Clinical implications of exenatide as a twice-daily or once-weekly therapy for type 2 diabetes

Exenatide (exendin-4) is a 39-amino acid peptide belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class that has been demonstrated to improve glycemic control in patients with type 2 diabetes mellitus. Exenatide can be injected twice daily (ExBID) before meals or once weekly (ExQW) when encompassed within dissolvable poly-(D,L-lactide-co-glycolide) microspheres. The primary difference between these formulations is the plasma concentration of exenatide over time, with the long-acting form providing continuous delivery. Clinical trials have examined the similarities and differences in the efficacy and safety/tolerability outcomes of these formulations. In 2 clinical studies spanning 24 and 30 weeks, significant (P < 0.05) reductions from baseline were observed in fasting plasma glucose (ExBID, -12 and -25 mg/dL; ExQW, -35 and -41 mg/dL), postprandial glucose (ExBID, -124 mg/dL; ExQW, -95 mg/dL), and glycated hemoglobin (HbA1c) (ExBID, -0.9% and -1.5%; ExQW, -1.6% and -1.9%). Reductions in body weight from baseline were significant and similar with both treatments (ExBID, -1.4 and -3.6 kg; ExQW, -2.3 and -3.7 kg). Reductions in systolic blood pressure from baseline were observed with both formulations, particularly in patients who were hypertensive at baseline. Beneficial improvements in lipid profiles were small and fluctuated in significance. Patients reported greater treatment satisfaction with ExQW compared with ExBID dosing. Gastrointestinal adverse events were commonly observed with both formulations but were less frequent with ExQW. These events were of mild-to-moderate intensity and rarely led to discontinuation. Real-world data for ExBID demonstrated decreases in HbA1c, fasting plasma glucose, and body weight that were consistent with clinical trial results. Cases of pancreatitis or renal impairment have been reported in patients treated with ExBID, although no causal relationship with treatment has been shown. This review describes the similarities and differences between exenatide delivered as a twice-daily or as a once-weekly injection to provide a better understanding of the clinical effects and potential clinical uses of each.     

Pharmacology and tolerability of a single dose of exenatide in adolescent patients with type 2 diabetes mellitus being treated with metformin: A randomized,placebo-controlled,single-blind,dose-escalation,crossover study

Objective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM).Methods: This was a randomized, single-blind, dose-escalation, crossover study in adolescent (age 10–16 years) patients with T2DM who were being treated with diet and exercise or a stable dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 μg, exenatide 5 μg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 μg always preceded exenatide 5 μg in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations.Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean [SD] age, 15 [1] years; body mass index, 32.5 [5.0] kg/m²; glycosylated hemoglobin, 8.2% [1.5%]). After administration of exenatide 5 μg, the geometric mean (SE) exenatide AUC_0?∞ and C_max were 339.5 (39.6) pg · h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-μg dose; after administration of exenatide 2.5-μg, the geometric mean AUC_0?∞) was 159.2 (23.1) pg · h/mL (n = 6) and the geometric mean C_max was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandialplasma glucose excursions compared with placebo (P < 0.01); the incremental mean (SE) AUC_15–360min was ?3465.6 (1587.3) mg · min/dL for exenatide 2.5 pg, ?4422.2 (2434.4) mg · min/dL for exenatide 5 μg, and 3457.4 (1615.5) mg · min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo (P < 0.01); the respective incremental mean values for AUC_15–180min were 125.5 (658.4), ?1403.8 (632.1), and 1843.1 (540.6) pg · min/mL. There were no significant differences in serum insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic events recorded during the study.Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-μg doses of exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254.     

The Effect of Exenatide Once Weekly on Carotid Atherosclerosis in Individuals With Type 2 Diabetes: An 18-Month Randomized Placebo-Controlled Study

