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.
143 sources
- 2026Cohortmoderaten=63,083
Risk of Heart Failure Hospitalization for GLP-1 Receptor Agonists Versus DPP-4 Inhibitors or SGLT-2 Inhibitors in Patients With Type 2 Diabetes: A Target Trial Emulation
Xu Y, Huang T, Zhang Y, +4 · Circulation
In a Stockholm 2010–2021 target-trial emulation of 63,083 adults with type 2 diabetes, GLP-1 receptor agonists reduced 3-year heart-failure hospitalization versus DPP-4 inhibitors (HR 0.77; 95% CI 0.66–0.91) but were not different from SGLT-2 inhibitors (HR 1.02; 95% CI 0.85–1.18) — the cleanest comparative-effectiveness signal to date that the GLP-1RA cardioprotective effect is real against DPP-4i but does not match SGLT-2i for the heart-failure endpoint.
- 2026Meta-analysismoderate
Effect of Incretin-Based and Nonpharmacologic Weight Loss on Body Composition: A Systematic Review
Batsis JA, Gavras A, Gross DC, +3 · Annals of Internal Medicine
Annals of Internal Medicine systematic review of 36 randomised controlled trials of liraglutide, semaglutide, tirzepatide, and dulaglutide in adults with obesity, evaluating fat mass, fat-free mass, lean soft tissue, and visceral adiposity outcomes against prespecified benchmarks — the most rigorous synthesis to date of the lean-mass concern that has dominated public discourse about incretin therapy.
- 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.
- 2026Mechanisticstrong
Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein
Tsang AH, Heeley N, Alcaino C, +3 · Cell Metabolism
Cambridge Institute of Metabolic Science group identifies Cav3.1 — a T-type voltage-gated calcium channel — as the hypothalamic POMC-neuron leucine sensor that mediates protein-induced satiety, and shows pharmacological Cav3.1 activation in the mediobasal hypothalamus drives weight loss in obese mice and potentiates liraglutide's anorectic response.
- 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.
- 2026Meta-analysismoderaten=1,593,554
Glucagon-like Peptide-1 Receptor Agonists and Risk of Nonarteritic Anterior Ischemic Optic Neuropathy: Systematic Review and Meta-Analysis
Dhivagaran T, Butt F, Arunasalam L, +3 · Neurology
Across 1,593,554 patients in a Neurology-published meta-analysis (682,456 semaglutide users vs 911,098 non-GLP-1RA users), semaglutide use was associated with a 2.5-fold increased risk of nonarteritic anterior ischemic optic neuropathy (RR 2.52; 95% CrI 1.56–4.72), with the strongest signal in patients with diabetes (RR 2.41; 95% CrI 1.57–4.10) — the strongest meta-analytic confirmation to date that the NAION safety signal is real.
- 2026Mechanisticsuggestiven=120
Combined antiretroviral therapy with low- or normal-protein, high-calorie diets appears to induce significant deleterious electrocardiographic changes in a rodent model
Chege BM, Mwangi PW, Githinji CG, +1 · Brazilian Journal of Medical and Biological Research
In 120 Sprague-Dawley rats fed calorie-dense diets and dosed with dolutegravir-based or classical combination antiretroviral regimens for 24 weeks, addition of tesamorelin prevented the ECG conduction abnormalities and myocardial fibrosis seen with dolutegravir or classical cART alone — implicating growth-hormone-axis dysfunction in cART-associated cardiotoxicity.
- 2026Mechanisticsuggestive
Glycyl-L-histidyl-L-lysine-Cu2+ (GHK-Cu) Attenuates CuSO4 or LPS induced-inflammation in Zebrafish larvae model
Hu J, Zhang C, Wang F · European Journal of Pharmacology
In a zebrafish larvae inflammation model, GHK-Cu suppressed neutrophil and macrophage migration, downregulated TNF-α, IL-1β, and IL-6, upregulated IL-10, and attenuated JAK1 signalling — extending the cosmetic-skin GHK-Cu literature into a whole-organism inflammation readout.
