Sherwyn Schwartz

Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination With Metformin and Thiazolidinedione in Patients With Type 2 Diabetes (LEAD-4 Met+TZD)

OBJECTIVE To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7–11% (previous oral antidiabetes drug [OAD] monotherapy ≥3 months) or 7–10% (previous OAD combination therapy ≥3 months), and BMI ≤45 kg/m2. RESULTS Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE −1.5 ± 0.1% for both 1.2 and 1.8 mg liraglutide and −0.5 ± 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 ± 0.3 and 2.0 ± 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 ± 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of β-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. CONCLUSIONS Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.

A Continuous Glucose Sensor Based on Wired Enzyme™ Technology - Results from a 3-Day Trial in Patients with Type 1 Diabetes

Wired Enzyme (Therasense, Alameda, CA) sensing technology for continuous measurement of in vivo glucose concentrations offers the benefits of (1). excellent sensor stability, (2). reduced susceptibility to variations of in vivo oxygen concentration, and (3). minimized response to common electroactive interferents. This study describes the response of 48 sensors (25 in the upper arm, 23 in the abdomen) implanted for 3 days in patients with Type 1 diabetes. Prospective calibration was performed using capillary blood; results were compared with venous plasma glucose values obtained at 15-min intervals. Ninety-eight percent of readings fell in the clinically accurate Clarke error grid zone A or clinically acceptable zone B. Choice of the site of the implanted sensor (upper arm vs. abdomen) or the capillary blood calibration site (arm vs. finger) did not affect system accuracy.

Accuracy of the 5-day FreeStyle Navigator Continuous Glucose Monitoring System: comparison with frequent laboratory reference measurements.

OBJECTIVE—The purpose of this study was to compare the accuracy of measurements of glucose in interstitial fluid made with the FreeStyle Navigator Continuous Glucose Monitoring System with Yellow Springs Instrument laboratory reference measurements of venous blood glucose. RESEARCH DESIGN AND METHODS—Fifty-eight subjects with type 1 diabetes, aged 18–64 years, were enrolled in a multicenter, prospective, single-arm study. Each subject wore two sensors simultaneously, which were calibrated with capillary fingerstick measurements at 10, 12, 24, and 72 h after insertion. Measurements from the FreeStyle Navigator system were collected at 1-min intervals and compared with venous measurements taken once every 15 min for 50 h over the 5-day period of sensor wear in an in-patient clinical research center. Periods of high rates of change of glucose were induced by insulin and glucose challenges. RESULTS—Comparison of the FreeStyle Navigator measurements with the laboratory reference method (n = 20,362) gave mean and median absolute relative differences (ARDs) of 12.8 and 9.3%, respectively. The percentage in the clinically accurate Clarke error grid A zone was 81.7% and that in the in the benign error B zone was 16.7%. During low rates of change (<±1 mg · dl−1 · min−1), the percentage in the A zone was higher (84.9%) and the mean and median ARDs were lower (11.7 and 8.5%, respectively). CONCLUSIONS—Measurements with the FreeStyle Navigator system were found to be consistent and accurate compared with venous measurements made using a laboratory reference method over 5 days of sensor wear (82.5% in the A zone on day 1 and 80.9% on day 5).

Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Pre-Diabetes

OBJECTIVE To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS Obese subjects (n = 152; age 46 ± 12 years, female 82%, weight 108.6 ± 23.0 kg, BMI 39.6 ± 7.0 kg/m2, IGT or IFG 25%) were randomized to receive exenatide (n = 73) or placebo (n = 79), along with lifestyle intervention, for 24 weeks. RESULTS Exenatide-treated subjects lost 5.1 ± 0.5 kg from baseline versus 1.6 ± 0.5 kg with placebo (exenatide − placebo, P < 0.001). Placebo-subtracted difference in percent weight reduction was −3.3 ± 0.5% (P < 0.001). Both groups reduced their daily calorie intake (exenatide, −449 cal; placebo, −387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively. CONCLUSIONS Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Physiological influences on off-finger glucose testing.

Products for monitoring blood glucose that allow extraction from sites other than the finger have recently been introduced. The FreeStyle Blood Glucose Monitor requires only 0.3 microL of blood, and allows extraction from the hand, arm, and leg, as well as the traditional finger site. Differences in circulatory physiology of the off-finger test sites lead to differences in the measured blood glucose concentration. The first study involved 160 clinic visits by 120 unique subjects with type 1 or type 2 diabetes. FreeStyle measurements were compared to YSI Model 2300 Stat Plus Glucose Analyzer plasma measurements using venous blood, capillary blood from the finger, and capillary blood from the arm. In a second study, the time course of glucose variation was tested by simultaneous measurements on the arm and finger taken every 15 min for 6 h. Thirteen subjects with type 1 diabetes were studied in two 6-h sessions. When FreeStyle was compared to YSI using venous samples and finger samples, the regression statistics were very similar. But when FreeStyle with arm samples was compared to YSI with finger samples, the regression equation was similar, but the scatter in the data was statistically significantly greater at the 95% confidence interval. By studying the time course of glucose changes, the difference between finger and arm measurements was attributed to a time lag in the glucose response on the arm with respect to glucose response on the finger. The lag was observed when the glucose concentration was increasing or decreasing, and the lag time varied from subject-to-subject in the range of 5-20 min. Using the Clarke Error Grid Analysis, the difference between arm and finger glucose measurements was not clinically significant. However, when the glucose concentration is decreasing rapidly into a state of hypoglycemia, the lag in measurements on the arm could delay detection of hypoglycemia. When specifically testing for hypoglycemia, the finger may be the preferable test site.

