Reduced daily risk of glycemic variability: comparison of exenatide with insulin glargine.

BACKGROUND: Conventional methods describing daily glycemic variability (i.e., standard deviation and coefficient of variation) do not express risk. Low and High Blood Glucose Indices (LBGI and HBGI, respectively) and Average Daily Risk Range (ADRR) are parameters derived from self-monitored blood glucose (SMBG) data that quantify risk of glycemic excursions and temporal aspects of variability. In the present study, variability parameters were used to assess effects of exenatide and insulin glargine on risk of acute blood glucose extremes. METHODS: New (LBGI, HBGI, and ADRR) and conventional variability analyses were applied retrospectively to SMBG data from patients with type 2 diabetes suboptimally controlled with metformin and a sulfonylurea plus exenatide or insulin glargine as a next therapeutic step. Exenatide- (n = 282) and insulin glargine-treated (n = 267) patients were well matched. RESULTS: Exenatide treatment reduced ADRR overall (exenatide, mean +/- SEM, 16.33 +/- 0.45; insulin glargine, 18.54 +/- 0.49; P = 0.001). Seventy-seven percent of exenatide-treated patients were at low risk for glucose variability compared with 62% of glargine-treated patients (P = 0.00023). LBGI for exenatide remained minimal for all categories and significantly lower than glargine for all comparisons, and HBGI for exenatide remained low or moderate for all categories and significantly lower than glargine after the morning and evening meals. Reduced variability in exenatide-treated patients was shown by conventional methods but provided no indications of risk. CONCLUSIONS: Average glycemic control was similar for both treatment groups. However, exenatide treatment minimized risk for glycemic variability and extremes to a greater degree than insulin glargine treatment.

Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea.

AIMS: To evaluate the efficacy of exenatide in Asian patients with type 2 diabetes (T2D) inadequately controlled with oral agents. METHODS: Patients taking metformin (MET) alone or with a sulphonylurea (SU) were randomly assigned to exenatide 5 microg then 10 microg twice-daily for 4 and 12 weeks, respectively, or placebo. The primary endpoint was baseline to endpoint HbA(1c) change. RESULTS: 466 patients (age 54+/-9 years, weight 68.7+/-11.2 kg, BMI 26.3+/-3.3 kg/m(2), and HbA(1c) 8.3+/-1.1%; mean+/-S.D.) were enrolled in the full analysis set. Endpoint HbA(1c) reduction (mean [95% CI]) with exenatide was superior to placebo (-1.2 [-1.3, -1.1]% vs. -0.4 [-0.5, -0.2]%, p<0.001). More exenatide- than placebo-treated patients achieved HbA(1c)

Quantifying the effect of exenatide and insulin glargine on postprandial glucose excursions in patients with type 2 diabetes.

In this report, we quantify the effects of exenatide and glargine on the relative contributions of fasting and postprandial glucose (PPG) excursion to overall hyperglycemia based on self-monitored blood glucose. After 26 weeks of treatment, insulin glargine reduced fasting glucose to a greater extent than exenatide without significant effect on PPG excursion. The principal effect of exenatide on hyperglycemia was mitigating the rise in PPG with moderate improvement on fasting glucose. These findings may be limited by the fact that glucose measurements were collected through self-monitoring with six time points measured during the daytime, the meals were not standardized and the exact time for glucose measurements was unknown.

Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial.

