Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.

Exenatide once-weekly is an extended release formulation of exenatide, a glucagon-like peptide-1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes. EXSCEL is an academically led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35 countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years. Participants will be randomized (1:1) to receive exenatide once-weekly 2 mg or matching placebo by subcutaneous injections. The trial will continue until 1,360 confirmed primary composite cardiovascular end points, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, have occurred. The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular end point. EXSCEL is powered to detect a 15% relative risk reduction in the exenatide once-weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that exenatide once-weekly is noninferior to usual care with respect to the primary cardiovascular composite end point. Noninferiority will be concluded if the upper limit of the CI is <1.30. EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broad range of cardiovascular risk. It will also provide long-term safety information on exenatide once-weekly in people with T2DM. ClinicalTrials.gov Identifier: NCT01144338.

Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial.

BACKGROUND: Most patients with type 2 diabetes begin pharmacotherapy with metformin, but eventually need additional treatment. We assessed the safety and efficacy of once weekly exenatide, a glucagon-like peptide 1 receptor agonist, versus maximum approved doses of the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the thiazolidinedione, pioglitazone, in patients treated with metformin. METHODS: In this 26-week randomised, double-blind, double-dummy, superiority trial, patients with type 2 diabetes who had been treated with metformin, and at baseline had mean glycosylated haemoglobin (HbA(1c)) of 8.5% (SD 1.1), fasting plasma glucose of 9.1 mmol/L (2.6), and weight of 88.0 kg (20.1), were enrolled and treated at 72 sites in the USA, India, and Mexico. Patients were randomly assigned to receive: 2 mg injected exenatide once weekly plus oral placebo once daily; 100 mg oral sitagliptin once daily plus injected placebo once weekly; or 45 mg oral pioglitazone once daily plus injected placebo once weekly. Primary endpoint was change in HbA(1c) between baseline and week 26. Analysis was by intention to treat, for all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00637273. FINDINGS: 170 patients were assigned to receive once weekly exenatide, 172 to receive sitagliptin, and 172 to receive pioglitazone. 491 patients received at least one dose of study drug and were included in the intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and 165 on pioglitazone). Treatment with exenatide reduced HbA(1c) (least square mean -1.5%, 95% CI -1.7 to -1.4) significantly more than did sitagliptin (-0.9%, -1.1 to -0.7) or pioglitazone (-1.2%, -1.4 to -1.0). Treatment differences were -0.6% (95% CI -0.9 to -0.4, p<0.0001) for exenatide versus sitagliptin, and -0.3% (-0.6 to -0.1, p=0.0165) for exenatide versus pioglitazone. Weight loss with exenatide (-2.3 kg, 95% CI-2.9 to -1.7) was significantly greater than with sitagliptin (difference -1.5 kg, 95% CI -2.4 to -0.7, p=0.0002) or pioglitazone (difference -5.1 kg, -5.9 to -4.3, p<0.0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%, respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively); upper-respiratory-tract infection (n=17, 10%) and peripheral oedema (n=13, 8%) were the most frequent events with pioglitazone. INTERPRETATION: The goal of many clinicians who manage diabetes is to achieve optimum glucose control alongside weight loss and a minimum number of hypoglycaemic episodes. Addition of exenatide once weekly to metformin achieved this goal more often than did addition of maximum daily doses of either sitagliptin or pioglitazone. FUNDING: Amylin Pharmaceuticals and Eli Lilly.

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 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.

Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria.

OBJECTIVE: To test the hypothesis that rosiglitazone combined with metformin provides a greater reduction in microalbuminuria and blood pressure than metformin and glyburide at comparable levels of glycemic control. METHODS: In a double-blind, parallel-group design 389 participants with type 2 diabetes were followed for 32 weeks. RESULTS: Urinary albumin: creatinine ratio was significantly reduced at 32 weeks compared with baseline in the rosiglitazone plus metformin group (-22.7%; P < 0.01) but not in the glyburide plus metformin comparator group (-7.1%; P = 0.32). Patients who completed the study (81.5%) demonstrated a treatment difference of -19.5% (P = 0.03), favoring the rosiglitazone group. Rosiglitazone plus metformin reduced both mean 24-h systolic (-3.4 mmHg; P = 0.01) and diastolic (-2.5 mmHg; P < 0.01) ambulatory blood pressure compared with glyburide plus metformin. Addition of rosiglitazone to metformin also reduced levels of plasminogen activator inhibitor-1 antigen and activity, C-reactive protein, von Willebrand factor and fibrinogen compared with addition of glyburide. CONCLUSIONS: Rosiglitazone added to background therapy with metformin provides greater reductions in microalbuminuria and blood pressure as compared with glyburide. These additional improvements in microalbuminuria, blood pressure and cardiovascular biomarkers were observed despite comparable improvements in glycemic control in both groups and may be related to the anti-inflammatory properties of rosiglitazone.

Rosiglitazone, but not glyburide, reduces circulating proinsulin and the proinsulin:insulin ratio in type 2 diabetes.

An elevation in the ratio of proinsulin (PI) to immunoreactive insulin (IRI) is inversely related to beta-cell function in type 2 diabetes, and increased PI is an independent risk factor for coronary heart disease. An objective of the present studies was to assess the effects of the thiazolidinedione insulin sensitizer, rosiglitazone, on indirect markers of beta-cell function and cardiovascular risk in people with type 2 diabetes by measuring plasma PI and the PI:IRI ratio. Parameters of insulin processing, including plasma PI and PI:IRI ratios, were determined in type 2 diabetes patients enrolled in two randomized double-blind studies comparing the effects of rosiglitazone (4 or 8 mg/d) with placebo (study 1, 26-wk treatment) or the sulfonylurea glyburide (study 2, 52-wk treatment). Treatment with rosiglitazone for 26 wk (study 1) produced significant dose-dependent decreases in both plasma PI concentrations (18-29%) and the PI:IRI ratio compared with baseline (7-14%) and placebo (19-29%) (P < 0.001). A significant increase in the PI:IRI ratio in placebo-treated patients occurred (P < 0.001). In study 2, rosiglitazone also significantly reduced both plasma PI and the PI:IRI ratio compared with baseline (P < 0.001). In contrast, glyburide significantly increased both plasma PI (45%; P < 0.001) and the PI:IRI ratio (10%) (P < 0.05 vs. baseline). These results show that rosiglitazone and glyburide have differential effects on absolute PI levels and the PI:IRI ratio in people with type 2 diabetes.