Safety, Pharmacokinetic, and Pharmacodynamic Profiles of Ipragliflozin (ASP1941), a Novel and Selective Inhibitor of Sodium-Dependent Glucose Co-Transporter 2, in Patients with Type 2 Diabetes Mellitus

BACKGROUND The sodium-dependent glucose co-transporter 2 (SGLT2) is a high-capacity, low-affinity transport system primarily expressed in the renal proximal tubules, where it plays an important role in the regulation of glucose levels. Inhibition of SGLT2 represents an innovative approach for plasma glucose control in type 2 diabetes mellitus (T2DM) by blocking glucose reabsorption and enhancing glucose loss in the urine. METHODS This Phase 2, randomized, placebo-controlled study investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of the novel oral SGLT2 inhibitor ipragliflozin (ASP1941) in T2DM patients. Sixty-one patients were randomized to placebo or ipragliflozin once daily at doses of 50, 100, 200, or 300 mg for 28 days. Patients were admitted to the clinic during the study and received a weight-maintenance diet. RESULTS The incidence of treatment-emergent adverse events was similar for placebo and ipragliflozin groups. There were no deaths, and no patients discontinued ipragliflozin because of adverse events. Ipragliflozin was absorbed rapidly, taking approximately 1 h to reach the maximum concentration. The area under the concentration-time curve and maximum ipragliflozin concentration at steady state displayed dose linearity. All ipragliflozin doses significantly reduced glycosylated hemoglobin, fasting plasma glucose, and mean amplitude of glucose excursions compared with placebo. Significant dose-dependent increases in urinary glucose excretion were observed in all ipragliflozin groups. Mean weight decreased in the placebo and ipragliflozin groups, with greater reductions occurring in ipragliflozin-treated patients. CONCLUSION Ipragliflozin was generally safe, well tolerated, and effective at blocking renal glucose reabsorption and decreasing plasma glucose levels in T2DM patients.

Accuracy of the SEVEN® Continuous Glucose Monitoring System: Comparison with Frequently Sampled Venous Glucose Measurements

Background: The purpose of this study was to compare the accuracy of measurements obtained from the DexCom™ SEVEN® system with Yellow Springs Instrument (YSI) laboratory measurements of venous blood glucose. Methods: Seventy-two subjects with insulin-requiring diabetes, aged 18–71, were enrolled in a multicenter, prospective single-arm study. All participants wore the SEVEN continuous glucose monitoring (CGM) system for one, 7-day wear period. Calibration with capillary finger stick measurements was performed 2 hours after sensor insertion and once every 12 hours thereafter. A subset of subjects (28) wore two systems simultaneously to assess precision. All subjects participated in one, 10-hour in-clinic session on day 1, 4, or 7 of the study to compare CGM measurements against a laboratory method (YSI analyzer) using venous measurements taken once every 20 minutes. Carbohydrate consumption and insulin dosing were adjusted in order to obtain a broad range of glucose values. Results: Comparison of CGM measurements with the laboratory reference method (n = 2318) gave mean and median absolute relative differences (ARDs) of 16.7 and 13.2%, respectively. The percentage was 70.4% in the clinically accurate Clarke error grid A zone and 27.5% in the benign error B zone. Performance of the SEVEN system was consistent over time with mean and median ARD lowest on day 7 as compared to YSI (13.3 and 10.2%, respectively). Average sensor time lag was 5 minutes. Conclusions: Measurements of the DexCom SEVEN system were found to be consistent and accurate compared with venous measurements made using a laboratory reference method over 7 days of wear.

Effect of exenatide on 24-hour blood glucose profile compared with placebo in patients with type 2 diabetes: a randomized, double-blind, two-arm, parallel-group, placebo-controlled, 2-week study.

