BACKGROUND:EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective.METHODS:Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions.RESULTS:Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection.CONCLUSIONS:EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.

OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI −0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70–1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74–0.98]). Retinopathy rates did not differ by treatment group or in the HbA1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m2 did not differ by group. Those with eGFR ≥60 mL/min/1.73 m2 had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58–0.93]; P for interaction = 0.035) and CV death (HR 1.08 [95% CI 0.85–1.38]; P for interaction = 0.031). CONCLUSIONS EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m2 in analyses unadjusted for multiplicity.

Large studies in patients with diabetes mellitus (DM) have identified agents that lower major adverse cardiovascular (CV) event (MACE) rates, but certain agents increase rates of lower extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of DM and risk for

Background: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW’s effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. Methods: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. Results: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77–0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80–0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85–1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68–0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71–0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89–1.29]; interaction P =0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68–0.99]; P =0.038). Conclusions: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01144338.

OBJECTIVE Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in exenatide-treated and placebo-administered participants and MTC incidence in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring. RESEARCH DESIGN AND METHODS EXSCEL participants were randomized 1:1 to once-weekly exenatide 2 mg or placebo. Serum calcitonin was measured at baseline (with trial medication discontinued if >40 ng/L) and annually thereafter (with trial medication discontinued if ≥50 ng/L). Median calcitonin concentrations were calculated at each time point, and thyroid malignancies were collected prospectively. Data regarding follow-up after an elevated calcitonin were collected retrospectively. RESULTS At baseline, 52 (30 exenatide and 22 placebo) participants had calcitonin >40 ng/L, and during follow-up an additional 23 participants (15 exenatide and 8 placebo) had calcitonin ≥50 ng/L in the intention-to-treat population. Median calcitonin concentrations were similar between treatment groups at baseline with no increase over time. Confirmed MTC occurred in three participants (2 exenatide and 1 placebo), all of whom had significantly elevated baseline calcitonin values (413, 422, and 655 ng/L). CONCLUSIONS During a median 3.2 years’ follow-up, no change in serum calcitonin was seen with exenatide therapy. The three confirmed cases of MTC all occurred in participants with markedly elevated baseline calcitonin levels, measured prior to trial medication administration. Regular calcitonin monitoring identified no additional cases of MTC, suggesting no benefit of routine calcitonin monitoring during exenatide treatment.

OBJECTIVE Healthy pancreatic β-cells secrete the hormones insulin and amylin in a fixed ratio. Both hormones are lacking in type 1 diabetes, and postprandial glucose control using insulin therapy alone is difficult. This study tested the pharmacodynamic effects of the amylin analog pramlintide and insulin delivered in a fixed ratio over a 24-h period. RESEARCH DESIGN AND METHODS Patients with type 1 diabetes were stabilized on insulin pump therapy with insulin lispro before a randomized, single-masked, two-way crossover, 24-h inpatient study in which regular human insulin was administered with pramlintide or placebo using separate infusion pumps in a fixed ratio (9 μg/unit). Meal content and timing and patient-specific insulin doses were the same with each treatment. The primary outcome measure was change in mean glucose by continuous glucose monitoring (CGM). Profiles of laboratory-measured glucose, insulin, glucagon, and triglycerides were also compared. RESULTS Mean 24-h glucose measured by CGM was lower with pramlintide versus placebo (8.5 vs. 9.7 mmol/L, respectively; P = 0.012) due to a marked reduction of postprandial increments. Glycemic variability was reduced, and postprandial glucagon and triglycerides were also lower with pramlintide versus placebo. Gastrointestinal side effects were more frequent during use of pramlintide; no major hypoglycemic events occurred with pramlintide or placebo. CONCLUSIONS Coadministration of fixed-ratio pramlintide and regular human insulin for 24 h improved postprandial hyperglycemia and glycemic variability in patients with type 1 diabetes. Longer studies including dose titration under daily conditions are needed to determine whether this regimen could provide long-term improvement of glycemic control.

