Research library
The research library
Every primary source behind a claim on this site, tier-graded for provenance and tagged for the strength of the evidence it carries.
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Reset allT1·Peer-primary literature
Randomized trials, peer-reviewed primary studies, and meta-analyses — the load-bearing layer of the corpus.
88 sources
- 2026RCTmoderaten=108
Once-weekly semaglutide versus placebo in patients with alcohol use disorder and comorbid obesity: a randomised, double-blind, placebo-controlled trial
Klausen MK, Justesen SK, Pedersen JN, +3 · The Lancet
Across 108 treatment-seeking adults with alcohol use disorder and comorbid obesity, 26 weeks of once-weekly semaglutide reduced heavy drinking days by −41.1 percentage points from baseline versus −26.4 in placebo — a 13.7-point between-group difference (p=0.0015), the first Lancet-tier RCT confirming a GLP-1RA effect on alcohol consumption.
- 2026RCTmoderaten=72
Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder: A Randomized Clinical Trial
Gill H, Badulescu S, Shah H, +3 · JAMA Psychiatry
Across 72 adults with major depressive disorder and BMI ≥25, 16 weeks of adjunctive oral semaglutide (14 mg) significantly reduced the perceived cost of effort relative to monetary reward on the Effort-Expenditure for Rewards Task — the first RCT to show GLP-1RA modulation of reward-related motivation in clinical depression.
- 2026RCTmoderaten=204
Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial
Edison P, Hooper N, Femminella GD, +7 · Nature Medicine
The ELAD Phase 2b in 204 non-diabetic adults with mild-to-moderate Alzheimer's disease missed its primary endpoint of cerebral glucose metabolic rate (p=0.14) — but secondary endpoints reported nearly 50% reduction in brain atrophy and 18% slower ADAS-Exec decline, the secondary-positive signal that handed the question to the larger semaglutide EVOKE Phase 3.
- 2026RCTstrongn=2,538
Shifts in waist-to-height ratio categories within tirzepatide groups: a post-hoc analysis of SURMOUNT-1
Sattar N, Tchang BG, Vincent RP, +3 · Journal of Endocrinological Investigation
Across 2,538 SURMOUNT-1 participants, 72 weeks of tirzepatide 10/15 mg moved 54.7% into a better waist-to-height-ratio category versus 9.6% with placebo, and 16.7% reached WHtR ≤0.49 — a non-obese-by-NICE-definition threshold — sustained to 176 weeks in the prediabetes subset.
- 2025RCTstrongn=610
Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight
Ji L, Jiang H, Bi Y, +7 · New England Journal of Medicine
GLORY-1 reported mean body-weight reductions of -12.55% on mazdutide 6 mg versus +0.45% on placebo at 32 weeks in Chinese adults with obesity — the first Phase 3 readout for a Chinese-developed incretin in a population the global obesity trials have under-recruited.
- 2025RCTstrongn=13,165
Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes
Nicholls SJ, Bhatt DL, Buse JB, +9 · New England Journal of Medicine
SURPASS-CVOT randomized 13,299 T2D patients with established atherosclerotic cardiovascular disease to tirzepatide versus dulaglutide; the MACE composite occurred in 12.2% on tirzepatide versus 13.1% on dulaglutide (HR 0.92, 95.3% CI 0.83–1.01), meeting non-inferiority but not demonstrating superiority.
- 2025RCTstrongn=95
Kisspeptin Administration Stimulates Reproductive Hormones but Does Not Affect Anxiety in Humans
Mills EG, Comninos AN, Dhillo WS · Journal of Clinical Endocrinology & Metabolism
A biologically active dose of kisspeptin-54 to 95 men and women produced no measurable effect on behavioral, biochemical, or physiological anxiety measures — a primary-negative result that disambiguates the limbic-circuit mood findings from a generalized anxiolytic claim.
- 2025RCTstrongn=1,206
Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes
Davies MJ, Bajaj HS, Broholm C, +8 · New England Journal of Medicine
The Phase 3 type 2 diabetes pivotal trial for CagriSema — 13.7% mean weight loss and 73.5% reaching HbA1c ≤6.5% on CagriSema at 68 weeks, versus 3.4% / 15.9% on placebo — the diabetic-cohort counterpart to REDEFINE-1, with the same magnitude-blunting pattern across the incretin class repeated here.
- 2025RCTstrongn=3,417
Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity
Garvey WT, Blüher M, Osorto Contreras CK, +9 · New England Journal of Medicine
In the pivotal Phase 3 obesity trial (n=3,417, 68 weeks), CagriSema produced 20.4% mean weight loss under the treatment-policy estimand versus 3.0% on placebo — a strong absolute result that nevertheless landed below Novo Nordisk's publicly stated 25% target and triggered a roughly 20–26% stock decline when the topline read out in December 2024.