OBJECTIVE The aim of this study was to examine the glucose-lowering effect of exenatide over 24 hours in patients with type 2 diabetes with inadequate glycemic control using metformin, with or without a thiazolidinedione (TZD). METHODS This randomized, double-blind, 2-arm, parallel-group, placebo-controlled, 2-week study was conducted in patients with type 2 diabetes with inadequate glycemic control, despite metformin with or without a TZD. Patients underwent a baseline and a week-2 (study end) 24-hour admission during which serial serum glucose measurements were taken. Preprandial and postprandial concentrations of triglycerides and free fatty acids were also measured. Meals provided for each patient were identical at the baseline and week-2 assessments. Following the baseline admission, patients were randomized to receive SC injections of either exenatide (5 microg BID for 1 week, then 10 microg BID for the next week) or placebo (volume equivalent) for 14 days. RESULTS A total of 30 patients (19 women [63%], 11 men [37%]; mean [SD] age, 52.6 [11.2] years; weight, 94.3 [23.0] kg; body mass index, 34.2 [6.1] kg/m(2); glycosylated hemoglobin value, 8.0% [0.9%]; diabetes duration, 8.7 [5.6] years; race, Hispanic 18 [60%], white 10 [33%], black 2 [7%]) were eligible. Seventeen patients (57%) were randomized to treatment with exenatide and 13 patients (43%) received placebo. Concurrent antidiabetic medications were metformin only (n = 19 [63%]) and metformin plus a TZD (n = 11 [37%]). All postbaseline values were least squares mean (SE). After 2 weeks (study end), the 24-hour time-average glucose values were 7.0 (0.2) and 8.8 (0.3) mmol/L for exenatide-treated and placebo-administered patients, respectively (P < 0.001). The glucose values for patients treated with exenatide were lower compared with those in patients who received placebo 2 hours after the morning meal (6.6 [0.4] vs 12.0 [0.5] mmol/L; P < 0.001), the midday meal (8.8 [0.5] vs 11.8 [0.6] mmol/L; P = 0.001), and the evening meal (6.8 [0.4] vs 11.3 [0.4] mmol/L; P < 0.001). The mean durations of patient exposure to glucose concentrations >7.8 and >11.1 mmol/L were significantly shorter for the exenatide group compared with the placebo group (>7.8 mmol/L: 6.8 [0.9] vs 14.1 [1.1] hours; >11.1 mmol/L: 1.0 [0.7] vs 4.7 [0.8] hours; both, P < 0.001). After 2 weeks, the postprandial triglyceride excursions after the morning and evening meals for patients treated with exenatide were significantly lower compared with those treated with placebo. There was no apparent effect on free fatty acid concentrations. CONCLUSIONS In these patients with type 2 diabetes, exenatide was associated with significantly reduced glucose concentrations at multiple time points during 24 hours, with the greatest effect seen on postprandial glucose concentrations. In addition, exenatide was associated with decreased overall hyperglycemic exposure and significantly decreased postprandial triglyceride excursions. These results are consistent with those seen in other studies that reported the effectiveness of exenatide in controlling hyperglycemia in patients with type 2 diabetes.

The Effect of Colesevelam Hydrochloride on Insulin Sensitivity and Secretion in Patients With Type 2 Diabetes: A Pilot Study

BACKGROUND This study evaluated the effect of colesevelam hydrochloride on insulin sensitivity, potential binding to glucose, and chronic effect(s) on fasting and postprandial glucose and insulin in patients with type 2 diabetes mellitus. METHODS Patients meeting inclusion criteria were withdrawn from all antidiabetes agents for 2 weeks and randomized to colesevelam 3.75 grams/day (n = 17) or placebo (n = 18) for 8 weeks. Hyperinsulinemic-euglycemic clamp studies were performed at baseline (week -1) and weeks 2 and 8. A meal tolerance test was conducted at weeks -1, 0, 2, and 8. The meal tolerance test and study drug were coadministered at week 0 to assess the direct effect of colesevelam on glucose absorption. RESULTS Insulin sensitivity as measured by the insulin clamp method did not change, but the Matsuda Index, a measure of whole-body insulin sensitivity calculated from postmeal tolerance test glucose and insulin levels, increased significantly within the colesevelam group from baseline to week 8 with last observation carried forward (P = 0.020). The postprandial area under the curve for glucose decreased with colesevelam versus placebo at weeks 2 and 8 with last observation carried forward (P = 0.012 and P = 0.061, respectively); the area under the curve for insulin did not decrease in concert with the decrease in area under the curve for glucose at week 2 (P = 0.585). Colesevelam had no effect on postmeal tolerance test glucose levels at week 0. CONCLUSIONS These results suggest that colesevelam has no effect on peripheral insulin sensitivity or glucose absorption, but may improve glucose control by improving whole-body insulin sensitivity, although not by an acute effect on glucose absorption. CLINICAL TRIAL IDENTIFIER: NCT00361153.

Rationale for and study design of the sulodexide trials in Type 2 diabetic, hypertensive patients with microalbuminuria or overt nephropathy.

Background  Patients with Type 2 diabetes and albuminuria are at high risk to progress to end‐stage renal disease (ESRD). Although angiotensin receptor blockers confer renoprotection, many diabetic patients still develop overt nephropathy and reach ESRD. Glycosaminoglycans belong to the same family as heparin and heparinoids. Pilot studies with sulodexide, a glycosaminoglycan, have shown that sulodexide can reduce urinary albumin excretion rates in diabetic patients. No hard renal end‐point data are available.