This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1 mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55 kg for body weight. Potential treatment-by-subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m2 (least-squares mean reductions of -23.6 vs -19.0 mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0 mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9 mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range -2.56 to -3.98 kg vs -0.56 to -2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

In patients with T2D uncontrolled on metformin alone, ExQW + DAPA significantly reduced glycemia, body weight and systolic blood pressure compared to ExQW + placebo (PBO) or DAPA + PBO at 28 weeks (NCT02229396). Here, we examined efficacy and safety after 104 weeks of double-blind therapy. Of 695 patients randomized, 431 (62%) completed 104 weeks; 4.3% withdrew due to adverse events (AEs). Absolute reductions and between-group differences in A1C were maintained over 104 weeks (Figure). Clinically relevant changes vs. baseline in other efficacy end points were also observed (Table). AEs and serious AEs were balanced across treatment groups. Hypoglycemia incidence was low (Table). In conclusion, ExQW + DAPA maintained efficacy over 104 weeks with no unexpected safety concerns.Changes in efficacy end points and hypoglycemia incidence from baseline through week 104ExQW+DAPA N=228 n=147ExQW+PBO N=227 n=132DAPA+PBO N=230 n=152ExQW+DAPA vs ExQW+PBOExQW+DAPA vs DAPA+PBOA1C, % BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 9.29 (1.06) −1.98 (0.09) −1.75 (0.10) −1.70 (0.11)□ 9.26 (1.08) −1.60 (0.10) −1.38 (0.10) −1.29 (0.12)□ 9.25 (1.02) −1.39 (0.09) −1.23 (0.10) −1.06 (0.12)□ □ −0.38 (0.13)** −0.37 (0.14)** −0.42 (0.15)**□ □ −0.59 (0.13)*** −0.52 (0.13)*** −0.64 (0.15)***FPG, mg/dL BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 195.0 (53.5) −65.8 (2.9) −63.0 (2.9) −49.0 (4.1)□ 189.3 (49.8) −45.8 (3.0) −45.4 (3.1) −29.8 (4.5)□ 188.5 (44.2) −49.2 (2.9) −39.8 (3.0) −21.9 (4.6)□ □ −20.1 (4.0)*** −17.6 (4.1)*** −19.2 (5.9)***□ □ −16.6 (3.9)*** −23.3 (4.0)*** −27.1 (6.0)***2h-PPG, mg/dL BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 268.5 (67.5) −87.8 (4.1) −82.4 (4.8) −86.2 (5.9)□ 266.1 (67.2) −60.1 (4.3) −64.0 (5.1) −79.0 (7.0)□ 261.5 (60.2) −61.1 (4.1) −59.6 (5.0) −64.0 (6.6)□ □ −27.7 (5.2)*** −18.4 (6.3)** −7.2 (7.9)□ □ −26.8 (5.1)*** −22.8 (6.2)*** −22.2 (7.9)**Body weight, kg BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 92.1 (21.8) −3.6 (0.3) −3.3 (0.4) −2.5 (0.4)□ 89.1 (18.7) −1.6 (0.3) −1.5 (0.4) −0.8 (0.5)□ 90.9 (19.6) −2.2 (0.3) −2.3 (0.4) −3.0 (0.5)□ □ −2.0 (0.4)*** −1.8 (0.5)*** −1.7 (0.6)**□ □ −1.3 (0.4)*** −1.0 (0.5) +0.5 (0.6)Systolic BP, mmHg BL mean (SD) 28 wk LSM change from BL (SE) 52 wk LSM change from BL (SE) 104 wk LSM change from BL (SE)□ 130.7 (12.1) −4.3 (0.8) −4.5 (0.8) −3.1 (1.0)□ 129.3 (12.5) −1.2 (0.8) −0.7 (0.9) −0.1 (1.1)□ 129.6 (12.8) −1.8 (0.8) −2.7 (0.8) −1.1 (1.0)□ □ −3.0 (1.1)** −3.9 (1.1)*** −3.0 (1.4)*□ □ −2.4 (1.1)* −1.8 (1.1) −2.0 (1.4)Hypoglycemia† through 104 wks Major, % pts Minor, % pts Other, % ptsN=231 0 1.7 6.9N=230 0 0 3.5N=233 0 0.4 3.4*P<0.05, **P<0.01, ***P≤0.001 (P-values at wk 52 and wk 104 are nominal). BL, baseline, BP, blood pressure; FPG, fasting plasma glucose; LSM, least-squares mean; N, number comprising the intention-to-treat analysis set; n, number completing 104 weeks of treatment; 2h-PPG, 2-hour post-prandial glucose; pts, patients; SD, standard deviation; SE, standard error; wk, week. †Major hypoglycemia: loss of consciousness, seizure or coma resolving after glucagon or glucose administration or events requiring third-party assistance due to severe impairment of consciousness or behavior with blood glucose concentration <54 mg/dL. Minor hypoglycemia: non-major event with symptoms consistent with hypoglycemia and blood glucose concentration <54 mg/dL. Other hypoglycemia: events not meeting major or minor hypoglycemia criteria. Disclosure S. Jabbour: None. C. Guja: Consultant; Self; AstraZeneca, Bayer AG, Eli Lilly and Company, Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Boehringer Ingelheim GmbH. E. Hardy: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. S. Bhattacharya: None. P.K. Ohman: Employee; Self; AstraZeneca. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc..