- 2024RCTstrongn=386
Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial
Le Roux CW, Steen O, Lucas KJ, +3 · Lancet Diabetes Endocrinol
Survodutide 4.8 mg produced 14.9% mean body-weight reduction at 46 weeks versus 2.8% on placebo — the first Phase 2 obesity readout for a glucagon / GLP-1 dual agonist competitive with tirzepatide-class magnitudes.
- 2024RCTmoderaten=413
Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial
Blüher M, Rosenstock J, Hoefler J, +2 · Diabetologia
Survodutide doses ≥1.8 mg achieved greater body-weight reduction than open-label semaglutide 1.0 mg (-5.3% to -8.7% vs -5.3%) at 16 weeks while matching HbA1c reductions — a short-window signal that motivated the Phase 3 program in obesity and T2D.
- 2024RCTmoderaten=176
ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation
Ehlers JP, Hu A, Boyer D, +4 · Ophthalmology Science
Across 176 patients with dry age-related macular degeneration and geographic atrophy, ReCLAIM-2 missed both prespecified primary endpoints — low-luminance visual acuity and GA area progression — but produced statistically significant secondary signals on ellipsoid zone preservation (43% reduction in total EZ attenuation, p = 0.0034) that Stealth has cited as proof-of-mechanism for future development.
- 2024RCTmoderaten=105
Cagrilintide is not associated with clinically relevant QTc prolongation: A thorough QT study in healthy participants
Gabe MBN, Fuhr R, Sinn A, +5 · Diabetes, Obesity and Metabolism
The thorough-QT study that cleared cagrilintide at the 4.5 mg dose for cardiac repolarisation safety — the regulatory-grade ECG study that closes the QT-prolongation question Phase 3 trials cannot answer at their resolution.
- 2024RCTmoderaten=3,533
Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial
Mann JFE, Rossing P, Bakris G, +9 · Nature Medicine
Among the 550 FLOW participants on baseline SGLT2 inhibitors, the primary outcome HR was 1.07 (P=0.755); among the 2,983 not on SGLT2 inhibitors it was 0.73 (P<0.001) — a P for interaction of 0.109 that is consistent with underpowered subgroup analysis rather than negative interaction, but leaves the formal stacking question incomplete.
- 2024RCTstrongn=293
A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis
Sanyal AJ, Bedossa P, Fraessdorf M, +7 · New England Journal of Medicine
MASH resolution without worsening of fibrosis was achieved by 47–62% of survodutide-treated patients versus 14% on placebo at 48 weeks — among the strongest histologic readouts in a non-cirrhotic MASH Phase 2 to date.
- 2024RCTstrongn=255
Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial
McGarry A, Rosanbalm S, Leinonen M, +7 · Lancet Neurology
A 36-week Phase 2 trial of NLY01 — a pegylated exenatide variant engineered for CNS exposure — found no difference from placebo on MDS-UPDRS-II+III in 255 early untreated Parkinson's patients, the largest negative GLP-1 readout in the disease to date.
- 2024RCTmoderaten=156
Trial of Lixisenatide in Early Parkinson's Disease
Meissner WG, Remy P, Giordana C, +7 · New England Journal of Medicine
Lixisenatide-treated patients showed no motor decline at 12 months while placebo-treated patients worsened by 3.04 MDS-UPDRS-III points — a 3.08-point between-group separation (p=0.0068) that is the first positive primary endpoint for a GLP-1 agonist in early Parkinson's disease.
- 2024RCTstrongn=98
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
Sanyal AJ, Kaplan LM, Frias JP, +9 · Nature Medicine
At 24 weeks, retatrutide reduced liver fat by 82.4% at the 12-mg dose versus +0.3% on placebo, with 86% of high-dose recipients reaching normal liver fat (<5%) — the largest liver-fat reduction of any pharmacotherapy ever published in MASLD.
- 2024RCTstrongn=3,533
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
Perkovic V, Tuttle KR, Rossing P, +8 · New England Journal of Medicine
Once-weekly semaglutide 1 mg reduced major kidney disease events by 24% and all-cause mortality by 20% across 3,533 patients with T2D and CKD on contemporary background therapy — the most clinically rigorous positive peptide-class kidney trial ever conducted.
- 2024RCTstrongn=469
Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity
Malhotra A, Grunstein RR, Fietze I, +10 · New England Journal of Medicine
AHI fell by roughly 20 events per hour more on tirzepatide than placebo across both arms — the data that turned Zepbound into the first pharmacologic approval for moderate-to-severe obstructive sleep apnea in adults with obesity.
- 2024RCTstrongn=670
Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial
Aronne LJ, Sattar N, Horn DB, +3 · JAMA
Stopping tirzepatide after 36 weeks of successful weight loss produced 14.0% weight regain over the next year versus continued loss of 5.5% on the active drug — the discontinuation curve that frames every clinical conversation about GLP-1 cessation.