OBJECTIVEGlucagon-like peptide 1 receptor agonists (GLP-1RAs) improved multiple proatherogenic risk factors and reduced cardiovascular events in recent clinical trials, suggesting that they may slow progression of atherosclerosis. We tested whether exenatide once weekly reduces carotid plaque progression in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODSIn a double-blind, pragmatic trial, 163 participants were randomized (2:1) to exenatide (n = 109) or placebo (n = 54). Changes in carotid plaque volume and composition were measured at 9 and 18 months by multicontrast 3 Tesla MRI. Fasting and post–high-fat meal plasma glucose and lipids, and endothelial function responses, were measured at 3, 9, and 18 months.RESULTSExenatide reduced hemoglobin A_1c (HbA_1c) (estimated difference vs. placebo 0.55%, P = 0.0007) and fasting and postmeal plasma glucose (19 mg/dL, P = 0.0002, and 25 mg/dL, P < 0.0001, respectively). Mean (SD) change in plaque volume in the exenatide group (0.3% [2%]) was not different from that in the placebo group (−2.2% [8%]) (P = 0.4). The change in plaque volume in the exenatide group was associated with changes in HbA_1c (r = 0.38, P = 0.0004), body weight, and overall plasma glucose (r = 0.29, P = 0.007 both). There were no differences in changes in plaque composition, body weight, blood pressure, fasting and postmeal plasma triglycerides, and endothelial function between the groups.CONCLUSIONSExenatide once weekly for up to 18 months improved fasting and postprandial glycemic control but did not modify change in carotid plaque volume or composition. This study raises the possibility that short-term antiatherosclerotic effects may not play a central role in the cardiovascular benefits of GLP-1RAs.     

Pathophysiological and Pharmacological Rationale for the Use of Exenatide Once Weekly in Patients with Type 2 Diabetes

Introduction

A new formulation of exenatide has become available recently that is the first antidiabetic medication for type 2 diabetes mellitus (T2DM) dosed on a weekly schedule. This review summarizes the pharmacology, efficacy, and safety of exenatide once weekly (exenatide QW). The results are interpreted in terms of the pathophysiology of T2DM, as well as the pharmacology of the new formulation.

Methods

Relevant literature on exenatide QW and diabetes was identified through PubMed database searches from inception until September 2013.

Discussion

In the new once-weekly formulation of exenatide, the exenatide molecule is dispersed in microspheres. Following subcutaneous injection, these microspheres degrade in situ and slowly release active agent. In clinical trials, therapy with exenatide QW as monotherapy or in combination with other antidiabetic treatments was associated with reductions in glycated hemoglobin (?1.3% to ?1.9%), fasting plasma glucose (?32 to ?41 mg/dL), and body weight (?2.0 to ?3.7 kg). These outcomes were achieved without an associated increase in the rate of hypoglycemic episodes, except when exenatide QW was used in combination with sulfonylureas. The primary tolerability issues in the trials were gastrointestinal adverse events, particularly during the first weeks of use, although the rate of nausea during startup with exenatide QW was lower than that with the related agents, exenatide twice daily and liraglutide once daily.

Conclusions

Exenatide QW may be particularly well suited to patients who desire the benefits associated with glucagon-like peptide-1 receptor agonists, including significant glycemic control, low risk of hypoglycemia, and moderate weight loss, but prefer the convenience of once-weekly dosing.     

Exenatide: an incretin mimetic for the treatment of type 2 diabetes mellitus

BACKGROUND: Exenatide is a subcutaneously injected incretin mimetic. It is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) who are already receiving therapy with metformin, a sulfonylurea, or both but continue to have suboptimal glycemic control. OBJECTIVE: This article reviews available information on the clinical pharmacology, comparative efficacy, tolerability, drug interactions, contraindications and precautions, dosage and administration, availability and storage, and cost of exenatide. METHODS: MEDLINE (1966-April 2006) and Web of Science (1995-April 2006) were searched for original research and review articles published in the English language. The search terms used were exenatide, exendin-4, glucagon-Like peptide-1, GLP-1, and incretin mimetic. The reference lists of identified articles were also consulted, as was selected information from the package insert for exenatide. All relevant comparative efficacy studies that were available in published form were included in the review. RESULTS: Naturally occurring incretins, such as glucagon-like peptide-1 (GLP-1), exhibit insulinotropic properties after release into the circulation from the gut. As a GLP-1 agonist, exenatide improves glucose homeostasis by mimicking the actions of naturally occurring GLP-1. It improves glycemic control by reducing fasting and postprandial glucose concentrations through a combination of known mechanisms, including glucose-dependent insulin secretion, restoration of first-phase insulin response, regulation of glucagon secretion, delaying gastric emptying, and decreasing food intake. Three Phase III comparative efficacy trials were identified that enrolled a total of 1,446 patients who received exenatide 5 pg SC BID, exenatide 10 mug SC BID, or placebo for 30 weeks in addition to their existing therapy with metformin, sulfonylurea, or both. In these trials, the addition of exenatide was associated with significant reductions in glycosylated hemoglobin (HbA(1c)) values (P < 0.001-P < 0.002), greater proportions of patients achieving an HbA(1c) 10% of patients receiving exenatide were hypoglycemia (19.6%), diarrhea (12.8%), and vomiting (12.8%). CONCLUSIONS: During clinical trials, exenatide added to existing metformin and/or sulfonylurea therapy in patients with T2DM reduced fasting and postprandial glucose concentrations, with improvements in HbA(1c) and modest weight loss. The main adverse effect associated with exenatide therapy was nausea.     

Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study

Objective: Therapeutic options are limited for diabetes patients with renal disease. This report presents 52‐week results from a study assessing the dipeptidyl peptidase‐4 inhibitor saxagliptin in patients with type 2 diabetes mellitus (T2DM) and renal impairment. Design: Double‐blind study in patients stratified by baseline renal impairment (moderate, severe or end‐stage renal disease [ESRD] on haemodialysis) randomised to saxagliptin 2.5 mg once daily or placebo added to other antidiabetic drugs in use at baseline, including insulin. Patients: A total of 170 adults with glycated haemoglobin (HbA_1c) 7–11% and creatinine clearance < 50 ml/min or ESRD were randomised and treated. Measurements: Absolute changes in HbA_1c and fasting plasma glucose (FPG) from baseline to week 52 were evaluated using analysis of covariance (ANCOVA) with last observation carried forward. Repeated‐measures analyses were also performed. Results: Adjusted mean decrease in HbA_1c was greater with saxagliptin than placebo (difference, ?0.73%, p < 0.001 [ANCOVA]). Reductions in adjusted mean HbA_1c were numerically greater with saxagliptin than placebo in patients with renal impairment rated as moderate (?0.94% vs. 0.19% respectively) or severe (?0.81% vs. ?0.49%), but similar to placebo for those with ESRD (?1.13% vs. ?0.99%). Reductions in adjusted mean FPG were numerically greater with saxagliptin in patients with moderate or severe renal impairment. Saxagliptin was generally well tolerated; similar proportions of patients in the saxagliptin and placebo groups reported hypoglycaemic events (28% and 29% respectively). Conclusions: Saxagliptin 2.5 mg once daily offers sustained efficacy and good tolerability for patients with T2DM and renal impairment.     

Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes

OBJECTIVE

To determine variables associated with glycemic and body weight responses when adding exenatide to basal insulin–treated type 2 diabetes.

RESEARCH DESIGN AND METHODS

Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 exenatide; 122 placebo).

RESULTS

Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001).

CONCLUSIONS

Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration.The combined use of glucagon-like peptide 1 (GLP-1) receptor agonists and insulin is of growing clinical interest (1–6), and the combined use of insulin glargine with exenatide is now approved in the U.S. In this recent study, exenatide twice daily added to optimized titration of glargine resulted in greater A1C improvements with weight loss and lesser increase in insulin dose than placebo plus optimized glargine (5). The current exploratory post hoc analysis assessed the relationship of baseline A1C, duration of diabetes, and BMI with glucose control, body weight changes, and insulin doses in that study.     

DURATION-1: Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks

OBJECTIVE

In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.

RESEARCH DESIGN AND METHODS

In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.

RESULTS

Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean −2.0% [95% CI −2.1 to −1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and ≤6.5%, respectively. In both treatment arms, FPG was reduced by >40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.

CONCLUSION

Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.Type 2 diabetes is a complex and increasingly prevalent disease associated with interrelated comorbidities, including obesity, dyslipidemia, and hypertension. The importance of treating not only hyperglycemia, but also the associated comorbidities, is recognized as necessary to reduce the risk of complications, particularly cardiovascular disease (1). Lifestyle modification can improve glycemic control as well as body weight, blood pressure, and lipid profiles; however, behavioral modifications are inherently difficult, and most patients eventually require multiple medications (2–6). Although several classes of antihyperglycemic medications are currently indicated for the treatment of type 2 diabetes, most of them do not improve the comorbidities and several are associated with weight gain.Exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, improves glycemic control in patients with type 2 diabetes through multiple mechanisms of action: increased glucose-dependent insulin secretion, attenuated postprandial glucagon secretion, slowed gastric emptying, and increased satiety (7,8). The twice-daily formulation of exenatide (exenatide BID) improves both fasting and postprandial glucose control, resulting in A1C reductions of roughly 0.8–1.0% in placebo-controlled trials (9–12) and 1.0–1.4% in open-label trials (13–15). These improvements in glucose control were maintained in patients completing 3 years of treatment (−1.0%) (16). Exenatide therapy is also associated with weight loss and improvement in cardiovascular risk factors, including blood pressure and serum lipid profiles (16). Furthermore, the glucose-dependent mechanisms of action of exenatide minimize the risk of hypoglycemia. GLP-1R agonists have recently been added to the American Diabetes Association and European Association for the Study of Diabetes consensus algorithm for the treatment of type 2 diabetes as an option after the addition of metformin in patients in whom body weight and hypoglycemia risk are concerns (1).Exenatide BID is administered within the 60-min period before the morning and evening meals and primarily exerts its pharmacodynamic effects on glucose concentrations during the postprandial period. A long-acting once-weekly formulation of exenatide (exenatide QW) has been developed. Weekly administration of 2 mg exenatide QW results in therapeutic plasma exenatide concentrations within 2 weeks and steady-state plasma exenatide concentrations within the therapeutic target range 6–7 weeks after initiation of therapy (17,18).The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) trial was designed as a two-stage protocol. We previously reported the first stage, a randomized open-label comparison of exenatide QW to exenatide BID in patients with type 2 diabetes over 30 weeks (17). Both therapies improved glycemic control, and the improvement in A1C observed with exenatide QW treatment was significantly greater than that observed with exenatide BID (−1.9 vs. −1.5%, respectively). Similar improvements in body weight, blood pressure, and fasting lipids were demonstrated with both forms of exenatide therapy. We now describe 52-week results from the second phase of the DURATION-1 trial which examined the safety and efficacy of 1) switching from exenatide BID to exenatide QW after 30 weeks of treatment and 2) continuing exenatide QW treatment for an additional 22 weeks (52 weeks total).     