This post hoc analysis assessed the effects on cardiovascular risk factors of body weight, systolic blood pressure (SBP) and triglycerides after 28 weeks’ treatment with exenatide once weekly plus dapagliflozin, as compared with exenatide once weekly or dapagliflozin, in patient subpopulations from the DURATION‐8 trial of patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone. Subgroups of patients were stratified according to their baseline body weight, SBP and triglyceride levels. Body weight, SBP and triglyceride levels were reduced across most respective subgroups, with no significant subgroup‐by‐treatment interactions. For each treatment, weight loss was numerically greater as baseline body mass index increased. SBP reductions were greater among patients with SBP ≥140 vs <140 mm Hg for exenatide once weekly plus dapagliflozin and exenatide once weekly. Reductions in triglyceride levels were greater among patients with baseline triglycerides <1.69 vs ≥1.69 mmol/L for each treatment. The combination of exenatide once weekly plus dapagliflozin reduced cardiovascular risk factors across baseline subgroups for each variable to a greater extent than did either individual drug; the greatest effects were observed in the high baseline subgroups for body weight and SBP.

OBJECTIVE Among patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin combination produced greater reductions in glycemia, weight, and systolic blood pressure (SBP) at 28 weeks than exenatide QW or dapagliflozin alone (DURATION-8). Here, we investigated the safety and maintenance of efficacy at 52 weeks, after a 24-week extension. RESEARCH DESIGN AND METHODS This phase 3, multicenter, double-blind study randomized adults with type 2 diabetes (with glycated hemoglobin [HbA1c] 8.0–12.0% [64–108 mmol/mol] and on metformin ≥1,500 mg/day) to exenatide QW (2-mg subcutaneous injection) plus once-daily dapagliflozin (10-mg oral tablet), exenatide QW plus oral placebo, or dapagliflozin plus injected placebo. Extension-period P values were nominal. RESULTS Of 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3% [78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment. At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin (least squares mean change −1.75% [−19.1 mmol/mol]) versus exenatide QW (−1.38% [−15.1 mmol/mol]; P = 0.006) or dapagliflozin (−1.23% [−13.4 mmol/mol]; P < 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol), and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greater with exenatide QW plus dapagliflozin (−3.31 kg and −4.5 mmHg) versus exenatide QW (−1.51 kg and −0.7 mmHg; both P < 0.001) but similar to those with dapagliflozin (−2.28 kg and −2.7 mmHg; P = 0.057 and P = 0.100, respectively). The exenatide QW plus dapagliflozin regimen was well tolerated with no unexpected safety findings; more patients treated with exenatide QW experienced gastrointestinal and injection site–related adverse events. No major hypoglycemia occurred. CONCLUSIONS Among patients with type 2 diabetes uncontrolled with metformin, exenatide QW plus dapagliflozin provided sustained improvements in glycemia, weight, and SBP over 52 weeks, with no unexpected safety findings.

Background In the EXSCEL (Exenatide Study of Cardiovascular Event Lowering), exenatide once‐weekly resulted in a nonsignificant reduction in major adverse cardiovascular events (MACEs) and a nominal 14% reduction in all‐cause mortality in 14 752 patients with type 2 diabetes mellitus (T2DM) with and without cardiovascular disease. Whether patients at increased risk for events experienced a comparatively greater treatment benefit with exenatide is unknown. Methods and Results In the EXSCEL population, we created risk scores for MACEs and all‐cause mortality using step‐wise selection of baseline characteristics. A risk score was calculated for each patient, and a time‐to‐event model for each end point was developed including the risk score, treatment assignment, and risk‐treatment interaction. Interaction P values evaluating for a differential treatment effect by baseline risk were reported. Over a median follow‐up of 3.2 years (interquartile range, 2.2, 4.4), 1091 (7.4%) patients died and 1744 (11.8%) experienced a MACE. Independent predictors of MACEs and all‐cause mortality included age, sex, comorbidities (eg, previous cardiovascular event), body mass index, blood pressure, hemoglobin A1c, and estimated glomerular filtration rate. The all‐cause mortality and MACE risk models had modest discrimination with optimism‐corrected c‐indices of 0.73 and 0.71, respectively. No interaction was observed between treatment effect and risk profile for either end point (both interactions, P>0.1). Conclusions Baseline characteristics (eg, age, previous cardiovascular events) and routine laboratory values (eg, hemoglobin A1c, estimated glomerular filtration rate) provided modest prognostic value for mortality and MACEs in a broad population of patients with type 2 diabetes mellitus. Exenatide's effects on mortality and MACEs were consistent across the spectrum of baseline risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01144338.