- 2023RCTstrongn=5,246
Cardiovascular Safety of Testosterone-Replacement Therapy
Lincoff AM, Bhasin S, Flevaris P, +8 · New England Journal of Medicine
Testosterone replacement was non-inferior to placebo on the primary composite cardiovascular endpoint (7.0% vs 7.3%, hazard ratio 0.96) in 5,246 hypogonadal men with prevalent or high cardiovascular risk over a mean 33-month follow-up — alongside elevated rates of atrial fibrillation, acute kidney injury, and pulmonary embolism that the primary endpoint did not capture.
- 2023RCTstrongn=579
Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial
Wadden TA, Chao AM, Machineni S, +3 · Nature Medicine
After a 12-week intensive lifestyle lead-in produced ≥5% weight loss, tirzepatide produced an additional 18.4% weight reduction over 72 weeks versus 2.5% on placebo — a total program effect of 24.3% from study start, the largest published response to a lifestyle-plus-pharmacotherapy obesity protocol.
- 2023RCTstrongn=17,604
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
Lincoff AM, Brown-Frandsen K, Colhoun HM, +6 · New England Journal of Medicine
In 17,604 patients with established cardiovascular disease and overweight/obesity but no diabetes, weekly semaglutide 2.4 mg reduced the composite primary cardiovascular endpoint by 20% over a mean 40-month follow-up — the trial that took semaglutide from a metabolic drug to a cardiovascular intervention.
- 2023RCTstrongn=338
Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
Jastreboff AM, Kaplan LM, Frías JP, +8 · New England Journal of Medicine
At the 12-mg dose, mean body-weight reduction reached 24.2% at 48 weeks, with every treated participant achieving at least 5% weight loss and 83% reaching at least 15% — the largest published pharmacotherapy result to date.
- 2023RCTmoderaten=92
Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial
Frias JP, Deenadayalan S, Erichsen L, +6 · Lancet
The Phase 2 type 2 diabetes trial that established CagriSema's combination signal in a diabetic cohort — 15.6% weight loss and 2.2-percentage-point HbA1c reduction at 32 weeks on CagriSema versus 5.1% / 1.8% on semaglutide alone, in 92 adults on metformin background. The cohort was small but it set the framing under which REDEFINE-2 was designed.
- 2023RCTstrongn=281
Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA
Rosenstock J, Frias J, Jastreboff AM, +8 · Lancet
In type 2 diabetes, retatrutide 12 mg drove a 2.02% absolute HbA1c reduction at 24 weeks and 16.94% body-weight reduction at 36 weeks — both the largest published Phase 2 effects of any incretin-class molecule in the diabetic cohort, and meaningfully above the dulaglutide active comparator on both endpoints.
- 2023RCTstrongn=938
Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial
Garvey WT, Frias JP, Jastreboff AM, +3 · Lancet
Tirzepatide produced 12.8% and 14.7% mean weight loss at 10 mg and 15 mg over 72 weeks in adults with both obesity and type 2 diabetes — roughly two-thirds the magnitude of SURMOUNT-1's non-diabetic cohort, but with HbA1c reduction from 8.0% to 5.9% at the higher dose.
- 2023RCTstrong
Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial
Karaa A, Bertini E, Carelli V, +3 · Neurology
MMPOWER-3 provides Class I evidence that elamipretide does not improve the six-minute walk test or fatigue at 24 weeks compared with placebo in primary mitochondrial myopathy — the failed pivotal trial that ended SS-31's lead indication and reframed the molecule's clinical story.
- 2023RCTstrongn=529
Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity
Kosiborod MN, Abildstrøm SZ, Borlaug BA, +12 · New England Journal of Medicine
KCCQ-CSS improved 16.6 points on semaglutide versus 8.7 on placebo — among the largest patient-reported-outcome gains ever recorded in an HFpEF trial, in a phenotype long resistant to pharmacological intervention.
- 2022RCTstrongn=2,539
Tirzepatide Once Weekly for the Treatment of Obesity
Jastreboff AM, Aronne LJ, Ahmad NN, +9 · New England Journal of Medicine
Mean weight loss at 72 weeks was 16.0%, 21.4%, and 22.5% on tirzepatide 5/10/15 mg versus 3.1% on placebo — the first non-surgical intervention to put more than half of treated patients past 20% weight loss in a Phase III trial.
- 2022RCTstrongn=327
Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension
Wilding JPH, Batterham RL, Davies M, +11 · Diabetes, Obesity and Metabolism
One year after stopping semaglutide, participants regained two-thirds of their lost weight (11.6 percentage points) — and cardiometabolic improvements reverted in parallel. The single most important paper for the discontinuation-rebound conversation.
- 2021RCTmoderaten=96
Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial
Enebo LB, Berthelsen KK, Kankam M, +4 · Lancet
The Phase 1b dose-escalation study that established cagrilintide's once-weekly pharmacokinetic profile (half-life 159–195 hours) and produced the first human signal that combination amylin + GLP-1 agonism could exceed semaglutide monotherapy — 17.1% weight loss at week 20 on cagrilintide 2.4 mg plus semaglutide 2.4 mg, all in 96 healthy-overweight adults at a single US site.
