in healthy individuals. Repeated episodes of hypoglycemia further impair vascular function by additionally reducing exogenously NO-mediated endothelial function and increasing coagulation biomarkers. We conclude that despite reduced neuroendocrine and ANS responses, antecedent hypoglycemia results in greater endothelial dysfunction and an increased proatherothrombotic state compared with a single acute episode of hypoglycemia.

Empagliflozin, a sodium glucose co-transporter 2 inhibitor, in the treatment of type 1 diabetes

Introduction: Available anti-hyperglycemic therapy in type 1 diabetes (T1DM) is currently restricted to insulin, pramlintide, and pancreas or islet cell transplantation. The imperfect replication of normal insulin secretion and glucose control has been a driver for development of other anti-hyperglycemic agents for this population. Empagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, is currently under investigation as an add-on therapy to insulin in T1DM. Areas covered: Within the drug evaluation, the authors describe the mechanism of action of SGLT2 inhibitors and preliminary results from studies investigating treatment in rodent models and in individuals with T1DM. Expert opinion: Studies on adjunct therapeutic effects of empagliflozin in individuals with T1DM are limited, but initial reports show favorable effects on reducing HbA1c, body weight, total daily insulin dose and hypoglycemic events. Intriguingly, this drug may confer a degree of renal protection by reducing glomerular hyperfiltration that can arise in the diabetic state. Currently, the primary concern seems to be the presence of ketone levels indicating an under-insulinized state. Long-term effects can only be inferred from studies in type 2 diabetes mellitus at this time. Empagliflozin represents a novel non-insulin-mediated therapy that warrants further investigation.

Exercise-related hypoglycemia in diabetes mellitus

Current recommendations are that people with Type 1 and Type 2 diabetes mellitus exercise regularly. However, in cases in which insulin or insulin secretagogues are used to manage diabetes, patients have an increased risk of developing hypoglycemia, which is amplified during and after exercise. Repeated episodes of hypoglycemia blunt autonomic nervous system, neuroendocrine and metabolic defenses (counter-regulatory responses) against subsequent episodes of falling blood glucose levels during exercise. Likewise, antecedent exercise blunts counter-regulatory responses to subsequent hypoglycemia. This can lead to a vicious cycle, by which each episode of either exercise or hypoglycemia further blunts counter-regulatory responses. Although contemporary insulin therapies cannot fully mimic physiologic changes in insulin secretion, people with diabetes have several management options to avoid hypoglycemia during and after exercise, including regularly monitoring blood glucose, reducing basal and/or bolus insulin, and consuming supplemental carbohydrates.

Pharmacokinetics, efficacy and safety of aleglitazar for the treatment of type 2 diabetes with high cardiovascular risk.

Introduction: In preliminary clinical studies, aleglitazar, a new dual PPAR-α–γ agonist, has been demonstrated to improve hyperglycemia and dyslipidemia in patients with type 2 diabetes mellitus. This review will provide up-to-date information on the clinical safety and efficacy of aleglitazar, which is currently under Phase III clinical investigation for reduction of cardiovascular events in patients with type 2 diabetes and recent acute coronary syndrome. Areas covered: A PubMed literature search (January 1950 to February 2011) was conducted using the following search terms: aleglitazar, PPAR, PPAR α agonist, PPAR γ agonist and PPAR α/γ agonist. Additional articles were gathered using reference lists from sources obtained from the original literature search. This review summarizes available information pertaining to pharmacodynamics, pharmacokinetics, clinical studies and safety/tolerability of aleglitazar. The effects of this new drug are compared and contrasted with those of fibrates (PPAR-α agonists), thiazolidinediones (PPAR-γ agonists) and other dual PPAR-α–γ agonists. Expert opinion: Preliminary evidence from clinical studies with aleglitazar is promising, with reported improvements in glycemia, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein B and blood pressure. However, PPAR-α- and -γ-associated side effects have been observed and additional large-scale, long-term clinical studies are necessary to better understand the clinical implications of these effects.

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/m2 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 β-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 μmol/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 ≥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.

Concentrated insulins: the new basal insulins

Introduction Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration.

Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes.