Background: EXSCEL was a multinational, randomized, blinded, placebo-controlled, pragmatic CV outcome trial of once-weekly exenatide on the background of usual care. We report exenatide’s impact on estimated glomerular filtration rate (eGFR), new macroalbuminuria and 2 renal composites from a prespecified analysis plan. Methods: Opportunistic local laboratory data were collected. Overall least squares mean difference (LSMD) eGFR (95% confidence interval [95% CI]) was calculated for 13844 patients with baseline and ≥1 follow-up value. Effect on new macroalbuminuria was estimated with a Cox regression model. Effects on renal composites were estimated with interval censored time to event models, with and without covariate adjustment (demographics and disease characteristics). Results: Intention-to-treat analyses showed no significant difference in eGFR levels with exenatide (LSMD +0.21 [-0.27, 0.70] mL/min.1.73m2, p=0.39). New macroalbuminuria occurred in 2.2% and 2.5% of the exenatide and placebo groups (p=0.19). There was a 15% lower renal composite 2 adjusted risk with exenatide (p=0.027) (Table). Conclusions: A composite of 40% eGFR decline, renal replacement, renal death or new macroalbuminuria was significantly reduced in an adjusted analysis by the addition of exenatide in a broad range of people with type 2 diabetes. Other renal outcomes were numerically but not statistically improved with exenatide. Disclosure M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. R.J. Mentz: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. P. Merrill: None. J.B. Buse: Other Relationship; Self; ADOCIA, AstraZeneca, Dexcom, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Fractyl Laboratories, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Metavention, NovaTarg, Novo Nordisk A/S, Sanofi, VTV Therapeutics. Research Support; Self; Boehringer Ingelheim GmbH, Johnson & Johnson Services, Inc., Theracos, Inc.. Other Relationship; Self; Shenzhen Hightide Biopharmaceutical, Ltd.. Research Support; Self; National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences. Other Relationship; Self; National Institute of Diabetes and Digestive and Kidney Diseases, American Diabetes Association. Research Support; Self; Patient-Centered Outcomes Research Institute. Other Relationship; Self; National Institute of Environmental Health Sciences. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck & Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company. S.G. Goodman: Research Support; Self; Amgen Inc.. Consultant; Self; Amgen Inc.. Research Support; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; Bayer AG. Consultant; Self; Bayer AG. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Bristol-Myers Squibb Company. Consultant; Self; Bristol-Myers Squibb Company. Research Support; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation. Research Support; Self; Pfizer Inc.. Consultant; Self; Pfizer Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Consultant; Self; Regeneron Pharmaceuticals, Inc.. Research Support; Self; CSL Behring. N. Iqbal: Employee; Self; AstraZeneca. N. Jakuboniene: None. B.G. Katona: Employee; Self; AstraZeneca. Y. Lokhnygina: None. R.D. Lopes: Consultant; Self; Bayer AG, Boehringer Ingelheim GmbH. Other Relationship; Self; Bristol-Myers Squibb Company. Consultant; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; GlaxoSmithKline plc., Medtronic. Consultant; Self; Merck & Co., Inc.. Other Relationship; Self; Pfizer Inc.. A.P. Maggioni: None. P.K. Ohman: Employee; Self; AstraZeneca. N.R. Poulter: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc.. Research Support; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc., Servier. Other Relationship; Self; International Society of Hypertension. A. Ramachandran: None. T. Tankova: None. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott. A.F. Hernandez: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. Consultant; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. R.R. Holman: Research Support; Self; AstraZeneca, Merck & Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck & Co., Inc.. Other Relationship; Self; AstraZeneca.