- 2021RCTmoderaten=12
A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism
Thompson WR, Hornby B, Manuel R, +4 · Genetics in Medicine
Across 12 subjects with genetically confirmed Barth syndrome, the randomized 12-week crossover period missed both primary endpoints, but the 36-week open-label extension produced a 95.9-metre improvement in six-minute walk distance and meaningful gains in patient-reported and strength endpoints — the foundational efficacy dataset behind the September 2025 FDA approval of Forzinity for Barth syndrome.
- 2021RCTstrongn=1,879
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes
Frías JP, Davies MJ, Rosenstock J, +7 · New England Journal of Medicine
In the only major head-to-head trial of the modern GLP-1 class, tirzepatide at all three doses produced superior glycemic control to semaglutide 1 mg, with the 15-mg dose producing nearly twice the weight loss — the trial that established the dual-incretin advantage as more than a marginal difference.
- 2021RCTstrongn=831
Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer
Sartor O, de Bono J, Chi KN, +18 · New England Journal of Medicine
Median overall survival of 15.3 versus 11.3 months on 177Lu-PSMA-617 plus protocol-permitted standard of care versus standard of care alone (HR 0.62) — the registration result that extended the somatostatin-receptor theranostic framework of NETTER-1 onto a second receptor target and licensed peptide-radionuclide therapy in PSMA-positive metastatic castration-resistant prostate cancer.
- 2021RCTstrongn=1,961
Once-Weekly Semaglutide in Adults with Overweight or Obesity
Wilding JPH, Batterham RL, Calanna S, +11 · New England Journal of Medicine
Mean body-weight change at week 68 was -14.9% on semaglutide versus -2.4% on placebo, with 86.4% of treated participants achieving at least 5% weight loss — the trial that anchored the cultural moment around GLP-1 agonists for obesity.
- 2021RCTstrongn=803
Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial
Rubino D, Abrahamsson N, Davies M, +12 · JAMA
After a 20-week run-in producing 10.6% weight loss, participants who continued semaglutide lost an additional 7.9% over 48 weeks while those switched to placebo regained 6.9% — a 14.8-percentage-point divergence that defines the maintenance question for the entire GLP-1 class.
- 2021RCTstrongn=706
Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial
Lau DCW, Erichsen L, Francisco AM, +7 · Lancet
The Phase 2 dose-finding monotherapy trial that established cagrilintide-alone performance — 10.8% weight loss at 26 weeks on cagrilintide 4.5 mg versus 9.0% on liraglutide 3.0 mg and 3.0% on placebo, a result consistent with an amylin agonist that operates through partially overlapping but mechanistically distinct satiety pathways from the GLP-1 class.
- 2020RCTstrongn=934
Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer
Shore ND, Saad F, Cookson MS, +12 · New England Journal of Medicine
Sustained castration through 48 weeks reached 96.7% on oral relugolix versus 88.8% on injectable leuprolide — the first head-to-head Phase III to put an oral GnRH antagonist directly against the depot-agonist standard of care in advanced prostate cancer.
- 2020RCTstrongn=4,304
Dapagliflozin in Patients with Chronic Kidney Disease
Heerspink HJL, Stefánsson BV, Correa-Rotter R, +11 · New England Journal of Medicine
Dapagliflozin reduced the primary kidney composite by 39% across 4,304 CKD patients (with and without diabetes) — the landmark SGLT2-inhibitor trial that established the second pillar of contemporary CKD pharmacology onto which the GLP-1 class now stacks.
- 2019RCTstrongn=1,267
Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials
Kingsberg SA, Clayton AH, Portman D, +5 · Obstetrics and Gynecology
Both RECONNECT trials met their primary endpoints — bremelanotide produced statistically significant increases in sexual desire and reductions in associated distress in premenopausal women with HSDD — and form the basis for the FDA approval of Vyleesi in June 2019.
- 2019RCTstrongn=168
Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes
Brown SA, Kovatchev BP, Raghinaru D, +18 · New England Journal of Medicine
Hybrid closed-loop insulin delivery (Tandem Control-IQ) improved time-in-range from 61% to 71% at six months versus unchanged 59% on sensor-augmented pump therapy — the regulatory-grade evidence that anchored the modern hybrid closed-loop ecosystem.
- 2019RCTstrongn=61
Effects of tesamorelin on non-alcoholic fatty liver disease in HIV: a randomised, double-blind, multicentre trial
Stanley TL, Fourman LT, Feldpausch MN, +16 · Lancet HIV
12-month randomized trial in HIV-associated NAFLD — tesamorelin reduced liver fat 37% on average, drove a third of treated participants below the 5% steatosis threshold, and prevented fibrosis progression on biopsy.