OBJECTIVE: This study was conducted to compare the efficacy and safety profiles of exenatide and insulin glargine therapy in patients with type 2 diabetes who had not achieved glucose control with metformin or sulfonylurea monotherapy. METHODS: This multinational, randomized, open-label, crossover noninferiority study compared the efficacy of exenatide 10 pg BID and insulin glargine QD (titrated targeting a fasting serum glucose (FSG) level < or =5.6 mmol/L) in patients with type 2 diabetes treated with a single oral antidiabetic agent. The study included two 16-week treatment periods. The primary a priori outcome variable was the change in glycosylated hemoglobin (HbA(lc)). Secondary outcomes included the proportion of patients achieving the American Diabetes Association (ADA) target HbA(lc) of < or =7% and the European Association for the Study of Diabetes target of < or =6.5%, the change in FSG, end-point values and change in the 7-point self-monitored glucose profile, and change in body weight. Adverse events were assessed based on standard laboratory tests and patient reports. RESULTS: One hundred thirty-eight patients were randomized to study treatment (52.9% female, 47.1% male; 79.7% white; mean [SEM] age, 54.9 [0.8] years; duration of diabetes, 7.4 [0.4] years; body mass index, 31.1 [0.4] kg/m(2); weight, 84.8 [1.4] kg) while continuing to receive metformin (55.1%) or a sulfonylurea (44.9%). The population had a baseline least squares (LS) mean (SEM) HbA(lc) of 8.95% (0.09%) and an LS mean FSG concentration of 12.0 (0.3) mmol/L. Both exenatide and titrated insulin glargine therapy were associated with similar significant changes from baseline in HbA(1c) (both, -1.36% [0.09%]; P < 0.001); the difference between groups was not statistically significant. The LS mean HbA(1c) at end point was above the ADA target with both treatments (exenatide, 7.57% [0.09%]; insulin glargine, 7.58% [0.09%]). Similar proportions of patients achieved an HbA(1c) < or =7% (37.5% and 39.8%, respectively; P = NS) or < or =6.5% (21.5% and 13.6%). Patients lost weight during exenatide treatment, whereas they gained weight during insulin glargine treatment; the between-group difference in weight change was statistically significant (LS mean difference, -2.2 [0.3] kg; 95% CI, -2.8 to-1.7; P < 0.001). Both exenatide and insulin glargine were associated with significant reductions from baseline in FSG (-2.9 [0.2] and -4.1 [0.2] mmol/L, respectively; both, P < 0.001), although the reduction was significantly greater with insulin glargine compared with exenatide (LS mean difference, 1.2 [0.3] mmol/L; 95% CI, 0.7 to 1.7; P < 0.001). Compared with insulin glargine, exenatide was associated with significantly lower 2-hour postprandial glucose (PPG) excursions (P < 0.016) and total daily mean glucose excursion (P < 0.001). The proportions of patients reporting nausea during exenatide and insulin glargine treatment were 42.6% and 3.1%, respectively; the proportions reporting vomiting were 9.6% and 3.1%. The incidence of hypoglycemia in the 2 groups was 14.7% and 25.2% (P = NS). CONCLUSIONS: In this open-label, crossover study, treatment with exenatide or insulin glargine for 16 weeks was associated with similar significant improvements from baseline in HbA(1c), independent of treatment order. The improvements in HbA(1c) from baseline did not differ significantly between treatment groups. Exenatide therapy was associated with significant reductions in body weight and PPG excursions compared with insulin glargine, whereas insulin glargine was associated with a significantly greater reduction in FSG compared with exenatide. These findings provide additional information to guide treatment decisions in patients with type 2 diabetes who are potential candidates for either therapy.

Exploring the substitution of exenatide for insulin in patients with type 2 diabetes treated with insulin in combination with oral antidiabetes agents.

OBJECTIVE: This 16-week study explored the safety of substituting exenatide for insulin in patients with type 2 diabetes using insulin in combination with oral antidiabetes agents. RESEARCH DESIGN AND METHODS: Successful maintenance of glycemic control was predefined as an A1C increase of < 0.5%. A total of 49 patients (aged 53 +/- 8 years, with BMI 34 +/- 4 kg/m2, A1C 8.1 +/- 1.1%, and duration of diabetes 11 +/- 7 years) were randomized to either substitute exenatide for insulin or remain on their current insulin regimen. Patients who either completed > or = 8 weeks of study or discontinued because of loss of glycemic control were included in primary efficacy analysis. RESULTS: A total of 62% (18 of 29) of the exenatide-treated patients maintained glycemic control compared with 81% (13 of 16) of the insulin-treated patients. Of the 11 exenatide-treated patients who did not maintain control, 5 discontinued before week 16 because of loss of glucose control. The overall safety profile was generally consistent with previous exenatide trials. The mean overall hypoglycemia rates were 1.72 and 0.97 events/patient-year for the exenatide and insulin reference groups, respectively. CONCLUSIONS: This pilot study suggests that it is feasible to sustain glycemic control when substituting exenatide for insulin. Although it is not possible to characterize clear predictors of outcome given the size and exploratory nature of the study, the data suggest that patients with longer disease duration, who are taking higher doses of insulin and have less endogenous beta-cell function, may experience deterioration in glucose control if exenatide is substituted for insulin therapy.

Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial.

BACKGROUND: Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. OBJECTIVE: To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea. DESIGN: 26-week multicenter, open-label, randomized, controlled trial. SETTING: 82 outpatient study centers in 13 countries. PATIENTS: 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy. INTERVENTION: Exenatide, 10 microg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL). MEASUREMENTS: Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. RESULTS: Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [CI, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/patient-year; difference, -1.6 events/patient-year [CI, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%). LIMITATIONS: The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL). CONCLUSIONS: Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.

Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes.

OBJECTIVE: The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested. RESEARCH DESIGN AND METHODS: This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA(1c) and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed. RESULTS: A greater proportion of patients treated with pioglitazone maintained HbA(1c) <8% over the 2-year period than those treated with gliclazide. A difference between the Kaplan-Meier curves was apparent as early as week 32 and widened at each time point thereafter, becoming statistically significant from week 52 onward. At week 104, 129 (47.8%) of 270 pioglitazone-treated patients and 110 (37.0%) of 297 gliclazide-treated patients maintained HbA(1c) <8%. Compared with gliclazide treatment, pioglitazone treatment produced a larger decrease in HbA(1c), a larger increase in HOMA-%S, and a smaller increase in HOMA-%B during the 2nd year of treatment. CONCLUSIONS: Pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment.

Comparison of effect of pioglitazone with metformin or sulfonylurea (monotherapy and combination therapy) on postload glycemia and composite insulin sensitivity index during an oral glucose tolerance test in patients with type 2 diabetes.

OBJECTIVE: Pioglitazone, metformin, and gliclazide lower HbA(1c) and fasting plasma glucose in patients with type 2 diabetes. We compared the effects of these three drugs, used as monotherapy and in combination, on postload glycemia and composite insulin sensitivity index (CISI) in these patients. RESEARCH DESIGN AND METHODS: Postload glycemia and CISI were analyzed for 940 patients who had oral glucose tolerance tests (OGTTs) in four multicenter, randomized, double-blind, double-dummy, parallel group clinical trials (pioglitazone versus metformin, pioglitazone versus gliclazide, pioglitazone plus sulfonylurea versus metformin plus sulfonylurea, and pioglitazone plus metformin versus gliclazide plus metformin). Plasma glucose and insulin were determined during the 3-h OGTT performed at baseline and after 1 year of therapy. Incremental area under the curve for glucose was the surrogate for postload glycemia. CISI was calculated using the formula {10,000/ radical of [(fasting glucose x fasting insulin) x (mean glucose x mean insulin)]} during the OGTT. RESULTS: In monotherapy, pioglitazone reduced postload glycemia and enhanced CISI more than metformin and gliclazide. In combination therapy, pioglitazone plus sulfonylurea reduced postload glycemia and increased CISI more than metformin plus sulfonylurea. Pioglitazone plus metformin also decreased postload glycemia and increased CISI more than gliclazide plus metformin. CONCLUSIONS: Pioglitazone improves postload glycemia and CISI more than metformin or gliclazide when used as monotherapy or in combination therapy in patients with type 2 diabetes.

Effects of pioglitazone and glimepiride on glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, parallel-group trial.