A workable model for the management of hyperglycemia in non-critically ill patients in an Asian population

Objective: The clinical efficacy of applying a western model for managing hyperglycemia in hospitalized patients in Asia has not been studied. Methods: For this observational case-control study, we divided six medical wards into two groups, an intervention group and a control group. The intervention group, consisting three medical wards on the same floor, received care under a computer-assisted consulting model in which special care was automatically indicated for patients who had two successive high glucose measurements in 1 day. The control group, consisting of another three medical wards distributed on different floors, received regular care. Outcome measures were baseline and post-intervention patient-day weighted mean glucose, percentage of patient-day weighted glucose ≥180 mg/dL, proportion of glucose level 100–180 mg/dL, and prevalence of inpatient hyperglycemia (>180 mg/dL) and hypoglycemia (individual measurement <70 mg/dL and patient-day with any measurement <70 mg/dL). Results: At baseline, the patient-day weighted mean glucose level was 181.6 mg/dL. All parameters were comparable between the intervention and control groups with the exception of prevalence of hypoglycemia, which was found to be higher in the intervention group. After intervention, patient-day weighted mean glucose levels for intervention and control groups were 169.9 mg/dL and 176.7 mg/dL, respectively (p < 0.001). The intervention group had a reduction in hypoglycemia and the control group an increase. Conclusion: This computer-assisted consulting model was found to be potentially very workable for the management of inpatient hyperglycemia in hospitals with high patient volumes in Asia.     

Associations of prediabetes with all-cause and cardiovascular mortality: A meta-analysis

Abstract

Background. Reports on the association of prediabetes with all-cause mortality and cardiovascular mortality are inconsistent.

Objective. To evaluate the risk of all-cause and cardiovascular mortality in association with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).

Methods. Prospective cohort studies with data on prediabetes and mortality were included. The relative risks (RRs) of all-cause and cardiovascular mortality were calculated and reported with 95% confidence intervals (95% CIs).

Results. Twenty-six studies were included. The risks of all-cause and cardiovascular mortality were increased in participants with prediabetes defined as IFG of 110–125 mg/dL (IFG 110) (RR 1.12, 95% CI 1.05–1.20; and RR 1.19, 95% CI 1.05–1.35, respectively), IGT (RR 1.33, 95% CI 1.24–1.42; RR 1.23, 95% CI 1.11–1.36, respectively), or combined IFG 110 and/or IGT (RR 1.21, 95% CI 1.11–1.32; RR 1.21, 95% CI 1.07–1.36, respectively), but not when IFG was defined as 100–125 mg/dL (RR 1.07, 95% CI 0.92–1.26; and RR 1.16, 95% CI 0.94–1.42, respectively).

Conclusions. Prediabetes, defined as IFG 110, IGT, or combined IFG 110 and/or IGT, was associated with increased all-cause and cardiovascular mortality.     