- 2019RCTstrongn=737
Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma
Facon T, Kumar S, Plesner T, +27 · New England Journal of Medicine
MAIA established daratumumab-anchored D-Rd as the transplant-ineligible frontline standard, displacing bortezomib-VMP for the median-age-73 newly-diagnosed multiple myeloma population and shifting the practical baseline against which subsequent proteasome-inhibitor regimens are now measured.
- 2018RCTstrongn=282
Clomiphene citrate and human chorionic gonadotropin are both effective in restoring testosterone in hypogonadism: a short-course randomized study
Habous M, Giona S, Tealab A, +8 · BJU International
In 282 fertility-preserving hypogonadal men randomized to clomiphene 50 mg daily, hCG 5,000 IU twice weekly, or both, all three arms produced equivalent testosterone restoration — and single-agent clomiphene was the simplest and cheapest of the three.
- 2018RCTmoderaten=36
Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy
Karaa A, Haas R, Goldstein A, +3 · Neurology
Across 36 adults with genetically confirmed primary mitochondrial myopathy, the highest-dose elamipretide arm walked 64.5 metres farther on the six-minute walk test at day 5 versus 20.4 metres on placebo — the positive Phase 2 signal that motivated the larger MMPOWER-3 trial that ultimately failed.
- 2017RCTstrongn=62
A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial
Abbara A, Jayasena CN, Christopoulos G, +15 · Human Reproduction
A second dose of kisspeptin-54 ten hours after the first lifted the proportion of women achieving ≥60% mature-oocyte yield from 45% to 71% — without an increase in OHSS rates in a high-risk population.
- 2017RCTmoderaten=29
Kisspeptin modulates sexual and emotional brain processing in humans
Comninos AN, Wall MB, Demetriou L, +24 · Journal of Clinical Investigation
Kisspeptin-54 enhanced limbic-brain responses to sexual and couple-bonding stimuli and attenuated negative mood in a placebo-controlled crossover fMRI study — the first human evidence linking the hypothalamic reproductive switch to the brain's affective circuitry.
- 2017RCTmoderaten=44
Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide
Daubert MA, Yow E, Dunn G, +7 · Circulation Heart Failure
A single high-dose elamipretide infusion produced acute reductions in left ventricular end-diastolic (−18 mL) and end-systolic (−14 mL) volume versus placebo in 44 stable heart-failure patients — the early signal that motivated the PROGRESS-HF Phase 2 trial, which then failed to confirm chronic-dosing benefit at 4 weeks.
- 2017RCTstrongn=229
Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors
Strosberg J, El-Haddad G, Wolin E, +33 · New England Journal of Medicine
Progression-free survival at 20 months was 65.2% on 177Lu-DOTATATE versus 10.8% on high-dose octreotide LAR — the result that opened peptide-receptor radionuclide therapy as an approved modality and licensed the somatostatin-receptor theranostic framework that now extends through PSMA-617 and beyond.
- 2017RCTstrongn=1,689
Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist
Taylor HS, Giudice LC, Lessey BA, +19 · New England Journal of Medicine
Two replicate phase 3 trials established the first orally bioavailable GnRH antagonist for endometriosis pain — and the dose-proportional bone mineral density loss that the label-mandated duration ceilings have to manage.
- 2016RCTstrongn=979
Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials
Temel JS, Abernethy AP, Currow DC, +4 · Lancet Oncology
Lean body mass rose on anamorelin versus placebo in both trials (ROMANA 1: +0.99 vs −0.47 kg, p<0.0001; ROMANA 2: +0.65 vs −0.98 kg, p<0.0001) — but handgrip strength did not differentiate in either trial. The class-defining mass-without-strength result that shaped the regulatory split between Japan's approval and the EMA's rejection.
- 2016RCTmoderaten=208
Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial
Muresanu DF, Heiss WD, Hoemberg V, +8 · Stroke
CARS-1 is the Cerebrolysin trial in which the protocol was tightest, the rehabilitation co-intervention was standardized, and the primary endpoint — upper-extremity motor recovery on the Action Research Arm Test at day 90 — favored Cerebrolysin with a Mann-Whitney effect size of 0.71 (95% CI 0.63–0.79, P<0.0001).
- 2016RCTstrongn=3,297
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
Marso SP, Bain SC, Consoli A, +13 · New England Journal of Medicine
In 3,297 high-cardiovascular-risk type 2 diabetes patients, weekly semaglutide reduced the composite primary cardiovascular endpoint by 26% over a median 2.1 years — the trial that established cardiovascular benefit for the GLP-1 class and presaged the 2023 SELECT result in obesity.
- 2016RCTstrongn=9,340
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes
Marso SP, Daniels GH, Brown-Frandsen K, +14 · New England Journal of Medicine
Across 9,340 high-cardiovascular-risk type 2 diabetes patients followed a median of 3.8 years, daily liraglutide reduced the composite primary cardiovascular endpoint by 13% (HR 0.87, 95% CI 0.78–0.97; p=0.01 for superiority) and cardiovascular death by 22% — the first GLP-1 receptor agonist cardiovascular-outcomes trial to demonstrate superiority over placebo on the FDA's post-rosiglitazone safety pathway.
