Poul Strange

Efficacy and Safety of ETC-1002, a Novel Investigational Low-Density Lipoprotein-Cholesterol–Lowering Therapy for the Treatment of Patients With Hypercholesterolemia and Type 2 Diabetes Mellitus

Objective— 8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid (ETC-1002) is a small molecule with a unique mechanism of action shown in nonclinical studies to modulate pathways of cholesterol, fatty acid, and carbohydrate metabolism. In previous phase 2 clinical trials, once daily oral treatment with ETC-1002 significantly reduced low-density lipoprotein-cholesterol in patients with hypercholesterolemia. In this trial, the lipid-lowering efficacy of ETC-1002 was evaluated in patients with type 2 diabetes mellitus and hypercholesterolemia. Additional cardiometabolic biomarkers, including glycemic measures, were also assessed. Approach and Results— A single-center, double-blind, placebo-controlled trial evaluated 60 patients with type 2 diabetes mellitus and elevated low-density lipoprotein-cholesterol. Patients discontinued all diabetes mellitus and lipid-regulating drugs and were randomized to receive ETC-1002 80 mg QD for 2 weeks followed by 120 mg QD for 2 weeks or placebo for 4 weeks. ETC-1002 lowered low-density lipoprotein-cholesterol levels by 43±2.6% (least squares mean±SE), compared with a reduction of 4±2.5% by placebo at day 29 (P<0.0001; primary end point). Non–high-density lipoprotein-cholesterol and total cholesterol were also significantly lowered by ETC-1002 compared with placebo (P<0.0001). High-sensitivity C-reactive protein was reduced by 41% (median) compared with a placebo reduction of 11% (P=0.0011). No clinically meaningful safety findings were observed. Conclusions— ETC-1002 lowered low-density lipoprotein-cholesterol and other lipids and demonstrated improvement in high-sensitivity C-reactive protein in patients with type 2 diabetes mellitus and hypercholesterolemia without worsening glycemic control. ETC-1002 was well tolerated in this population. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT# 01607294.

Treat-to-Target Insulin Titration Algorithms When Initiating Long or Intermediate Acting Insulin in Type 2 Diabetes

Background: Until recently, titration of insulin in type 2 diabetes clinical trials was typically left up to the investigators discretion with a simple statement of the target ranges for glucose. In type 2 diabetes trials the average glycemic control achieved was usually less than desirable. Since then a number of trials have been conducted and reported utilizing various algorithms under various conditions. The objective of this article is to provide a review of the evidence to date. Methods: In addition to studies already identified through work in the area, the literature was searched using PubMed with the search words “insulin and titration” and subsequently “insulin and algorithm” from which studies starting insulin therapy using insulin titration algorithms in type 2 diabetes were selected. Results: The different algorithms and achieved results for glycemic control and hypoglycemia, as well as factors appearing to impact the results, are reviewed. Conclusion: The recent introduction of rigorously implemented insulin titration algorithms when adding on basal insulin to oral drugs in inadequately treated type 2 diabetes patients has led to better average glycemic control with little risk of severe hypoglycemia, as long as the morning fasting plasma glucose target is not lower than 100 mg/dl. Insulin titration algorithms have undergone and continue evolution in the direction of increased patient control.

Use of Fourier Models for Analysis and Interpretation of Continuous Glucose Monitoring Glucose Profiles

Background: The introduction of continuous glucose monitoring (CGM) devices has dramatically increased the amount of information available about each patient. While CGM has become a useful diagnostic tool for the individual patient, interpretive issues including noise reduction remain and further analytical work is needed to fully utilize the data richness. Method: We applied discrete Fourier transform methodology to CGM data to obtain an overall statistical model providing the dimension reduction necessary for insightful analyses of the whole function and explored some properties and possible applications of this technology. Results: The following example applications are shown. Discrete Fourier transform allows reduction of noise using an objective statistical criterion and may, as a first step, possibly enhance the value of various measures of variability through this noise reduction. Average functions of groups in a prospective randomized clinical are demonstrated and the aggregate function is readily visualized. Second and third harmonic amplitudes at baseline correlate with hemoglobin A1c after a 6-month treatment period. The time points of most rapid glucose decreases are identified easily with the functional through the second derivative, and its correlation with subsequent reported symptomatic hypoglycemia is shown. Conclusions: Discrete Fourier transform offers an attractive analytical methodology for CGM data given the achievable dimension reduction without loss of essential information as well as its ability to eliminate noise.