BACKGROUND: Pioglitazone and glimepiride improve glycemic control in patients with type 2 diabetes mellitus by different mechanisms. Pioglitazone is a thiazolidinedione that reduces insulin resistance, and glimepiride is a sulfonylurea insulin secretagogue. OBJECTIVE: The goals of this study were to compare changes in measures of glycemic control and insulin sensitivity in Mexican patients with type 2 diabetes who received pioglitazone or glimepiride for 1 year. METHODS: This was a multicenter, 52-week, double-blind, parallel-group trial. Patients were randomized to receive monotherapy with either glimepiride (2 mg QD initially) or pioglitazone (15 mg QD initially). Doses were titrated (maximal doses: pioglitazone 45 mg, glimepiride 8 mg) to achieve glycemic targets (fasting blood glucose < or =7 mmol/L and 1-hour postprandial blood glucose < or =10 mmol/L). Insulin sensitivity (primary end point) was evaluated in terms of the Homeostasis Model Assessment for Insulin Sensitivity (HOMA-S), the Quantitative Insulin Sensitivity Check Index (QUICKI), and fasting serum insulin (FSI) concentrations. Glycemic control was evaluated in terms of glycosylated hemoglobin (HbA(1c)) values and fasting plasma glucose (FPG) concentrations. Patients were encouraged to maintain their individual diet and exercise regimens throughout the study. RESULTS: Two hundred forty-four patients (125 women, 119 men; all but 1 Hispanic) were randomized to receive pioglitazone (n = 121) or glimepiride (n = 123). In the intent-to-treat sample, pioglitazone and glimepirede produced comparable reductions in HbA(1c) from baseline to the end of the study (-0.78% and -0.68%, respectively). The pioglitazone group had significantly higher HbA(1c) values compared with the glimepiride group after 12 weeks of therapy (8.66% vs 7.80%; P = 0.007) but had significantly lower values after 52 weeks (7.46% vs 7.77%; P = 0.027). Pioglitazone significantly reduced FPG compared with glimepiride (-0.6 vs 0.6 mmol/L; P = 0.01). Pioglitazone therapy was associated with significant increases in insulin sensitivity (reduced insulin resistance), whereas glimepiride had no effect. HOMA-S values changed 18.0% for pioglitazone and -7.9% for glimepiride (P < 0.001), QUICKI values changed a respective 0.013 and -0.007 (P < 0.001), and FSI values were -21.1 and 15.1 pmol/L (P< 0.001). Both drugs were well tolerated, with pioglitazone associated with more peripheral edema (number of treatment-emergent cases: 35/121[28.9%] vs 17/123 [13.8%]; P = 0.005) and fewer hypoglycemic episodes (19 [15.7%] vs 38 [30.9%]; P = 0.024). The incidence of weight gain was not significantly different between treatment groups. CONCLUSIONS: These data suggest that long-term treatment with pioglitazone enhances insulin sensitivity relative to glimepiride in Mexican patients with type 2 diabetes and that pioglitazone may have a more sustained antihyperglycemic effect.

Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes.

BACKGROUND: Miyazaki et al. demonstrated using the hyperinsulinemic, euglycemic clamp that pioglitazone (PIO) enhanced insulin sensitivity in patients (n = 23) with type 2 diabetes (T2D). Although considered the reference method for measuring insulin sensitivity, the clamp is seldom used in large clinical trials because of its complexity. The Homeostasis Model Assessment Insulin Sensitivity (HOMA-S) and Quantitative Insulin Sensitivity Check Index (QUICKI) are two alternative insulin sensitivity surrogates that correlate with the clamp method and are suitable for use with large study populations. STUDY AIM: To evaluate the effect of PIO monotherapy and in combination therapy with sulfonylurea (SU) or metformin (MET) on insulin sensitivity as assessed by HOMA-S and QUICKI in a large group of patients (approximately 1000). RESEARCH DESIGN AND METHODS: Patient data from three randomized, double blind, multicenter, parallel group, placebo-controlled registration trials (Studies-001 PIO monotherapy and 010 and 027 combination therapy with SU or MET, respectively) were analyzed for this study. We evaluated insulin sensitivity for all three studies using HOMA-S and QUICKI. RESULTS: PIO 15, 30 and 45 mg enhanced HOMA-S compared with baseline (56.9-63.6%, p = 0.0298); (53.7-64.7%, p = 0.0008); (59.0-75.9%, p < 0.0001), respectively. Only the 45 mg dose showed a difference from placebo (p = 0.0025). Similarly, PIO enhanced QUICKI versus baseline (0.290-0.296, p = 0.0026); (0.287-0.299, p = 0.0001); (0.290-0.306, p = 0.0001), respectively. Both the 30 and 45 mg doses were different from placebo for QUICKI (p = 0.0005, p < 0.0001). PIO 15 and 30 mg plus SU enhanced HOMA-S compared with baseline (58.4-66.7%, p = 0.0007; 53.2-68.4%, p < 0.0001) and placebo plus SU (p = 0.0129, p < 0.0001, respectively). Likewise, PIO 15 and 30 mg plus SU enhanced QUICKI versus baseline (0.289-0.300, p = 0.0001; 0.287-0.305, p = 0.0001, respectively). Both doses had different effects from placebo plus SU (p = 0.0001) for QUICKI. PIO 30mg combined with MET enhanced HOMA-S versus baseline (66.2-82.2%, p < 0.0001) and placebo plus MET (p = 0.0002). Similarly, PIO 30 mg plus MET enhanced QUICKI compared with baseline (0.295-0.309, p = 0.0001) and placebo plus MET (p = 0.0001). CONCLUSION: PIO monotherapy and combination therapy with SU or MET enhanced insulin sensitivity as evaluated by HOMA-S and QUICKI. Both measures can detect changes in sensitivity for large numbers of subjects when the reference method hyperinsulinemic euglycemic clamp, or other complex methods are not feasible.