Aims To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready‐to‐use autoinjector with a M iglyol diluent (exenatide QWS‐AI ). This study compared the efficacy and safety of exenatide QWS‐AI with the first‐in‐class glucagon‐like peptide‐1 receptor agonist exenatide twice daily ( BID ). Materials and M ethods This randomized, open‐label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose‐lowering medication randomized patients 3:2 to either exenatide QWS‐AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28‐week change in glycated haemoglobin ( HbA1c ). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. Results A total of 375 patients (mean HbA1c , 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m 2 ; diabetes duration, 8.5 years) received either exenatide QWS‐AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by −1.4% and −1.0%, respectively (least‐squares mean difference, −0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS‐AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups ( P = .37 for difference). Gastrointestinal adverse events ( AE s) were reported in 22.7% (exenatide QWS‐AI ) and 35.6% (exenatide BID ) of patients; fewer patients in the exenatide QWS‐AI group withdrew because of AE s than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. Conclusions Exenatide QWS‐AI was associated with a greater reduction in HbA1c , similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID .

The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) was an international trial in a broad population of patients with type 2 diabetes (T2DM) including by design those with (~70%) and without (~30%) known cardiovascular (CV) disease.1-3 Once-weekly exenatide (EQW) resulted in a nominal 9% relative reduction in major adverse CV events (MACE; P-value for superiority = .061) and a 14% relative reduction in all-cause mortality (nominal P-value for superiority = .016) compared with placebo. These effects on MACE were consistent in those with and without known CV disease at baseline (interaction P-value = .50). We performed a prespecified subgroup analysis of EQW on outcomes in EXSCEL in patients with known CV disease at baseline. EXSCEL enrolled 14,752 patients between June 2010 and September 2015. The design, baseline characteristics, and primary results have been published.1-3 In brief, EXSCEL investigated the effects of the once-weekly GLP-1 receptor agonist (GLP-1 RA) exenatide (2-mg injection) on...

Aim To evaluate the effectiveness and tolerability of exenatide once weekly (EQW) compared with basal insulin (BI) among injectable‐drug‐naïve patients with type 2 diabetes mellitus (T2DM) who are elderly or have renal impairment (RI). Materials and methods Initiators of EQW and BI with T2DM were identified for the period 2012 to 2015 within a US electronic health record database and matched by propensity score. Matched EQW and BI initiators aged ≥65 years or who had RI were compared. Data on weight, glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), blood pressure and lipids were obtained at baseline and quarterly (Q1–Q4) or semi‐annually for 1 year after drug initiation. Hypoglycaemia and gastrointestinal symptoms were identified using diagnosis codes and data abstracted from clinical notes. Results Among patients aged ≥65 years, HbA1c changed by −0.50 and −0.31 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by −1.6 kg among EQW initiators compared with 0.2 kg among BI initiators. Compared with BI initiators, EQW initiators had a 1.45‐fold increased risk of nausea and vomiting. Among patients with RI, HbA1c changed by −0.58 and −0.33 percentage points from baseline to Q4 for EQW and BI initiators, respectively. Weight changed by −1.9 kg for EQW initiators while BI initiators had no change in weight. EQW initiators had a 1.28‐fold increased risk of constipation and diarrhoea compared with BI initiators. Conclusion Regardless of age or renal function, the benefits of EQW relative to BI treatment are improved glycaemic control and increased weight loss, which should be weighed against the increased risk of gastrointestinal symptoms.

Robert J Mentz , M. Angelyn Bethel , Vivian P Thompson , Yuliya Lokhnygina , John B Buse , Julian C Chan , Jasmine Choi , Stephanie M Gustavson , Nayyar Iqbal , Aldo P Maggioni , Steven P Marso , Peter Öhman , Neha J Pagidipati , Neil Poulter , Ambady Ramachandran , Bernard Zinman , Rury R Holman , Adrian F Hernandez , on behalf of the EXSCEL Study Group; Duke Clinical Rsch Institute, Duke Univ Sch of Medicine, Durham, NC, Diabetes Trials Unit, Univ of Oxford, Oxford, United Kingdom, Div of Endocrinology, Univ of North Carolina Sch of Medicine, Chapel Hill, NC, Dept of Medicine & Therapeutics, The Chinese Univ of Hong Kong, Hong Kong, China, AstraZeneca Rsch and Development, AstraZeneca Rsch and Development, Gaithersburg, MD, ANMCO Rsch Cntr, ANMCO Rsch Cntr, Florence, Italy, Dept of Cardiology, UT Southwestern Med Cntr, Dallas, TX, International Cntr for Circulatory Health, Imperial College London, London, United Kingdom, India Diabetes Rsch Foundation, Dr. A. Ramachandran’s Diabetes Hosps, Chennai, India, Lunenfeld Tanenbaum Rsch Institute, Mount Sinai Hosp and Univ of Toronto, Toronto, Canada.

BACKGROUNDThe cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.METHODSWe randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.RESULTSIn all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P < 0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P = 0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.CONCLUSIONSAmong patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo.