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Exe6.0
Exenatide Research
Mostly mechanism / observationalLimited safety
12 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Exenatide studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from high-quality meta-analyses and randomised trials published 2004–2017 with a typical study size of 377 participants.
Based on 12 studies · 3 meta-analyses · 9 RCTs · 18,216 total participants
Confidence
High
By outcome
Blood sugar & glycemic control
Mostly mechanism / observational12 studies
Safety & adverse effects
Mostly mechanism / observational10 studies
Weight management
Mostly mechanism / observational8 studies
Cardiovascular outcomes
Too few graded studies2 studies
Older research base
Newest study from 2017 · Latest meta-analysis: 2017
200420102017
1RCTn=14,752 · very large study2017
A primary composite outcome event occurred in 839 of 7356 patients (11.4%) in the exenatide group and in 905 of 7396 patients (12.2%) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00)... 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).
Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, Chan JC, Choi J, Gustavson SM, Iqbal N, Maggioni AP, Marso SP, Öhman P, Pagidipati NJ, Poulter N, Ramachandran A, Zinman B, Hernandez AF; EXSCEL Study Group. · N Engl J Med (2017)
Large cardiovascular-outcomes RCT: 14,752 patients with type 2 diabetes (73.1% with prior cardiovascular disease), once-weekly exenatide 2 mg vs placebo added to usual care, median 3.2 years
Primary MACE composite NEUTRAL: HR 0.91 (95% CI 0.83-1.00); non-inferior for safety but NOT superior for efficacy (P=0.06 for superiority)
No significant difference in CV death, MI, stroke, heart-failure hospitalization, pancreatitis, pancreatic cancer, or medullary thyroid carcinoma
the patients given exenatide once a week had significantly greater changes in HbA(1c) than those given exenatide twice a day (-1.9 [SE 0.1%] vs -1.5 [0.1%], 95% CI -0.54% to -0.12%; p=0.0023).
Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L; DURATION-1 Study Group. · Lancet (2008)
30-week open-label RCT in 295 patients with type 2 diabetes comparing once-weekly extended-release exenatide 2 mg with 10 µg twice daily
Once-weekly produced greater HbA1c reduction (-1.9% vs -1.5%; P=0.0023) and more patients reaching HbA1c ≤7% (77% vs 61%)
Similar bodyweight reductions and no increased hypoglycemia risk between formulations
The least-squares mean change in HbA(1c) was greater in patients in the liraglutide group (-1.48%, SE 0.05; n=386) than in those in the exenatide group (-1.28%, 0.05; 390) with the treatment difference (0.21%, 95% CI 0.08-0.33) not meeting predefined non-inferiority criteria.
Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, Hoogwerf BJ, Gao A, Boardman MK, Fineman M, Porter L, Schernthaner G. · Lancet (2013)
26-week head-to-head open-label RCT in 911 patients: once-weekly exenatide 2 mg vs once-daily liraglutide 1.8 mg added to oral therapy
Exenatide once-weekly did NOT meet non-inferiority vs liraglutide on HbA1c (-1.28% vs -1.48%; difference 0.21%)
Liraglutide produced more nausea/vomiting/diarrhea early on; exenatide was better tolerated for GI effects
At 3 years, least-squares mean HbA1c change was -1.01% in the exenatide group versus -0.81% in the glargine group (difference -0.20%, 95% CI -0.39 to -0.02; p=0.03).
Diamant M, Van Gaal L, Guerci B, Stranks S, Han J, Malloy J, Boardman MK, Trautmann ME. · Lancet Diabetes Endocrinol (2014)
3-year open-label RCT in 456 patients comparing once-weekly exenatide 2 mg with titrated once-daily insulin glargine as first injectable therapy
Exenatide maintained a small HbA1c advantage at 3 years (-1.01% vs -0.81%; P=0.03)
Exenatide led to weight loss whereas glargine led to weight gain; transient GI adverse events were more frequent with exenatide
At week 30, HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg), -0.40 +/- 0.11% (5 microg), and +0.08 +/- 0.10% (placebo... Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg], -1.6 +/- 0.4 kg [5 microg]).
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. · Diabetes Care (2005)
30-week triple-blind placebo-controlled RCT in 336 metformin-treated patients with type 2 diabetes — a pivotal twice-daily AMIGO trial
Dose-dependent HbA1c reduction (-0.78% at 10 µg vs +0.08% placebo); 46% reached HbA1c ≤7% at the 10 µg dose vs 13% on placebo
Dose-dependent weight loss (-2.8 kg at 10 µg) with no weight gain and no severe hypoglycemia
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).
Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. · Diabetes Care (2004)
30-week triple-blind placebo-controlled RCT in 377 sulfonylurea-treated patients — the second pivotal twice-daily AMIGO trial
Dose-dependent HbA1c reduction (-0.86% at 10 µg vs +0.12% placebo); 41% reached HbA1c ≤7% at 10 µg vs 9% on placebo
Dose-dependent weight loss (-1.6 kg at 10 µg); no severe hypoglycemia
The HbA1c level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, -0.93% to -0.46%]; P<0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo.
Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, Hoogwerf BJ, Rosenstock J. · Ann Intern Med (2011)
30-week placebo-controlled RCT in 261 patients on insulin glargine: add-on twice-daily exenatide 10 µg vs placebo
Exenatide added to basal insulin reduced HbA1c by an extra 0.69% (P<0.001) without increasing insulin dose
Weight fell 1.8 kg with exenatide vs +1.0 kg with placebo; minor hypoglycemia rates were similar
Liraglutide reduced mean HbA1c significantly more than did exenatide (-1.12% vs -0.79%; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001).
Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L; LEAD-6 Study Group. · Lancet (2009)
26-week head-to-head open-label RCT in 464 patients: liraglutide 1.8 mg once daily vs exenatide 10 µg twice daily added to oral therapy
Liraglutide lowered HbA1c more than twice-daily exenatide (-1.12% vs -0.79%; P<0.0001) and fasting glucose more
Similar weight loss (~3 kg both); exenatide gave better post-meal glucose control but more persistent nausea and more minor hypoglycemia
Patients who received only exenatide once-weekly demonstrated significant 52-week improvements in HbA1c (-1.6%), fasting plasma glucose (-1.8 mmol/l) and weight (-1.8 kg).
Wysham C, Bergenstal R, Malloy J, Yan P, Walsh B, Malone J, Taylor K. · Diabet Med (2011)
52-week RCT/open-label extension in 364 patients on metformin: once-weekly exenatide vs maximum-dose sitagliptin or pioglitazone, then switching to exenatide
Exenatide once-weekly gave greater HbA1c improvement and weight reduction than sitagliptin or pioglitazone in the controlled phase
Switching to exenatide produced incremental HbA1c and weight improvements; nausea was the most frequent adverse event
GLP-1 treatment achieved a greater SBP reduction than comparator therapy (WMD = 2.22mm Hg; 95% confidence interval (CI) = -2.97 to -1.47)... GLP-1 had beneficial effects on weight loss (WMD = -2.56kg... HbA1c reduction (WMD = -0.41%... but was associated with a heart rate increase (WMD = 1.30 bpm; 95% CI = 0.26-2.33).
Katout M, Zhu H, Rutsky J, Shah P, Brook RD, Zhong J, Rajagopalan S. · Am J Hypertens (2014)
Meta-analysis/meta-regression of 33 trials (12,469 patients) of GLP-1 agonists, of which 59% were treated with exenatide (5-10 µg twice daily or 2 mg weekly)
GLP-1 agonists reduced systolic blood pressure (~2.2 mm Hg), body weight (~2.6 kg) and HbA1c (~0.41%) vs comparators
Associated with a small increase in heart rate (~1.3 bpm) — a recognized class effect
The incidence of pancreatitis and pancreatic cancer with GLP1-RA was not significantly different from that observed in comparator arms... whereas, a significantly increased risk of cholelithiasis (MH-OR [95% CI] 1.30 [1.01-1.68], P = .041) was detected.
Monami M, Nreu B, Scatena A, Cresci B, Andreozzi F, Sesti G, Mannucci E. · Diabetes Obes Metab (2017)
Meta-analysis of 113 RCTs of GLP-1 receptor agonists (including exenatide) >11 weeks in type 2 diabetes, incorporating the major CVOTs
No significant increase in pancreatitis (OR 0.93) or pancreatic cancer (OR 0.94) — reassuring on the long-standing pancreatitis concern
Significantly increased risk of cholelithiasis/gallstones (OR 1.30; 95% CI 1.01-1.68; P=0.041)
Weight loss was associated with the use of metformin (1.1 kg)... liraglutide (1.7 kg), exenatide (1.2 kg), zonisamide (7.7 kg), topiramate (3.8 kg)...
Domecq JP, Prutsky G, Leppin A, Sonbol MB, Altayar O, Undavalli C, Wang Z, Elraiyah T, Brito JP, Mauck KF, Lababidi MH, Prokop LJ, Asi N, Wei J, Fidahussein S, Montori VM, Murad MH. · J Clin Endocrinol Metab (2015)
Systematic review and meta-analysis of 257 randomized trials (54 drugs, 84,696 patients) quantifying drug-associated weight change
Exenatide was associated with a mean ~1.2 kg weight loss vs placebo — modest, and smaller than the double-digit reductions seen with newer GLP-1 agents
Confirms exenatide causes weight loss rather than weight gain, but contextualizes the modest magnitude