Pioglitazone reduces atherogenic index of plasma in patients with type 2 diabetes.

BACKGROUND: Insulin resistance is often associated with increased triglyceride (TG) and decreased HDL-cholesterol (HDL-C) concentrations and increased small LDL particles. The Atherogenic Index of Plasma (AIP), defined as log(TG/HDL-C), has recently been proposed as a marker of plasma atherogenicity because it is increased in people at higher risk for coronary heart disease and is inversely correlated with LDL particle size. We studied the effect of pioglitazone, a thiazolidinedione that reduces insulin resistance, on the AIP of patients with type 2 diabetes. METHODS: The data for the analysis of AIP in this report were obtained from four randomized, double-blind, multicenter, parallel-group, placebo-controlled clinical trials. Pioglitazone was used as monotherapy in one study and in combination therapy in three studies. Fasting glucose, insulin, HDL-C, and TGs plus glycohemoglobin (HbA(1C)) were measured at baseline and various points during each study. RESULTS: Patients in this study population with type 2 diabetes had high AIP values at baseline. Pioglitazone treatment significantly decreased AIP from baseline in each of the study groups. Pioglitazone treatment groups had a significantly lower AIP compared with their respective placebo controls. Finally, AIP was inversely and significantly correlated with measures of insulin sensitivity, such as the homeostasis model assessment and quantitative insulin sensitivity check index. In contrast, AIP was not significantly correlated with HbA(1C). CONCLUSIONS: Pioglitazone reduced AIP when used as monotherapy or in combination therapy with sulfonylurea, metformin, or insulin. AIP was inversely correlated with measures of insulin sensitivity.

A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus.

OBJECTIVE: The goal of this study was to compare the effects of 2 doses of pioglitazone hydrochloride (a thiazolidinedione insulin sensitizer) with placebo on glycated hemoglobin (HbA(1c)), insulin sensitivity, and lipid profiles in patients with type 2 diabetes mellitus who had suboptimal glycemic control and mild dyslipidemia. METHODS: Patients with type 2 diabetes mellitus (HbA(1c) >/=6.5% and /=7% to <8%) or high (>/=8% to

Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes.

Pioglitazone, a thiazolidinedione, improves glycemic control primarily by increasing peripheral insulin sensitivity in patients with type 2 diabetes, whereas metformin, a biguanide, exerts its effect primarily by decreasing hepatic glucose output. In the first head-to-head, double-blind clinical trial comparing these two oral antihyperglycemic medications (OAMs), we studied the effect of 32-wk monotherapy on glycemic control and insulin sensitivity in 205 patients with recently diagnosed type 2 diabetes who were naive to OAM therapy. Subjects were randomized to either 30 mg pioglitazone or 850 mg metformin daily with titrations upward to 45 mg (77% of pioglitazone patients) and 2550 mg (73% of metformin patients), as indicated, to achieve fasting plasma glucose levels of less than 7.0 mmol/liter (126 mg/dl). Pioglitazone was comparable to metformin in improving glycemic control as measured by hemoglobin A1C and fasting plasma glucose. At endpoint, pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity, as determined by reduction of fasting serum insulin (P = 0.003) and by analysis of homeostasis model assessment for insulin sensitivity (HOMA-S; P = 0.002). Both OAM therapies were well tolerated. Therefore, pioglitazone and metformin are equally efficacious in regard to glycemic control, but they exert significantly different effects on insulin sensitivity due to differing mechanisms of action. The more pronounced improvement in indicators of insulin sensitivity by pioglitazone, as compared with metformin monotherapy in patients recently diagnosed with type 2 diabetes who are OAM-naive, may be of interest for further clinical evaluation.