- 2015RCTstrongn=6,068
Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome
Pfeffer MA, Claggett B, Diaz R, +8 · New England Journal of Medicine
ELIXA established lixisenatide's cardiovascular safety in 6,068 post-ACS T2D patients with a primary MACE composite of 13.4% versus 13.2% on placebo (HR 1.02, 95% CI 0.89–1.17) — non-inferior but not superior.
- 2015RCTmoderaten=9
Thymosin β4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial
Sosne G, Dunn SP, Kim C · Cornea
In a 9-patient Phase 2 dry eye trial, 0.1% thymosin β4 ophthalmic solution reduced ocular discomfort by 35.1% and corneal fluorescein staining by 59.1% versus vehicle control — small but the cleanest published signal that the cardiac-mechanism literature on thymosin β4 might translate clinically.
- 2015RCTmoderaten=72
Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE) model
Sosne G, Ousler GW · Clinical Ophthalmology
A 72-subject Phase 2 dry-eye RCT of 0.1% thymosin β4 ophthalmic solution: the formal primary endpoints did not separate from placebo, but treated subjects showed a 27% reduction in discomfort during controlled adverse environment exposure and statistically significant improvements in corneal staining — the larger companion to the Sosne 2015 Cornea trial.
- 2015RCTmoderaten=342
Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial
Leffler DA, Kelly CP, Green PHR, +8 · Gastroenterology
Larazotide acetate at 0.5 mg three times daily improved celiac-disease symptom scores versus placebo (ANCOVA p=0.022) in adults with persistent symptoms despite a gluten-free diet — the Phase IIb signal that licensed an attempt at registration that the Phase 3 program failed to confirm in 2022.
- 2015RCTstrongn=3,731
A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management
Pi-Sunyer X, Astrup A, Fujioka K, +9 · New England Journal of Medicine
In 3,731 non-diabetic adults with overweight or obesity, 56 weeks of daily liraglutide 3.0 mg produced a mean weight loss of -8.0% versus -2.6% on placebo — the pivotal trial that established once-daily GLP-1 receptor agonism as a chronic-weight-management therapy and underwrote Saxenda's 2014 FDA approval.
- 2014RCTstrongn=204
Lanreotide in metastatic enteropancreatic neuroendocrine tumors
Caplin ME, Pavel M, Ćwikła JB, +13 · New England Journal of Medicine
Lanreotide Autogel 120 mg every 28 days cut the hazard of disease progression or death by 53% versus placebo in 204 patients with metastatic grade 1 or 2 enteropancreatic neuroendocrine tumors — the trial that extended the somatostatin-analog antiproliferative framework beyond the midgut sites covered by PROMID.
- 2014RCTmoderaten=114
Prospective, randomized, controlled, proof-of-concept study of the ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients
Beck DE, Sweeney WB, McCarter MD · International Journal of Colorectal Disease
Median time to first tolerated meal was 25.3 hours with ipamorelin versus 32.6 hours with placebo — a seven-hour edge in the expected direction, but p = 0.15, and the rigorous indication trial that should have made ipamorelin a prescription drug fell short of statistical significance.
- 2014RCTmoderaten=50
Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial
Stanley TL, Feldpausch MN, Oh J, +4 · JAMA
First randomized trial to demonstrate that tesamorelin reduces liver fat — not just visceral fat — in HIV-infected adults with abdominal fat accumulation, opening the door to the NAFLD line of investigation that the Grinspoon group has pursued since.
- 2013RCTmoderaten=48
ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density
Dahan A, Dunne A, Swartjes M, +9 · Molecular Medicine
Twenty-eight days of daily subcutaneous cibinetide in sarcoidosis patients with documented small-nerve-fiber loss produced a significant increase in corneal small-nerve-fiber density, improved thermal sensitivity, and increased exercise capacity — the trial that anchored the move from a pilot signal to a structurally defensible Phase II readout.
- 2012RCTstrongn=1,070
Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial
Heiss WD, Brainin M, Bornstein NM, +2 · Stroke
CASTA is the largest Cerebrolysin acute-stroke RCT ever conducted — 1,070 patients across Asia — and the primary endpoint was negative. The trial is the structural reason every honest reading of the Cerebrolysin literature has to address how to reconcile a large negative pivotal-scale trial with a positive manufacturer-aligned meta-analysis.
- 2012RCTstrongn=86
Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure
Jeppesen PB, Pertkiewicz M, Messing B, +6 · Gastroenterology
63% of teduglutide-treated short-bowel-syndrome patients achieved 20–100% reduction in weekly parenteral-support volume versus 30% on placebo at 24 weeks — the pivotal Phase 3 result behind FDA approval and the closest precedent the GI-peptide field has for a peptide carrying a registration-quality program to a marketed indication.