The V-Go Insulin Delivery Device Used in Clinical Practice: Patient Perception and Retrospective Analysis of Glycemic Control

OBJECTIVE To describe patient perceptions regarding their experience and to report findings in a retrospective analysis of glycemic control in a cohort of patients who used the V-Go, a mechanical, 24-hour disposable, subcutaneous continuous insulin delivery device that delivers a preset basal infusion rate and on-demand insulin. METHODS Patients used the V-Go and answered telephone surveys about their perception of device use. Corresponding clinical data were retrospectively collected before V-Go initiation, after 12 weeks of use, at the end of treatment, and 12 weeks after discontinuation. Analyses were performed with nonparametric statistical tests. RESULTS Twenty-three patients participated. Mean values of the following characteristics were documented: patient age, 61 years; body mass index, 30 kg/m2; diabetes duration, 16 years; duration of insulin therapy, 7 years; average duration of V-Go use, 194 days; and mean total daily insulin dose, 50 U at baseline, 46 U while on V-Go, and 51 U after stopping V-Go treatment. Mean patient rating of the overall experience was 9.1 at 12 weeks on a scale from 1 to 10 (10 being most positive). Mean hemoglobin A1c value decreased from baseline (8.8% to 7.6%; [P = .005]) while using the V-Go, and it increased to 8.2% after treatment. Fasting plasma glucose trended from 205 mg/dL at baseline to 135 mg/dL while using V-Go and increased to 164 mg/dL after V-Go was stopped. Weight was essentially unchanged. No differences in hypoglycemic events were found; site reactions were minor. CONCLUSION Glycemic control improved when patients were switched to the V-Go for insulin delivery, and it deteriorated when the V-Go was discontinued.

Basal—Prandial Insulin Delivery in Type 2 Diabetes Mellitus via the V-Go™: A Novel Continuous Subcutaneous Infusion Device

Background: The V-Go™ is a once-daily disposable device that allows coverage of basal and prandial insulin requirements over a period of 24 hours. The aim of this proof-of-concept study was to evaluate the clinical functionality, safety, and pharmacodynamics of the V-Go delivering insulin aspart and redistributing a single basal dose of insulin glargine as a constant basal infusion supplemented with prandial insulin in subjects with type 2 diabetes mellitus. Methods: In six subjects receiving once-daily subcutaneous (SC) injections of insulin glargine (≥15 U/day) with or without concomitant oral antidiabetic drugs, glargine was discontinued following a 3-day baseline phase. The V-Go was then applied to the lower abdomen of the subjects once daily for 7 days (days 1–3 inpatient, days 4–7 outpatient). Each V-Go provided a continuous 24-hour preset basal infusion rate of insulin aspart (0.6 U/h) and up to three daily prandial doses at mealtimes. Capillary blood glucose concentrations were measured at 11 time points per day during the baseline and inpatient phases and at 4 time points per day during the outpatient phase. Additionally, glucose profiles were measured continuously on all days. Results: The V-Go was well tolerated and operated as anticipated. The mean ± SEM prestudy daily dose of SC insulin glargine was 33.3 ± 13.8 U; the mean daily total insulin aspart dose infused with the V-Go was 31.5 ± 7.5 and 32.3 ± 7.8 U for the inpatient and outpatient periods, respectively. Fasting blood glucose values were similar to those observed at baseline throughout the study, with nonsignificant (NS) reductions in readings collected during the outpatient phase before lunch (−35 ± 27 mg/dl) and before dinner (−38 ± 25 mg/dl). The 2-hour postprandial glucose trended lower from 231 to 195 mg/dl (NS) at breakfast, 234 to 166 mg/dl (NS) at lunch, and 222 to 171 mg/dl (NS) at dinner. Bedtime blood glucose decreased (mean change from baseline −52 ± 21 mg/dl; P = 0.0313), as did nighttime (3:00 AM) measurements (−20 ± 9 mg/dl; P = 0.0313). Overall glycemic control tended to improve, as shown by continuous glucose monitoring changing from 173 to 157 mg/dl (P = 0.063, NS) and 156 mg/dl (P = 0.219) during inpatient and outpatient periods, respectively. Glycemic variability assessed by the M value similarly tended to decrease from 33 ± 9 to 25 ± 4 (NS) and 21 ± 4 (NS) for inpatient and outpatient periods, respectively. Conclusions: These first data suggest that use of the V-Go is an attractive alternative to SC insulin injection therapy because metabolic control appears to be maintained or even improved without increasing daily insulin doses.

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

Background: There is currently no stable liquid form of glucagon commercially available. The aim of this study is to assess the speed of absorption and onset of action of G-Pump™ glucagon at 3 doses as compared to GlucaGen®, all delivered subcutaneously via an OmniPod®. Methods: Nineteen adult subjects with type 1 diabetes participated in this Phase 2, randomized, double-blind, cross-over, pharmacokinetic/pharmacodynamic study. Subjects were given 0.3, 1.2, and 2.0 µg/kg each of G-Pump glucagon and GlucaGen via an OmniPod. Results: G-Pump glucagon effectively increased blood glucose levels in a dose-dependent fashion with a glucose Cmax of 183, 200, and 210 mg/dL at doses of 0.3, 1.2, and 2.0 µg/kg, respectively (P = ns vs GlucaGen). Mean increases in blood glucose from baseline were 29.2, 52.9, and 77.7 mg/dL for G-Pump doses of 0.3, 1.2, and 2.0 µg/kg, respectively. There were no statistically significant differences between treatments in the glucose T50%-early or glucagon T50%-early with one exception. The glucagon T50%-early was greater following G-Pump treatment at the 2.0 μg/kg dose (13.9 ± 4.7 min) compared with GlucaGen treatment at the 2.0 μg/kg dose (11.0 ± 3.1 min, P = .018). There was more pain and erythema at the infusion site with G-Pump as compared to GlucaGen. No serious adverse events were reported, and no unexpected safety issues were observed. Conclusions: G-Pump glucagon is a novel, stable glucagon formulation with similar PK/PD properties as GlucaGen, but was associated with more pain and infusion site reactions as the dose increased, as compared to GlucaGen.

Comparison Pharmacokinetics of Two Concentrations (0.7% and 1.0%) of Nasulin™, an Ultra-Rapid-Acting Intranasal Insulin Formulation

Background: This pharmacokinetic (PK) study was designed to characterize the dose response of two concentrations (0.7% and 1%) of a nasal spray of recombinant regular human insulin in combination with cyclopentadecalactone (CPE-215), a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals). Nasulin has been effective in lowering blood glucose in both normal subjects and diabetes patients, and additional dosing options would allow greater titration flexibility. Method: A five-period crossover study of 24 healthy, nonsmoking subjects (ages 18–50, basal metabolic index <33 kg/m2, weight >70 kg) were studied. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 μl. Doses tested were 25, 35, 50, 70, and 100 U. Maximum concentration (Cmax) and area under the curve (AUC) were estimated for each dose group. Glucose measurements were also performed. Results: A dose response (slope of the natural log response versus dose) was demonstrated by baseline-adjusted Cmax of 22, 27, 56, 62, and 84 μU/ml for the 25, 35, 50, 70, and 100 U doses (p < .0001), respectively, and by baseline-adjusted AUC(0–45 min) values of 491, 592, 1231, 1310, and 1894 μU/ml/min (p < .0001). Glucose AUC(0–45 min) determinations also demonstrated a pharmacodynamic (PD) dose response. Conclusions: Proportional and linear dose responses for both PK and PD parameters were demonstrated for the two concentrations, making multiple doses available for clinical development.

Enhanced Absorption of Nasulin™, an Ultrarapid-Acting Intranasal Insulin Formulation, Using Single Nostril Administration in Normal Subjects

Background: This pharmacokinetic (PK) study was designed to investigate the maximum intranasal insulin dose that could be achieved by repeated doses in a single nostril of a nasal spray of recombinant regular human insulin 1% in combination with cyclopentadecalactone (CPE-215) 2%, a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals, Inc.). Method: A nine-period crossover study of 8 healthy, nonsmoking subjects (ages 18–50, body mass index <33 kg/m2, weight >70 kg) were studied. In a fasted state, subjects were randomly given 25, 50, and 75 U in a single nostril on the first day and randomly given 50, 75, and 100 U doses utilizing both nostrils on two subsequent days. After a 45-minute PK assessment, subjects were given a meal. To determine the mechanism of enhanced absorption in a single nostril, a second study utilizing 24 subjects under similar conditions received 25 U, placebo (P) that included CPE-215 plus 25 U, and 50 U in a single nostril. Results: Single nostril administration revealed enhanced absorption with maximum concentrations (Cmax) of 13, 65, and 96 μU/ml for the 25, 50, and 75 U doses, respectively. Dual nostril administration in two cohorts resulted in Cmax of 31/42, 65/52, and 88/79 μU/ml for the 50, 75, and 100 U, respectively. In the second cohort, Cmax was 23, 19, 56 μU/ml for the 25, P + 25, and 50 U doses, respectively. Conclusions: Repeated dosing in a single nostril resulted in enhanced absorption; this was not due to the increased CPE-215 but to the increased insulin administered.

Reconsideration of severe hypoglycemic events in the treat-to-target trial.

OBJECTIVE This article reevaluates the hypoglycemic episodes reported as severe in the Treat-to-Target Trial comparing insulin glargine and NPH insulin use in patients with inadequately controlled type 2 diabetes. METHODS Case report forms from the Treat-to-Target Trial were reviewed to identify additional severe hypoglycemic events and to further characterize those events already identified. Severe hypoglycemia was defined as symptoms consistent with hypoglycemia requiring assistance of another person and associated with either glucose levels < or =56 mg/dL or prompt recovery after oral carbohydrate intake, intravenous glucose administration, or glucagon injection. RESULTS This analysis confirmed that severe hypoglycemia was similarly uncommon with both insulins (insulin glargine [n = 367], nine patients, 14 events; NPH insulin [n = 389], nine patients, 13 events); all hypoglycemic events for glargine and nine for NPH were treated effectively at home. All severe hypoglycemic episodes were associated with sulfonylurea use. A review of case report forms demonstrated inconsistencies in identification of severe hypoglycemia (seven of 14 severe events for glargine and three of 13 severe events for NPH were coded as moderate). CONCLUSIONS The rate of severe hypoglycemia in this trial was low. Difficulties in gathering and interpreting hypoglycemia data highlight the need for more objective methods.

Exenatide once weekly improved 24-hour glucose control and reduced glycaemic variability in metformin-treated participants with type 2 diabetes: a randomized, placebo-controlled trial.

To assess the effects of once‐weekly exenatide on 24‐hour glucose control and variability.