Introduction: Type 2 diabetes often involves derangements in lipid levels in addition to insulin resistance and diminishing insulin secretion. Colesevelam hydrochloride, a bile acid sequestrant (BAS), is approved for adjunctive therapy to diet and exercise for glycemic control in type 2 diabetes. In clinical studies in patients with type 2 diabetes, colesevelam, added to existing metformin, sulfonylurea or insulin therapy, reduced hemoglobin A1c (HbA1c) by a mean of 0.5% and low-density lipoprotein-cholesterol (LDL-C) by 13 – 17%. Areas covered: Information pertaining to colesevelam and other BAS was collected using a PubMed literature search of journal articles dating from 1960 to present. Additional articles were identified from bibliographies and from abstracts from American Diabetes Association conferences. The authors review the pharmacology of colesevelam as well as clinical efficacy, safety and tolerability data generated from clinical trials. Expert opinion: Colesevelam induces moderate but significant improvements in HbA1c and LDL-C. Outcomes data are needed to determine whether or not colesevelam confers long-term protection against micro- and macrovascular complications. Although colesevelam does not induce weight gain, triglyceride levels tend to increase ∼ 15%, the implications of which are unknown at this time. The mechanism(s) by which colesevelam improves glycemia are not yet understood but might involve enhanced meal-induced incretin secretion and altered farnesoid X receptor signaling.

Physical activity in adolescents with type 1 diabetes: is more better for glycemic control?

The Diabetes Control and Complications Trial (DCCT) determined that adolescents receiving intensive diabetes therapy were at lower risk for the development and/or progression of diabetes complications than adolescents assigned to conventional therapy (1). Furthermore, the Epidemiology of Diabetes Interventions and Complications (EDIC) study demonstrated that the favorable outcomes associated with intensive treatment in the DCCT persist despite a loosening of glucose control for at least 10 years (2). Both studies concluded that diabetes care teams should establish management plans to provide the best metabolic control possible to reduce the risk of future diabetes complications. The Hvidoere Study Group (HSG) and others have shown that glycemic control varies among pediatric diabetes centers internationally (3–7). The HSG has focused on various confounding factors (i.e., ethnicity, socioeconomic status, gender, age, diabetes duration, body mass index, insulin dose, and method of insulin administration) in an attempt to isolate the parameters necessary to improve diabetes care (4, 8). The current study, published in this edition of Pediatric Diabetes, pursued the possibility that physical activity and sedentary behavior may account for the discrepancy in hemoglobin A1c (HbA1c) among centers. Although it is now generally accepted that physical activity increases insulin sensitivity and acutely reduces blood glucose levels in patients with diabetes, evidence is inconsistent regarding the ability of physical activity to decrease HbA1c (9). Large cohort studies, such as this present HSG study, are necessary to determine whether or not a relationship exists between physical activity and HbA1c. Given that physical activity is recommended for adolescents with type 1 diabetes to help control the disease (9), it is disappointing that no correlation was found between physical activity and HbA1c levels in the current study. However, other researchers have reported similar outcomes (10, 11). Several factors, though, may have prevented the detection of a correlation in the HSG study. The method for assessing physical activity may not have been sensitive enough to detect an association. The investigators used a questionnaire format validated by the World Health Organization (12), but because subjects only reported days on which they engaged in 60 min or more of physical activity, anyone engaging in less than 60 min of physical activity was considered inactive. If there is a threshold relationship between physical activity and HbA1c, a 60-min cutoff may be appropriate but only if a comparison is made between those above or below the cutoff. Two other studies have provided somewhat conflicting data. Herbst et al. (13)studied a group of 19 143 threeto twenty-year-old subjects and found that the mean HbA1c was lower in adolescent subjects reporting 30 min or more of physical activity on at least one day per week than in subjects reporting no physical activity. Valerio et al. (14) however, reported a significant beneficial association of 60 min or more of physical activity on HbA1c. Data from intervention studies may provide insight regarding a number of self-care behaviors that may have prevented a correlation between improved glycemic control and physical activity from being determined in this present study. Ruzic et al. (15) created a highly controlled environment within a diabetes summer camp. The investigators individually regulated/monitored daily caloric intake, number of glucose measurements (four times each day), frequency of insulin dosing, and dosage. Under these conditions, subjects participated in three physical activity sessions every day for 2 weeks. The mean HbA1c level dropped significantly from 8.28% (before camp) to 7.92% (10 days after camp). In another study, subjects participated in 45-min swimming sessions twice a week for 14 weeks. Diet and insulin dose were self-regulated, but exercise intensity (using heart rate as a surrogate marker), duration, and time of day of activity were controlled, and blood glucose was monitored before and after exercise. Average HbA1c decreased from 8.5 to 7.8% (16). A third intervention study, conducted by Ramalho et al., did not observe a decrease in HbA1c. The authors reported that study participants decreased