- 2012RCTmoderaten=60
Metabolic Effects of a Growth Hormone-Releasing Factor in Obese Subjects with Reduced Growth Hormone Secretion: A Randomized Controlled Trial
Makimura H, Feldpausch MN, Rope AM, +4 · Journal of Clinical Endocrinology and Metabolism
Twelve months of tesamorelin in non-HIV abdominally obese adults with reduced GH secretion selectively reduced visceral adipose tissue without affecting subcutaneous fat, improved triglycerides and carotid intima-media thickness, and preserved glucose tolerance — the cleanest non-HIV reading of tesamorelin's metabolic effect available.
- 2012RCTmoderaten=22
Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study
Heij L, Niesters M, Swartjes M, +8 · Molecular Medicine
Twelve patients on ARA-290 versus ten on placebo, intravenous 2 mg three times weekly for four weeks — and a statistically significant improvement in the Small Fiber Neuropathy Screening List score versus placebo at week 4. The first human trial of cibinetide in sarcoidosis-associated small-fiber neuropathy.
- 2011RCTmoderaten=123
MK-0677 (ibutamoren mesylate) for the treatment of patients recovering from hip fracture: A multicenter, randomized, placebo-controlled phase IIb study
Adunsky A, Chandler J, Heyden N, +5 · Archives of Gerontology and Geriatrics
IGF-1 rose, gait speed improved modestly (p=0.011), most functional measures did not differentiate — and the trial was terminated early on a congestive heart failure signal (4 of 62 active-arm versus 1 of 61 placebo-arm patients). The MK-677 sarcopenia-adjacent reading that reproduced the Nass mass-without-function pattern with a safety signal attached.
- 2010RCTmoderaten=40
A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin beta4 in healthy volunteers
Ruff D, Crockford D, Girardi G, +1 · Annals of the New York Academy of Sciences
The Phase 1 human-safety paper that gated everything downstream: 40 healthy volunteers received IV thymosin β4 at 42, 140, 420, or 1260 mg single doses then daily for 14 days, with no dose-limiting toxicities, no serious adverse events, and a dose-proportional PK profile.
- 2010RCTstrongn=130
Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema
Cicardi M, Banerji A, Bracho F, +57 · New England Journal of Medicine
FAST-1 missed its primary endpoint at P=0.14 because the placebo arm recovered faster than expected; FAST-2 separated icatibant from oral tranexamic acid at 2.0 versus 12.0 hours, P<0.001 — the split that put icatibant on the path to regulatory approval once FAST-3 closed the placebo gap a year later.
- 2009RCTstrongn=85
Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group
Rinke A, Müller H-H, Schade-Brittinger C, +11 · Journal of Clinical Oncology
Octreotide LAR 30 mg every 28 days extended median time to tumor progression from 6.0 to 14.3 months in patients with well-differentiated metastatic midgut neuroendocrine tumors — the first randomized controlled trial to establish a somatostatin analog as a tumor-control rather than purely symptom-control intervention.
- 2008RCTstrongn=682
Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma
San Miguel JF, Schlag R, Khuageva NK, +18 · New England Journal of Medicine
VISTA established bortezomib-melphalan-prednisone as the frontline standard for transplant-ineligible multiple myeloma — time to progression 24.0 versus 16.6 months and a 31 percent reduction in mortality that persisted on 5-year follow-up — the trial that converted the proteasome-inhibitor class from a relapsed-disease therapy into first-line oncology and held that position for a decade.
- 2008RCTmoderaten=62
Efficacy and possible mechanisms of action of a new peptide anxiolytic Selank in the therapy of generalized anxiety disorders and neurasthenia
Zozulia AA, Neznamov GG, Siuniakov TS, +11 · Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova
Across 62 patients with GAD or neurasthenia, Selank's anxiolytic effect was reported as comparable to medazepam — the only English-indexed clinical trial that puts Selank head-to-head against a benzodiazepine.
- 2008RCTstrongn=65
Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial
Nass R, Pezzoli SS, Oliveri MC, +7 · Annals of Internal Medicine
Daily oral MK-677 raised GH and IGF-1 to young-adult levels and added 1.1 kg of fat-free mass over a year — but the gain did not translate into measurable strength or functional improvement.
- 2007RCTstrongn=412
Metabolic effects of a growth hormone-releasing factor in patients with HIV
Falutz J, Allas S, Blot K, +9 · New England Journal of Medicine
Visceral adipose tissue decreased by 15.2% on tesamorelin and rose 5.0% on placebo over 26 weeks (p<0.001) — the trial that earned tesamorelin its FDA indication and its credibility-flagship status on this site.
- 2006RCTstrong
Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults
Teichman SL, Neale A, Lawrence B, +3 · Journal of Clinical Endocrinology & Metabolism
A single subcutaneous dose of CJC-1295 with DAC produced 2- to 10-fold GH elevations for six days and 1.5- to 3-fold IGF-1 elevations for nine to eleven days, with a plasma half-life of 5.8 to 8.1 days.