Effect of 50 Milliliters of 50% Dextrose in Water Administration on the Blood Sugar of Euglycemic Volunteers

Abstract. Objective : To evaluate the effect of administration of 1 ampule of 50% dextrose in water solution (D₅₀W) on serum glucose levels in healthy adult volunteers, the authors set out to determine whether a pre-D₆₀W serum glucose level can be predicted from the ED sample. Methods : This was a prospective, interventional study conducted from the ED of an urban, university-affiliated hospital. All subjects were healthy employee volunteers between 25 and 40 years of age. Baseline serum glucose levels were determined and all subjects were given an IV bolus of 25 grams of 50% dextrose solution. The main outcome measures were post-D₅₀W serum glucose levels (observed) at 5 predetermined time intervals (5 min, 15 min, 30 min, 1 hr, and 2 hr). An expected change in serum glucose was calculated using the volume of distribution formula for glucose. Results : Twenty-five volunteers (17 males and 8 females) participated in the study. The mean baseline serum glucose was 82.3 ± 13.5 mg/dL. The mean post-infusion levels were: 244.4 ± 44.6 mg/dL (5 min), 145.8 ± 52.3 mg/dL (15 min), 88.1 ± 28.8 mg/dL (30 min), 77.6 ± 13.6 mg/dL (60 min), and 83.2 ± 11.4 mg/dL (120 min). Using a mixed-effect regression model, statistically significant increases in serum glucose levels were found at 5 minutes (p < 0.001) and 15 minutes (p < 00001) following administration of D₅₀W. There was a return to baseline serum glucose by 30 minutes. The expected change based on the volume of distribution formula (53.7 ± 34.9) did not correlate with the observed changes at any measured time interval. Conclusion : Without pre-intervention blood drawing by emergency medical services, it is not possible to accurately predict pre-D₅₀W serum glucose levels based on post-D₅₀W glucose levels. The diagnosis of hypoglycemia as the etiology of altered mental status must therefore remain a diagnosis of exclusion. In addition, the return of serum glucose to baseline after 30 minutes suggests the duration of the effect of 1 ampule of D₅₀W. Frequent re-evaluation of the serum glucose levels of suspected or proven hypoglycemic patients after administration of D₅₀W should be considered.     

Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes

OBJECTIVE: This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. RESEARCH DESIGN AND METHODS: This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy. RESULTS: At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA(1c) > 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c) 相似文献   

When glycaemic targets can no longer be achieved with basal insulin in type 2 diabetes,can simple intensification with a modern premixed insulin help? Results from a subanalysis of the PRESENT study

Aims: The aim of this analysis was to assess the efficacy and safety of intensifying insulin therapy from a basal‐only regimen to biphasic insulin aspart 30 (BIAsp 30) in patients with type 2 diabetes previously failing to reach glycaemic targets. Methods and patients: The analysis is based on data from a subpopulation of the Physicians’ Routine Evaluation of Safety and Efficacy of NovoMix^® 30 Therapy (PRESENT) study, which was a 6‐month observational study in 15 countries. This subanalysis included patients previously receiving long‐acting analogue insulin (AB; n = 348), or human basal insulin (long and intermediate acting) (HB; n = 3414), who were transferred to BIAsp 30. Efficacy end‐points included change in glycated haemoglobin (HbA_1c), fasting plasma glucose (FPG) and postprandial plasma glucose (PPG), from baseline to the end of the study. Episodes of hypoglycaemia, adverse events, and physician and patient satisfaction were also recorded. End‐points were considered separately by previous basal regimen (AB or HB). Results: After 6 months’ treatment with BIAsp 30, HbA_1c was significantly lowered in both groups (?1.60% and ?1.42% in the AB and HB groups; p < 0.0001 compared with baseline). Reductions in FPG and PPG were also statistically significant in both groups. The rate (events/patient/year) of overall hypoglycaemia remained relatively constant in patients switching from AB, but it was statistically lower in patients switching from HB (change from baseline ?3.8; p < 0.001). Conclusion: In routine clinical practice, patients with type 2 diabetes who are failing to reach glycaemic targets on basal insulin can achieve better glycaemic control without an increase in overall hypoglycaemia by intensifying with BIAsp 30.     