- 2026Mechanisticsuggestive
Anti-inflammatory and anabolic effects of liraglutide on 3D inflammatory osteoarthritic spheroid and scaffold models of human chondrocytes
Ciftci E, Eberlein SC, Grad S, +3 · Osteoarthritis and Cartilage
In 3D human-chondrocyte spheroid and scaffold cultures stimulated with IL-1β, liraglutide reduced IL-8 release roughly four-fold (877.8 vs 3127.0 ng), elevated ACAN and PRG4 anabolic markers, and preserved extracellular-matrix composition under cyclic mechanical loading — the first systematic in-vitro mechanistic case for a direct GLP-1RA effect on osteoarthritic cartilage independent of weight loss.
- 2026Mechanisticmoderate
GIPR:GCGR co-agonism restores normal weight in obese rodents
Perez-Tilve D, Zhang F, Zhang Y, +6 · Molecular Metabolism
BWB3054, a dual GIPR:GCGR co-agonist designed to attenuate GLP-1R signalling >100-fold, normalised body weight in diet-induced obese mice and rats and matched retatrutide's weight effect — including in GLP-1R-knockout mice — suggesting the GIP and glucagon arms of the triple-agonist can deliver the bulk of the obesity effect without GLP-1R-driven gastrointestinal liability.
- 2025Reviewstrong
Retraction notice: 'The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System' and related Wright/Harding lab Dihexa publications
Journal of Pharmacology and Experimental Therapeutics (editorial) · Journal of Pharmacology and Experimental Therapeutics
April 2025 retraction notices removed two of the key Wright/Harding lab mechanism papers for Dihexa — Benoist 2014 on HGF/c-Met dependence and Kawas 2012 on AngIV analog development — following research-integrity investigations. The McCoy 2013 foundational paper has been under an expression of concern since 2021. The mechanism case for Dihexa is now substantially weaker than the public peptide-vendor literature acknowledges.
- 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=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.
- 2025Cohortmoderaten=224
GLP-1 Receptor Agonists Confer No Increased Rates of IBD Exacerbation Among Patients With IBD
Levine I, Sekhri S, Schreiber-Stainthorp W, +6 · Inflammatory Bowel Diseases
Among 224 IBD patients prescribed GLP-1 receptor agonists at a large US academic health network between 2009 and 2023, twelve-month rates of IBD exacerbation, IBD-related hospitalization, corticosteroid use, medication escalation, and surgery did not differ from pre-prescription baseline — a null safety signal that independently corroborates the Israeli Epi-IIRN findings.
- 2025Cohortmoderaten=3,737
GLP-1 Analog Use is Associated With Improved Disease Course in Inflammatory Bowel Disease: A Report from the Epi-IIRN
Gorelik Y, Ghersin I, Lujan R, +9 · Journal of Crohn's and Colitis
In 3,737 patients with IBD and type 2 diabetes drawn from the Israeli Epi-IIRN nationwide cohort, GLP-1-analog use was associated with reduced composite poor IBD outcomes (adjusted HR 0.74) — and the protective signal was carried specifically by the obese subgroup (aHR 0.61), with no detectable effect in non-obese patients.
- 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=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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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=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.
- 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.
- 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.
- 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.
- 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.
- 2023Mechanisticsuggestiven=30
Thymosin alpha 1 restores the immune homeostasis in lymphocytes during Post-Acute sequelae of SARS-CoV-2 infection
Minutolo A, Petrone V, Fanelli M, +16 · International Immunopharmacology
An ex-vivo study from the Garaci–Matteucci group examining lymphocyte populations in 10 PASC patients, 15 acute-COVID-19 controls, and 5 healthy donors — the only PASC-specific thymosin α-1 paper in the indexed literature, documenting persistent immune dysregulation and partial ex-vivo rescue with greatest effect in patients who had required respiratory support during the acute phase.
- 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=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=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.
- 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.
- 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.
- 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.
- 2022Case reportmoderaten=17
Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID
Oaklander AL, Mills AJ, Kelley M, +4 · Neurology - Neuroimmunology & Neuroinflammation
A 17-patient referred case series — 59% with at least one confirmatory neuropathy test, 63% with abnormal skin biopsies, and at least 10 receiving small-fiber neuropathy diagnoses — the pivotal characterisation paper establishing small-fiber neuropathy as a measurable, biopsy-confirmable component of long COVID.
- 2021Mechanisticstrong
Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans
Kjeldsen TB, Hubálek F, Hjørringgaard CU, +15 · Journal of Medicinal Chemistry
Three insulin substitutions (A14E, B16H, B25H) plus a C20 fatty-diacid acylation at LysB29 — the molecular-engineering combination that produced a ~196-hour terminal half-life and made once-weekly basal insulin a clinical reality.
- 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=1,879
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=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.
- 2021Mechanisticstrong
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, Lai RW, Woodhead JST, +9 · Nature Communications
Acute exercise raised skeletal-muscle MOTS-c expression nearly 12-fold and circulating MOTS-c by approximately 50% in human volunteers; exogenous MOTS-c administered to mice approximately doubled treadmill running capacity at young, middle-aged, and old time points — the strongest single-paper integration of MOTS-c human physiology and mouse pharmacology to date.
- 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.
- 2021Mechanisticmoderaten=224
Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning
Patterson BK, Guevara-Coto J, Yogendra R, +7 · Frontiers in Immunology
A 224-individual immune-profiling study that documented PASC-distinctive elevations in CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF alongside expanded CD14+/CD16+/CCR5+ monocyte subsets — the most-cited immune-signature characterisation in the early PASC literature, and structurally separate from the same group's subsequent treatment claims.
- 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.
- 2021Mechanisticstrong
Development of Cagrilintide, a Long-Acting Amylin Analogue
Kruse T, Hansen JL, Dahl K, +12 · Journal of Medicinal Chemistry
The molecular design paper for cagrilintide — a stabilised, lipidated long-acting analogue of pramlintide engineered around the same C20-fatty-diacid + albumin-binding architecture that produced once-weekly semaglutide, here transplanted onto an amylin backbone.
- 2021Mechanisticmoderaten=49
Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin
Pretorius E, Vlok M, Venter C, +4 · Cardiovascular Diabetology
The foundational microclot-in-PASC observation paper — fluorescent staining and proteomics on plasma from 11 PASC patients identified amyloid fibrin deposits resistant to trypsin-mediated fibrinolysis, with α2-antiplasmin elevated approximately eightfold within the resistant pellet versus healthy controls.
- 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.
- 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.
- 2020Mechanisticstrong
Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist
Willard FS, Douros JD, Gabe MBN, +15 · JCI Insight
Tirzepatide is not a balanced dual GIP / GLP-1 agonist — it engages the GIP receptor with native-ligand potency and the GLP-1 receptor with approximately 5-fold weaker affinity, and at the GLP-1 receptor it is biased toward cAMP signaling over β-arrestin recruitment.
- 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.
- 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.
- 2019Cohortmoderaten=684
Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder
Simon JA, Kingsberg SA, Portman D, +5 · Obstetrics and Gynecology
52-week open-label extension of the RECONNECT phase-3 trials — 684 women received bremelanotide for up to 76 weeks total, with nausea (40.4%), flushing (20.6%), and headache (12.0%) the most common adverse events and no new safety signals beyond the on-demand-use profile already established in the core trials.
- 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=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.
- 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.
- 2018Mechanisticmoderate
Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice
Neelakantan H, Vance V, Wetzel MD, +5 · Biochemical Pharmacology
Eleven days of subcutaneous 5-Amino-1MQ at 20 mg/kg three times daily produced approximately 5% body weight loss and a roughly 35% reduction in epididymal white adipose tissue mass in diet-induced-obese mice — the pharmacological replication of the Kraus 2014 antisense-knockdown phenotype that anchors every subsequent NNMT-inhibitor claim.
- 2018Mechanisticstrong
LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept
Coskun T, Sloop KW, Loghin C, +13 · Molecular Metabolism
The discovery paper for LY3298176 — later named tirzepatide — established the molecule as a single 39-residue, fatty-acid-conjugated peptide engineered to engage both the GIP and GLP-1 receptors with once-weekly pharmacokinetics, framing it explicitly as a unimolecular dual agonist rather than a co-administered combination.
- 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=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.
- 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=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.
- 2017Mechanisticmoderate
GABA, Selank, and Olanzapine Affect the Expression of Genes Involved in GABAergic Neurotransmission in IMR-32 Cells
Filatova E, Kasian A, Kolomin T, +8 · Frontiers in Pharmacology
Selank alone produced no change in GABAergic gene expression in IMR-32 cells; the effect appeared only in combination with GABA or olanzapine — the cleanest Western-indexed mechanism paper showing Selank as a co-modulator rather than a primary releaser.
- 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.
- 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.
- 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.
- 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=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.
- 2015Mechanisticstrong
Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide
Lau J, Bloch P, Schäffer L, +5 · Journal of Medicinal Chemistry
The molecular design paper for semaglutide — the C18 fatty diacid plus the Aib(8) substitution, paired together to produce week-long albumin binding and full DPP-4 resistance, were the design moves that opened once-weekly GLP-1 dosing as a clinical category.
- 2015Mechanisticsuggestiven=32
Effect of intra-articular injection of AOD9604 with or without hyaluronic acid in rabbit osteoarthritis model
Kwon DR, Park GY · Annals of Clinical and Laboratory Science
In 32 rabbits with collagenase-induced knee osteoarthritis, combined weekly intra-articular AOD-9604 plus hyaluronic acid produced better histological cartilage and lameness scores than either agent alone — the only published animal-model evidence for AOD-9604's post-obesity-program orthopaedic indication.
- 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.
- 2015Mechanisticstrong
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Lee C, Zeng J, Drew BG, +8 · Cell Metabolism
MOTS-c — the first mitochondrial-encoded peptide characterized as a circulating signaling molecule — prevented age- and diet-induced insulin resistance in mice through skeletal-muscle AMPK activation.
- 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.
- 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.
- 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.
- 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.
- 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.
- 2014Mechanisticstrong
Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity
Kraus D, Yang Q, Kong D, +16 · Nature
Antisense knockdown of nicotinamide N-methyltransferase in white adipose tissue and liver of diet-induced-obese mice protected against weight gain, improved insulin sensitivity, and elevated tissue SAM and NAD+ levels — without changes in food intake. The mechanistic anchor for every subsequent 5-Amino-1MQ paper.
- 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.
- 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.
- 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.
- 2013Mechanisticstrong
The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin
Birk AV, Liu S, Soong Y, +6 · Journal of the American Society of Nephrology
Birk and Szeto demonstrated that SS-31 binds cardiolipin selectively on the inner mitochondrial membrane, inhibits cytochrome c peroxidase activity, preserves cristae structure during ischemia, and accelerates ATP recovery after renal reperfusion — the foundational mechanism paper for every subsequent SS-31 indication.
- 2013Mechanisticmoderate
Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents
McCoy AT, Benoist CC, Wright JW, +6 · Journal of Pharmacology and Experimental Therapeutics
Dihexa restored cognitive performance in scopolamine-impaired and aged rats, distributed effectively to brain after oral administration, and produced marked synaptogenic activity in hippocampal cultures — the foundational paper for everything that followed.
- 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.
- 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.
- 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.
- 2012Cohortmoderaten=402
Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin
Stanley TL, Falutz J, Marsolais C, +6 · Clinical Infectious Diseases
Among 402 tesamorelin-treated HIV patients, the visceral-fat responders (>=8% VAT reduction) showed dramatically better triglycerides, fasting glucose, and adiponectin than nonresponders at both 26 and 52 weeks — establishing that the metabolic benefit follows the body-composition response.
- 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.
- 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.
- 2010Cohortstrongn=3,369
Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men
Wu FC, Tajar A, Beynon JM, +18 · New England Journal of Medicine
Of nine candidate symptoms tested against the testosterone gradient, only three — poor morning erection, low libido, and erectile dysfunction — clustered syndromically with low testosterone, and the prevalence of symptom-and-biochemistry-confirmed late-onset hypogonadism in men aged 40–79 was approximately 2.1%.
- 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.
- 2010Meta-analysisstrongn=806
Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data
Falutz J, Mamputu JC, Potvin D, +6 · Journal of Clinical Endocrinology & Metabolism
Pooled across two phase 3 trials in 806 ART-treated HIV patients with abdominal fat accumulation, tesamorelin reduced visceral adipose tissue and maintained the reduction for 52 weeks while preserving subcutaneous fat — the extended-evidence companion to the 2007 NEJM pivotal.
- 2010Mechanisticmoderate
Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin
Ueba H, Brines M, Yamin M, +5 · PNAS
The 11-amino-acid helix B surface peptide that became ARA-290 inhibits TNF-α-induced cardiomyocyte apoptosis by approximately 80% and reduces in-vivo cardiac apoptosis by approximately 70% in a hamster dilated-cardiomyopathy model — extending the IRR mechanism into a cardiac-protection indication that did not progress to clinical development.
- 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.
- 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=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.
- 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.
- 2008Mechanisticmoderate
Melanocortin-derived tripeptide KPV has anti-inflammatory potential in murine models of inflammatory bowel disease
Kannengiesser K, Maaser C, Heidemann J, +7 · Inflammatory Bowel Diseases
KPV given orally rescued every animal in the MC1Re/e DSS-colitis arm from death — demonstrating that the tripeptide's anti-inflammatory activity does not require a functional melanocortin-1 receptor and runs in parallel to the Dalmasso PepT1-transport mechanism.
- 2008Mechanisticstrong
Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin
Brines M, Patel NSA, Villa P, +13 · PNAS
An eleven-amino-acid peptide reproducing the aqueous face of helix B of human erythropoietin retains the tissue-protective activity of EPO across stroke, retinal, renal, and peripheral-nerve injury models while remaining inactive at the homodimeric EPO receptor — the foundational design paper for ARA-290 / cibinetide.
- 2008Mechanisticmoderate
PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation
Dalmasso G, Charrier-Hisamuddin L, Nguyen HTT, +3 · Gastroenterology
KPV enters epithelial and immune cells through PepT1, suppresses NF-κB at nanomolar concentrations, and reduces colitis severity in two independent mouse models — the foundational paper for the entire current case for KPV in inflammatory bowel disease.
- 2008Mechanisticmoderate
Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL14736), is effective in the healing of colocutaneous fistulas in rats: role of the nitric oxide-system
Klicek R, Sever M, Radic B, +17 · Journal of Pharmacological Sciences
BPC-157 accelerated closure of colon-to-skin fistulas in rats whether given by injection or orally; corticosteroids — the conventional comparator — worsened healing.
- 2007Mechanisticmoderate
Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization
Smart N, Risebro CA, Melville AAD, +4 · Nature
Thymosin β4 stimulated outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation into fibroblasts, smooth muscle cells, and endothelial cells — the second foundational Nature paper that drove the cardiac-repair clinical-development arc.
- 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.
- 2007Mechanisticmoderate
Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue
Ferdinandi ES, Brazeau P, High K, +3 · Basic and Clinical Pharmacology & Toxicology
The preclinical design and characterization paper for tesamorelin — TH9507's hexenoyl modification of native GHRH conferred DPP-IV resistance and a 21–45 minute half-life in dogs, the engineering moves that enabled the clinical-trial program.
- 2006Mechanisticmoderate
Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: promoted tendon-to-bone healing and opposed corticosteroid aggravation
Krivic A, Anic T, Seiwerth S, +2 · Journal of Orthopaedic Research
Tendon-to-bone — a tissue interface that does not heal spontaneously after sharp transection in rats — was functionally and biomechanically restored by intraperitoneal BPC-157, including in animals concurrently treated with corticosteroids that worsened healing alone.
- 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.
- 2006Mechanisticmoderaten=8
Pulsatile Secretion of Growth Hormone (GH) Persists during Continuous Stimulation by CJC-1295, a Long-Acting GH-Releasing Hormone Analog
Ionescu M, Frohman LA · Journal of Clinical Endocrinology & Metabolism
After a single subcutaneous dose, CJC-1295 elevated trough GH by 7.5-fold and IGF-I by 45% while leaving the frequency and amplitude of GH pulses unchanged — a continuous GHRH signal that does not flatten physiological pulsatility.
- 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.
- 2005Mechanisticmoderate
Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents
Eremin KO, Kudrin VS, Saransaari P, +4 · Neurochemical Research
Semax did not move dopamine on its own, but pretreatment dramatically enhanced amphetamine-induced dopamine release — a neuromodulatory amplifier rather than a primary releaser.
- 2004Mechanisticmoderate
Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair
Bock-Marquette I, Saxena A, White MD, +2 · Nature
Thymosin β4 promoted myocyte migration and survival through an integrin-linked-kinase / Akt pathway and improved cardiac function in mice after coronary artery ligation — the mechanistic foundation for everything that followed in the cardiac-repair literature.
- 2003Mechanisticmoderate
Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells
Khavinson VKh, Bondarev IE, Butyugov AA · Bulletin of Experimental Biology and Medicine
In telomerase-negative human fetal fibroblasts, Epithalon induced expression of the telomerase catalytic subunit, enzymatic activity, and telomere elongation — the foundational mechanistic claim that anchors the entire modern Epitalon literature.
- 2002Mechanisticstrong
CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart
Bodart V, Febbraio M, Demers A, +8 · Circulation Research
A radioactive photoactivatable hexarelin derivative cross-linked to an 84-kDa cardiac membrane protein identified by sequencing as CD36 — and the hexarelin coronary-perfusion-pressure effect was abolished in CD36-null mice and in CD36-deficient spontaneously hypertensive rats. The molecular identification of hexarelin's cardiac receptor.
- 2002Cohortmoderaten=80
Inhibitory effect of peptide Epitalon on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats
Anisimov VN, Khavinson VKh, Popovich IG, +1 · Cancer Letters
The Khavinson-group cancer-prevention companion to their longevity work — 80 male LIO rats, DMH-induced colon carcinogenesis model, 1 microgram Epitalon five days a week for 6 months. Total colon tumors per rat fell from 4.1 (control) to 2.7 (continuous Epitalon) and 2.9 (Epitalon during DMH exposure only); the post-DMH-only arm at 3.7 did not reach significance. Continuous-exposure arm also showed significantly decreased tumor incidence and multiplicity in ascending and descending colon and inhibition of tumor development in jejunum and ileum.
- 2001Mechanisticmoderate
The Effects of Human GH and Its Lipolytic Fragment (AOD9604) on Lipid Metabolism Following Chronic Treatment in Obese Mice and β3-AR Knock-Out Mice
Heffernan M, Summers RJ, Thorburn A, +4 · Endocrinology
Both hGH and AOD-9604 upregulated β3-adrenergic-receptor expression and produced weight loss in obese wild-type mice, but neither compound sustained those effects in β3-AR knockout animals — the experiment that localised AOD-9604's lipolytic mechanism to the β3 channel.
- 2001Cohortmoderaten=150
Effect of synthetic thymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumour incidence in female CBA mice
Anisimov VN, Khavinson VKh, Mikhalski AI, +1 · Mechanisms of Ageing and Development
The Khavinson group's central long-term-dosing animal study supporting geroprotective claims for Vilon (Lys-Glu thymic dipeptide) and Epitalon (Ala-Glu-Asp-Gly pineal tetrapeptide) — 50 female CBA mice per arm, lifelong monthly dosing from 6 months of age, +5.3% mean survival on Epitalon (p<0.05) and decreased lung-adenoma incidence on both peptides.
- 2000Mechanisticmoderate
Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone
Ng FM, Sun J, Sharma L, +3 · Hormone Research
Nineteen days of oral 500 µg/kg/day AOD-9604 in obese Zucker rats reduced body-weight gain by more than half versus control (15.8 vs. 35.6 g), increased ex vivo adipose lipolytic activity, and produced no detectable insulin-sensitivity decrement under euglycemic clamp — the foundational preclinical paper for the molecule.
- 1999Mechanisticstrongn=40
Pharmacokinetic-Pharmacodynamic Modeling of Ipamorelin, a Growth Hormone Releasing Peptide, in Human Volunteers
Gobburu JV, Agersø H, Jusko WJ, +1 · Pharmaceutical Research
Ipamorelin's terminal half-life is roughly two hours and clearance is 0.078 L/h/kg — short enough that the GH pulse it produces is over within six hours, the pharmacological signature behind its 'physiological pulse' reputation.
- 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.
- 1998Mechanisticstrong
Ipamorelin, the first selective growth hormone secretagogue
Raun K, Hansen BS, Johansen NL, +4 · European Journal of Endocrinology
At doses more than 200-fold above the ED50 for GH release, Ipamorelin produced no significant elevation of ACTH, cortisol, prolactin, FSH, LH, or TSH — the selectivity that distinguished it from every prior GHRP.
- 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.
- 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.
- 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.
- 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.
- 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.
- 1992Mechanisticstrong
The cloning of a family of genes that encode the melanocortin receptors
Mountjoy KG, Robbins LS, Mortrud MT, +1 · Science
The original cloning paper for the melanocortin receptor family — identification of the murine and human MSH receptor and the human ACTH receptor as G-protein-coupled receptors, deposited in GenBank as X65633, X65634, and X65635. The molecular foundation of every melanocortin-targeted peptide on this site.
- 1979Mechanisticstrong
Expression in Escherichia coli of chemically synthesized genes for human insulin
Goeddel DV, Kleid DG, Bolivar F, +7 · Proceedings of the National Academy of Sciences of the United States of America
The paper that turned synthetic biology into pharmaceutical manufacturing — separate E. coli expression of the A and B chains as β-galactosidase fusions, chemical cleavage, in vitro chain reassembly, and a biologically active human insulin three years before Humulin reached the market.
- 1978Mechanisticmoderate
The delta EEG (sleep)-inducing peptide (DSIP). XI. Amino-acid analysis, sequence, synthesis and activity of the nonapeptide
Schoenenberger GA, Maier PF, Tobler HJ, +2 · Pflügers Archiv
Synthetic DSIP, given to recipient rabbits, reproduced the original blood-fraction's delta- and spindle-EEG-enhancing activity — a 35% delta-power increase in neocortex and limbic cortex versus controls.
- 1963Mechanisticstrong
Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide
Merrifield RB · Journal of the American Chemical Society
The 1963 JACS paper that introduced solid-phase peptide synthesis — anchoring the C-terminal amino acid to an insoluble polymer support and extending the chain through repeated coupling cycles. The methodology earned Merrifield the 1984 Nobel Prize in Chemistry and remains the workhorse of synthetic-peptide manufacturing six decades later.