- 2005RCTstrongn=669
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma
Richardson PG, Sonneveld P, Schuster MW, +18 · New England Journal of Medicine
Bortezomib improved time to progression to 6.22 months versus 3.49 months with high-dose dexamethasone in relapsed multiple myeloma — the pivotal trial that established the proteasome-inhibitor peptide-pharmacophore class as standard-of-care therapy and licensed full FDA approval of the first-in-class drug.
- 2005RCTstrongn=29
Low-Dose Human Chorionic Gonadotropin Maintains Intratesticular Testosterone in Normal Men with Testosterone-Induced Gonadotropin Suppression
Coviello AD, Matsumoto AM, Bremner WJ, +9 · Journal of Clinical Endocrinology and Metabolism
At 500 IU every other day, hCG maintained intratesticular testosterone 26% above baseline despite full pituitary suppression by exogenous testosterone — the foundational dose-response that anchors all subsequent hCG-during-TRT fertility-preservation protocols.
- 1998RCTmoderaten=8
MK-677, an Orally Active Growth Hormone Secretagogue, Reverses Diet-Induced Catabolism
Murphy MG, Plunkett LM, Gertz BJ, +4 · Journal of Clinical Endocrinology & Metabolism
In an 8-volunteer crossover trial, oral MK-677 (25 mg daily) reversed nitrogen wasting induced by 14 days of caloric restriction — the first published human evidence that an orally bioavailable ghrelin-mimetic could produce a clinically meaningful anabolic signal.
- 1998RCTmoderaten=12
Growth hormone status during long-term hexarelin therapy
Rahim A, O'Neill PA, Shalet SM · Journal of Clinical Endocrinology & Metabolism
Sixteen weeks of twice-daily subcutaneous hexarelin in elderly subjects: mean GH AUC fell from 19.1 µg/L/h at baseline to 13.1 at week 1, 12.3 at week 4, and 10.5 at week 16 — a roughly 45% loss of the GH response, reversible after four weeks of washout. The receptor-desensitisation paper that grounds modern hexarelin cycling logic.
- 1998RCTstrongn=3,867
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
UK Prospective Diabetes Study (UKPDS) Group · Lancet
Across 3,867 newly-diagnosed type 2 diabetes patients followed a median 10 years, intensive sulphonylurea-or-insulin therapy reduced microvascular endpoints by 25% — the landmark T2D companion to DCCT and the foundation of the contemporary HbA1c-target framework.
- 1997RCTmoderaten=19
Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women
Khorram O, Laughlin GA, Yen SS · Journal of Clinical Endocrinology & Metabolism
Nineteen healthy adults aged 55–71 received nightly subcutaneous [Nle27]GHRH(1-29)-NH2 at 10 µg/kg or placebo for five months. Nocturnal GH and IGF-1 rose, lean-body-mass effects appeared in men, skin thickness rose in women — the load-bearing controlled adult sermorelin-analog trial whose modest scale defines the evidence ceiling for adult GHRH-axis modulation.
- 1997RCTmoderaten=11
Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men
Vittone J, Blackman MR, Busby-Whitehead J, +10 · Metabolism
Eleven healthy older men aged 64–76 received a single nightly subcutaneous GHRH(1-29) dose of 2 mg for six weeks. Nocturnal GH release rose and isolated muscle-strength measures improved, but IGF-1, body weight, DEXA body composition, glucose, insulin, and lipids did not change — the trial that established single-nightly dosing as less effective than multiple-daily regimens.
- 1996RCTmoderaten=33
A randomized controlled trial of thymosin-alpha1 versus interferon alfa treatment in patients with hepatitis B e antigen antibody-- and hepatitis B virus DNA--positive chronic hepatitis B
Andreone P, Cursaro C, Gramenzi A, +9 · Hepatology
In a 33-patient head-to-head comparison, thymosin-α1 produced a similar response rate to interferon alfa in anti-HBe-positive chronic hepatitis B at end-of-treatment and a higher complete response rate at six-month follow-up — the comparator-grade evidence that anchored thymosin-α1's hepatitis B regulatory record.
- 1994RCTstrongn=12
Growth hormone-releasing activity of hexarelin in humans. A dose-response study
Imbimbo BP, Mant T, Edwards M, +6 · European Journal of Clinical Pharmacology
Twelve adult male volunteers in a placebo-controlled rising-dose IV study; an ED50 of approximately 0.5 µg/kg, peak plasma GH at 30 minutes, return to baseline by 240 minutes — the foundational human pharmacokinetic and pharmacodynamic characterisation of hexarelin.
- 1993RCTstrongn=1,441
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus
Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, +6 · New England Journal of Medicine
Intensive insulin therapy reduced retinopathy development by 76% in primary prevention and slowed progression by 54% in secondary intervention across 1,441 type 1 diabetes patients followed a mean of 6.5 years — the landmark demonstration that microvascular complications track glycemic burden.