Exenatide twice daily: analysis of effectiveness and safety data stratified by age, sex, race, duration of diabetes, and body mass index

Background: Exenatide, a glucagon-like peptide-1 receptor agonist, is used twice daily (BID) as monotherapy or adjunctive therapy for the improvement of glycemic control in patients with type 2 diabetes mellitus. The purpose of this pooled analysis was to evaluate the safety and efficacy of exenatide BID in patients stratified by various demographic characteristics. Methods: This post hoc analysis included data from 16 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with 10-μg exenatide BID. Each patient was classified into subgroups on the basis of his or her baseline values for age (< 65 or ≥ 65 years), sex (male or female), race (white, black, Asian, or Hispanic), duration of diabetes (< 10 years or ≥ 10 years), and body mass index (BMI; ≥ 20 to < 25, ≥ 25 to < 30, ≥ 30 to < 35, or ≥ 35 kg/m2). Results: A total of 2067 patients were included. All groups experienced significant improvements in glycated hemoglobin, fasting plasma glucose levels (other than black patients, who had a relatively low baseline fasting plasma glucose level), and body weight from baseline to endpoint. Most groups had significant improvements in systolic blood pressure. All of the age, sex, and duration of diabetes groups experienced significant improvements in lipid levels (other than high-density lipoprotein cholesterol). Whites and Asians generally experienced significant improvements in lipid levels, whereas blacks and Hispanics did not. Significant improvements in lipid levels were generally seen across BMI groups. The most common adverse events overall were nausea (38.6%), hypoglycemia (28.4%), and vomiting (14.0%). Hypoglycemia was more common overall in patients who were taking a concomitant sulfonylurea than it was in patients who were not. Conclusion: In this pooled analysis, exenatide BID improved glycemic control and body weight, and had generally beneficial effects on blood pressure and lipid levels in patients regardless of baseline age, sex, race, duration of diabetes, or BMI. Gastrointestinal events were the most common adverse events.Trial registration: www.ClinicalTrials.gov [NCT00039026, NCT00039013, NCT00082381, NCT00035984, NCT00082407, NCT00381342, NCT00360334, NCT00375492, NCT00603239, NCT00765817, NCT00577824, NCT00434954].     

C OMPARISON OF C APILLARY AND V ENOUS G LUCOSE M EASUREMENTS IN H EALTHY V OLUNTEERS

Background. Out-of-hospital (OOH) emergency personnel measure serum glucose in order to determine the need for dextrose therapy. Most devices that measure serum glucose are designed to use capillary blood obtained from a finger puncture. However, OOH emergency personnel often use venous blood obtained during intravenous line (IV) placement to determine serum glucose. Objective. To compare capillary and venous glucose measurements. Methods. This prospective study used healthy, non-fasting volunteers. Simultaneous venous and capillary blood samples were obtained from each subject. Glucose levels were measured using a glucometer designed for capillary samples. The capillary and venous measurements were compared using a Pearson correlation coefficient. Power analysis revealed that the study had the ability to detect a difference of 15?mg/dL. Results. Ninety-seven volunteers (56 males, 41 females) with a mean age of 37 ± 11.9 years were enrolled. The mean capillary and venous glucose values were 104.5 ± 20.7?mg/dL and 109.7 ± 22.4?mg/dL, respectively. The Pearson correlation coefficient was 0.24. Conclusions. The correlation between venous and capillary blood glucose measurements is relatively poor in this group of healthy volunteers. Further research must be conducted on patients at risk for abnormal blood glucose.     

Comparison of normal fasting and one-hour glucose levels as predictors of future diabetes during a 34-year follow-up

Abstract

Introduction. Early identification of those at risk of developing type 2 diabetes (T2DM) is essential. We examined how normoglycemic levels of fasting blood glucose (FBG) and 1-hour glucose predict the development of diabetes among men initially at low risk.

Methods. In the Helsinki Businessmen Study (men born in 1919– 1934), 1,145 men had normal FBG (< 5.0 mmol/L) in 1974, and 1-hour glucose values available. Multivariate, adjusted models were used to investigate how fasting and 1-hour glucose at baseline related to new-onset diabetes during a follow-up of 34 years.

Results. The median FBG and 1-hour glucose values at baseline were 4.4 and 6.6 mmol/L, respectively. During follow-up, 108 men developed diabetes. The risk of incident diabetes was doubled for the highest quintile of FBG (fully adjusted relative risk (RR) 2.22, 95% confidence interval (CI) 1.10–4.50), and quadrupled for that of 1-hour glucose (RR 4.23, 95% CI 2.49–7.17). FBG could not separate the risk for those with higher levels of glucose in the range < 5.0 mmol/L, whereas 1-hour glucose discriminated the risk better at higher values.

Conclusions. Higher values in the normoglycemic range for both fasting and 1-hour glucose predicted long-term incidence of diabetes in healthy middle-aged men.     

Exenatide Treatment for 6 Months Improves Insulin Sensitivity in Adults With Type 1 Diabetes

OBJECTIVE

Exenatide treatment improves glycemia in adults with type 2 diabetes and has been shown to reduce postprandial hyperglycemia in adolescents with type 1 diabetes. We studied the effects of exenatide on glucose homeostasis in adults with long-standing type 1 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients with type 1 diabetes participated in a crossover study of 6 months'' duration on exenatide (10 μg four times a day) and 6 months off exenatide. We assessed changes in fasting and postprandial blood glucose and changes in insulin sensitivity before and after each study period.

