Hypoglycemia Risk Related to Double Dose Is Markedly Reduced with Basal Insulin Peglispro Versus Insulin Glargine in Patients with Type 2 Diabetes Mellitus in a Randomized Trial: IMAGINE 8.

Background: Basal insulin peglispro (BIL) has a peripheral-to-hepatic distribution of action that resembles endogenous insulin and a prolonged duration of action with a flat pharmacokinetic/pharmacodynamic profile at steady state, characteristics that tend to reduce hypoglycemia risk compared to insulin glargine (GL). The primary objective was to demonstrate that clinically significant hypoglycemia (blood glucose ≤54 mg/dL [3.0 mmol/L] or symptoms of severe hypoglycemia) occurred less frequently within 84 h after a double dose (DD) of BIL than a DD of GL.

Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection.

GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment.

Novel hepato-preferential basal insulin peglispro (BIL) does not differentially affect insulin sensitivity compared with insulin glargine in patients with type 1 and type 2 diabetes.

Aims: Basal insulin peglispro (BIL) is a novel PEGylated basal insulin with a flat pharmacokinetic and glucodynamic profile and reduced peripheral effects, which results in a hepato-preferential action. In Phase 3 trials, patients with T1DM treated with BIL had lower prandial insulin requirements, yet improved prandial glucose control, relative to insulin glargine (GL). We hypothesized that this may be because of an enhanced sensitivity to prandial insulin with BIL resulting from lower chronic peripheral insulin action.

Glucose: archetypal biomarker in diabetes diagnosis, clinical management and research.

The clinical utility of diabetes biomarkers can be considered in terms of diagnosis, management and prediction of long-term vascular complications. Glucose satisfies all of these requirements. Thresholds of hyperglycemia diagnostic of diabetes reflect inflections that confer a risk of developing long-term microvascular complications.

Pharmacokinetic and Pharmacodynamic Properties of a Novel Inhaled Insulin.

Advances in insulin treatment options over recent decades have markedly improved the management of diabetes. Despite this, glycemic control remains suboptimal in many people with diabetes. Although postprandial glucose control has been improved with the development of subcutaneously injected rapid-acting insulin analogs, currently available insulins are not able to fully mimic the physiological time-action profile of endogenously secreted insulin after a meal.

Antisense-Mediated Lowering of Plasma Apolipoprotein C-III by Volanesorsen Improves Dyslipidemia and Insulin Sensitivity in Type 2 Diabetes.

Objective: To determine the effects of volanesorsen (ISIS 304801), a second-generation 2'-O-methoxyethyl chimeric antisense inhibitor of apolipoprotein (apo)C-III, on triglyceride (TG) levels and insulin resistance in patients with type 2 diabetes.

Research Design And Methods: A randomized, double-blind, placebo-controlled trial was performed in 15 adult patients with type 2 diabetes (HbA1c >7.5% [58 mmol/mol]) and hypertriglyceridemia (TG >200 and <500 mg/dL).

Glucodynamics of long-acting basal insulin peglispro compared with insulin glargine at steady state in patients with type 1 diabetes: substudy of a randomized crossover trial.

Aims: To compare, in an open-label, randomized, crossover phase II substudy, the glucodynamics of insulin glargine and those of basal insulin peglispro (BIL) in patients with type 1 diabetes.

Methods: Patients (n = 23) underwent 24-h euglycaemic clamps after 8 weeks of treatment with glargine or with BIL. Clinically-titrated basal insulin doses (BIL group 16-64 U; glargine group 19-60 U) were administered on the morning of the clamp.

Evolution of pharmacological obesity treatments: focus on adverse side-effect profiles.

Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g.

Biosimilar insulins: guidance for data interpretation by clinicians and users.

Biosimilar insulins are approved copies of insulins outside patent protection. Advantages may include greater market competition and potential cost reduction, but clinicians and users lack a clear perspective on 'biosimilarity' for insulins. The manufacturing processes for biosimilar insulins are manufacturer-specific and, although these are reviewed by regulators there are few public data available to allow independent assessment or review of issues such as intrinsic quality or batch-to-batch variation.

Subcutaneous Injection Depth Does Not Affect the Pharmacokinetics or Glucodynamics of Insulin Lispro in Normal Weight or Healthy Obese Subjects.

Background: An 8-mm needle length is commonly used for insulin injections; however, recent recommendations suggest shorter needles may help patients avoid intramuscular injections and reduce pain, while maintaining adequate glucose control. The goal of these analyses was to compare the pharmacokinetics (PK) and glucodynamics (GD) of insulin lispro after a 5-mm or an 8-mm injection depth administration in 2 populations: normal weight (study 1) or obese (study 2).

Methods: In both open-label, randomized, 2-period crossover euglycemic clamp studies, subjects received single 0.

Steady state is reached within 2-3 days of once-daily administration of degludec, a basal insulin with an ultralong duration of action.

Background: Various factors influence the pharmacokinetic and pharmacodynamic properties of insulin analogs. The aim of the present study was to determine time to steady state of insulin degludec (IDeg), a basal insulin analog with an ultralong duration of action, after once-daily subcutaneous administration in subjects of varying age, diabetes type, and ethnicity.

Methods: Time to steady state was analyzed in 195 subjects across five Phase I randomized single-center double-blind studies: three in subjects with type 1 diabetes (T1DM), including one in elderly subjects, and two in subjects with type 2 diabetes (T2DM), including one with African American and Hispanic/Latino subpopulations.

Albiglutide does not impair the counter-regulatory hormone response to hypoglycaemia: a randomized, double-blind, placebo-controlled, stepped glucose clamp study in subjects with type 2 diabetes mellitus.

Aim: To determine if the glucagon-like peptide-1 (GLP-1) receptor agonist albiglutide, once weekly, impairs counter-regulatory responses during hypoglycaemia.

Methods: We conducted a randomized, double-blind, parallel, placebo-controlled study in subjects with type 2 diabetes mellitus. A single dose of albiglutide 50 mg (n = 22) or placebo (n = 22) was administered on day 1.

Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes.

Introduction: This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.

Methods: Patients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks.

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial.

Objective: Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin.

Materials/methods: Patients (N=37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods.

Effect of exogenously administered glucagon versus spontaneous endogenous counter-regulation on glycaemic recovery from insulin-induced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, AZD1656, and metformin.

Aims: To study the effect of exogenous i.m. glucagon on recovery from controlled insulin-induced hypoglycaemia in patients with type 2 diabetes treated with the novel glucokinase activator AZD1656, in combination with metformin.

Impact of Biosimilar Insulins on Clinical Practice: Meeting Report.

The availability of biosimilar insulins can potentially lead to lower insulin costs and increased access for patients with diabetes, worldwide. However, clinicians and regulatory agencies have raised several concerns regarding the safety and efficacy of these new medications. The European regulatory agencies have established guidelines for market approval of biosimilar insulins; however, many issues remain unresolved.

Biosimilar Insulins: Basic Considerations.

Until now most of the insulin used in developed countries has been manufactured and distributed by a small number of multinational companies. Beyond the established insulin manufacturers, a number of new players have developed insulin manufacturing capacities based on modern biotechnological methods. Because the patents for many of the approved insulin formulations have expired or are going to expire soon, these not yet established companies are increasingly interested in seeking market approval for their insulin products as biosimilar insulins (BI) in highly regulated markets like the EU and the United States.

Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies.

Unlabelled: GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin.

Pharmacokinetic and pharmacodynamic responses of insulin degludec in African American, white, and Hispanic/Latino patients with type 2 diabetes mellitus.

Background: Pharmacokinetic and pharmacodynamic profiles of exogenous insulin may be affected by intrinsic factors, such as age, ethnicity/race, and hepatic and renal function. Insulin degludec (IDeg) is a basal insulin with an ultralong duration of action and a flat and stable glucose-lowering effect profile.

Objective: The purpose of this study was to investigate whether the pharmacokinetic and pharmacodynamic responses to IDeg at steady state vary according to patient race/ethnicity.

Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase.

Objective: To compare the pharmacokinetics and glucodynamics of three rapid-acting insulin analogs (aspart, glulisine, and lispro) injected subcutaneously with or without recombinant human hyaluronidase (rHuPH20).

Research Design And Methods: This double-blind six-way crossover euglycemic glucose clamp study was conducted in 14 healthy volunteers. Each analog was injected subcutaneously (0.

Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus.

Aims: To assess the safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus (T2DM).

Methods: This randomized, single-blind, placebo-controlled, monotherapy study was carried out in two parts. In part A, 32 patients received AZD1656 (7, 20, 40 or 80 mg) twice daily or placebo for 8 days in hospital.

Improved postprandial glycemic control in patients with type 2 diabetes from subcutaneous injection of insulin lispro with hyaluronidase.

Background: Coinjection of hyaluronidase has been shown to accelerate insulin absorption in healthy volunteers and patients with type 1 diabetes mellitus. This study was undertaken to compare the postprandial glycemic response of patients with type 2 diabetes mellitus (T2DM) administered insulin lispro with and without recombinant human hyaluronidase (rHuPH20) and regular human insulin (RHI) with rHuPH20.

Methods: This double-blind three-way crossover study compared the insulin pharmacokinetics and glucodynamic response to a standardized liquid meal (80 g of carbohydrate) in 21 patients with T2DM who received subcutaneous injections of individually optimized doses of lispro±rHuPH20 and RHI+rHuPH20.