RESULTS

High-dose exenatide therapy reduced postprandial blood glucose but was associated with higher fasting glucose concentrations without net changes in hemoglobin A_1c. Exenatide increased insulin sensitivity beyond the effects expected as a result of weight reduction.

CONCLUSIONS

Exenatide is a promising adjunctive agent to insulin therapy because of its beneficial effects on postprandial blood glucose and insulin sensitivity in patients with type 1 diabetes.Glucagon-like peptide 1 (GLP-1) agonists, including exenatide, are promising agents for the treatment of type 2 diabetes. Exenatide, the first GLP-1 agonist to be Food and Drug Administration approved, and other members of this class of drugs have been shown to improve fasting and postprandial blood glucose and hemoglobin A_1c (A1C) and to promote weight loss, resulting in increased insulin sensitivity (1–3). Few reports have focused on GLP-1 agonist treatment in patients with type 1 diabetes. Herein, we report the effects of 6 months of therapy with exenatide in patients with long-standing type 1 diabetes focusing on outcomes related to glucose homeostasis, including fasting and postprandial blood glucose and insulin sensitivity, as determined by the reference glucose clamp method (4).     

Systematic review of the effect of telmisartan on insulin sensitivity in hypertensive patients with insulin resistance or diabetes

What is known and Objective: Telmisartan is an angiotensin receptor blocker (ARB) originally developed for the treatment of hypertension. It can also partially activate peroxisome proliferator‐activated receptor (PPAR)‐γ, which may improve insulin sensitivity. This effect may prove useful in hypertensive patients with insulin resistance or diabetes mellitus. Such activity is more marked than that observed with other ARBs. This systematic review and meta‐analysis evaluated the benefit of telmisartan on insulin sensitivity compared with that of other ARBs in hypertensive patients who had either insulin resistance or diabetic states. Methods: Clinical trials of telmisartan were identified through electronic searches (MEDLINE, CINAHL, Scopus, and The Cochrane Library) up to and including May 2011. Studies were included if they met the following inclusion criteria: (i) randomized controlled trials that compared telmisartan with other ARBs in hypertensive patients who had insulin resistance or type 2 diabetes mellitus; (ii) using telmisartan as an add‐on therapy or a monotherapy for treating hypertension; and (iii) reporting fasting plasma glucose (FPG) and fasting plasma insulin (FPI), or homeostasis model assessment of insulin resistance (HOMA‐IR), or adiponectin as an outcome measure. Treatment effect was estimated with the mean difference in the final value of FPG, FPI, HOMA‐IR and adiponectin between the telmisartan and the control groups. Results and Discussion: Eight trials involving a total of 763 patients met the inclusion criteria. Telmisartan was superior to other ARBs in reducing FPG level (mean difference, ?8·63 mg/dL; 95% CI ?12·29 mg/dL to ?4·98 mg/dL; P < 0·00001) and increasing adiponectin level (mean difference, 0·93 μg/dL; 95% CI 0·28 μg/dL to 1·59 μg/dL; P = 0·005). At 80 mg dose, telmisartan may reduce FPI level and HOMA‐IR. What is new and Conclusions: The available evidence suggests a beneficial effect of telmisartan in improving insulin sensitivity in hypertensive patients with insulin resistance or diabetes as demonstrated by the decrease in FPG and increase in adiponectin levels. The effect in decreasing FPG was greater with 80 mg dose than with the 40 mg dose. FPI and insulin resistance may be improved with 80 mg of telmisartan.     

Efficacy and Safety of Lixisenatide Once Daily Versus Exenatide Twice Daily in Type 2 Diabetes Inadequately Controlled on Metformin: A 24-week,randomized, open-label,active-controlled study (GetGoal-X)

OBJECTIVE

To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin.

RESEARCH DESIGN AND METHODS

Adults with diabetes inadequately controlled (HbA_1c 7–10%) with metformin were randomized to lixisenatide 20 μg once daily (n = 318) or exenatide 10 μg twice daily (n = 316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA_1c change from baseline to week 24.

RESULTS

Lixisenatide once daily demonstrated noninferiority in HbA_1c reduction versus exenatide twice daily. The least squares mean change was −0.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus −0.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033–0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA_1c <7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P < 0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P < 0.05).

CONCLUSIONS

Add-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA_1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily.The glucagon-like peptide-1 (GLP-1) receptor system has become an attractive target for type 2 diabetes therapies (1–5). GLP-1 receptor agonists increasingly have become established as effective therapeutic options in type 2 diabetes management (6,7).Glucose-lowering effects of GLP-1 receptor agonists are mediated by glucose-dependent stimulation of insulin release and inhibition of glucagon secretion, which decreases prandial blood glucose excursion and hepatic glucose production (1–5). Notably, GLP-1 receptor agonists achieve physiological blood glucose–insulin response with a low risk of hypoglycemia (as a result of their glucose-dependent action) (8), delay gastric emptying, and are associated with beneficial effects on weight and appetite reduction (9).Currently available GLP-1 receptor agonists include twice-daily and once-weekly formulations of exenatide, a once-daily formulation of liraglutide, and a once-daily formulation of lixisenatide. Both exenatide and liraglutide have been shown to improve glycemic control associated with beneficial effects on weight and a low risk of hypoglycemia (10,11). However, although exenatide and liraglutide share the same basic mechanisms, each has a distinct pharmacokinetic profile and molecular structure, with potential clinical implications in terms of efficacy against fasting plasma glucose (FPG) and postprandial plasma glucose, and in terms of regimen burden and safety. This has been demonstrated in a 26-week, randomized, parallel-group, open-label trial in adults with inadequately controlled type 2 diabetes who were assigned to receive additional liraglutide 1.8 mg once daily or additional exenatide 10 µg twice daily (11). Liraglutide reduced mean FPG more than did exenatide (−29.0 mg/dL vs. −10.8 mg/dL; P < 0.0001), whereas exenatide reduced postprandial plasma glucose increment after breakfast and dinner more than did liraglutide (breakfast: estimated treatment difference, 23.9 mg/dL; P < 0.0001; dinner: estimated treatment difference, 18.2 mg/dL; P = 0.0005) (11). These findings suggest that liraglutide and exenatide should not be used interchangeably, but instead should be prescribed on an individual basis according to the glycemic requirements of each patient.Lixisenatide is a once-daily prandial GLP-1 receptor agonist for the treatment of type 2 diabetes that was approved by the European Medicines Agency in February 2013 (12,13). It is a 44–amino-acid peptide that is amidated at the COOH terminal amino acid and shares some structural elements with the GLP-1 receptor agonist exenatide; the primary difference is the addition of six lysine residues at the C terminus (13). A 13-week, randomized, double-blind, placebo-controlled, dose-ranging study that evaluated the dose-dependent effects of lixisenatide (5, 10, 20, or 30 µg once daily or twice daily) found that lixisenatide 20 µg administered once daily provided the best efficacy-to-tolerability ratio, with no additional benefits with any of the twice-daily doses (14). Lixisenatide 20 μg once daily subsequently has been shown to significantly improve glycemic control, with low rates of hypoglycemia and beneficial weight effects, when administered as monotherapy (15), as add-on therapy to oral agents (14,16–18), and in combination with basal insulin with or without oral antidiabetic therapy (19–21).In the current study, we report the results from a head-to-head study (GetGoal-X) that compared the benefit/risk profile of lixisenatide once daily versus exenatide twice daily in patients with type 2 diabetes inadequately controlled with metformin monotherapy.     

Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials

BACKGROUND: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA(1c)) and weight in 30-week placebo-controlled trials. Some patients were followed up in open-label extensions to provide 'real-world' exenatide clinical experience. OBJECTIVE: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. METHODS: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-microg exenatide, 10-microg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. RESULTS: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean [SD] age, 57 [10] years; mean [SD] weight, 100[19] kg; sex, 63% male; mean [SD] body mass index, 34 [6] kg/m(2); mean [SD] HbA(1c), 8.3% [1.0%]) completed 2 years of exenatide treatment. Reductions in mean (SE) HbA(1c) from baseline to week 30 (-0.9% [0.1%]) were sustained through 2 years (-1.1% [0.1%]; P < 0.05 vs baseline), with 50% of the population achieving HbA(1c) < or = 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (-2.1 [0.2] kg), with progressive reductions after 2 years (-4.7 [0.3] kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 [47%]; normal: female < or =19 IU/L; male < or =30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (-11 [1] IU/L from baseline 38 [1] IU/1; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline (P = 0.04). However, weight change was minimally correlated with baseline ALT (r = -0.09) or ALT change (r = 0.31). Also, homeostasis model assessment of the beta-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. CONCLUSIONS: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA(1c), progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.