Compounds with a graded row

Ordered by rung, strongest first. The rung rates the study design; the chip beside it says what the study measured. Both are needed.

1. Cagrilintide

   human RCT Direct outcome In registered trials

   Who was studied

   adults with type 2 diabetes and BMI 27 kg/m2 or higher on metformin with or without an SGLT2 inhibitor, n=92 (cagrilintide monotherapy arm n=30), 32 weeks; 59 (64%) male, mean age 58 years

   Phase 2 trial (NCT04982575) with change in HbA1c as the primary endpoint; the cagrilintide 2.4 mg monotherapy arm changed HbA1c by -0.9 percentage points at week 32 against -1.8 for semaglutide and -2.2 for the combination. HbA1c was measured directly, alongside bodyweight, fasting plasma glucose and CGM time in range. Cagrilintide is not approved by any regulator for type 2 diabetes.

   Source PubMed 1 primary source read for this row

2. Dulaglutide

   human RCT Direct outcome Approved for this condition

   Who was studied

   men and women aged at least 50 years with type 2 diabetes and either a previous cardiovascular event or cardiovascular risk factors, n=9901, median follow-up 5.4 years; median baseline HbA1c 7.2% (IQR 6.6-8.1), 4589 (46.3%) women

   REWIND randomised 9901 participants to weekly dulaglutide 1.5 mg or placebo across 371 sites. The primary endpoint was a cardiovascular composite; HbA1c was measured at baseline and through follow-up, which is why this is graded direct_outcome rather than surrogate. Dulaglutide is FDA-approved for glycaemic control in type 2 diabetes.

   Source PubMed 1 primary source read for this row

3. Exenatide

   human RCT Direct outcome Approved for this condition

   Who was studied

   patients with type 2 diabetes with or without previous cardiovascular disease, n=14752 (10782, 73.1%, with previous cardiovascular disease), median follow-up 3.2 years (IQR 2.2-4.4); the abstract does not report the HbA1c entry range

   EXSCEL randomised 14752 patients to extended-release exenatide 2 mg weekly or placebo. The primary endpoint was a cardiovascular composite and was not met for superiority; HbA1c was measured as a secondary outcome, which is the basis for the direct_outcome grade. Exenatide is FDA-approved for glycaemic control in type 2 diabetes.

   Source PubMed 1 primary source read for this row

4. Liraglutide

   human RCT Direct outcome Approved for this condition

   Who was studied

   patients with type 2 diabetes and high cardiovascular risk, n=9340, median follow-up 3.8 years; the abstract does not report the HbA1c entry range or background therapy

   LEADER randomised 9340 patients to liraglutide or placebo added to standard care. The primary endpoint was a cardiovascular composite; HbA1c was measured as a reported outcome, so the row is direct_outcome, but no glycaemic endpoint was primary here. Liraglutide is FDA-approved for type 2 diabetes.

   Source PubMed 1 primary source read for this row

5. Lixisenatide

   human RCT Direct outcome Approved for this condition

   Who was studied

   patients with type 2 diabetes who had had a myocardial infarction or been hospitalised for unstable angina within the previous 180 days, n=6068, median follow-up 25 months

   ELIXA randomised 6068 patients to lixisenatide or placebo added to local standard of care. The primary endpoint was a cardiovascular composite and showed non-inferiority but not superiority; HbA1c was measured as a secondary outcome. The enrolled population is narrow — recent acute coronary syndrome — and is not the general type 2 diabetes population.

   Source PubMed 1 primary source read for this row

6. Pramlintide

   human RCT Direct outcome Approved for this condition

   Who was studied

   insulin-treated adults with type 2 diabetes (insulin alone or with sulfonylurea and/or metformin), n=656, 52 weeks; mean age 57 years, diabetes duration 12 years, BMI 34.0 kg/m2, baseline HbA1c 9.1%

   A 52-week double-blind placebo-controlled trial of preprandial pramlintide (60 mcg three times daily, 90 mcg twice daily, or 120 mcg twice daily) added to insulin. HbA1c was the measured glycaemic outcome, falling 0.62 percentage points from baseline at week 52 in the 120 mcg twice-daily arm; weight change was reported alongside it. Approved by the FDA as a mealtime adjunct to insulin, not as monotherapy.

   Source PubMed 1 primary source read for this row

7. Retatrutide

   human RCT Direct outcome In registered trials

   Who was studied

   adults aged 18-75 with type 2 diabetes, HbA1c 7.0-10.5% (53.0-91.3 mmol/mol) and BMI 25-50 kg/m2, on diet and exercise alone or stable metformin >=1000 mg daily for at least 3 months, n=281 randomised (275 in the efficacy analysis), 36 weeks

   Phase 2 trial (NCT04867785) with change in HbA1c at 24 weeks as the primary endpoint and HbA1c and bodyweight at 36 weeks as secondary; placebo and 1.5 mg dulaglutide were both comparators. Retatrutide is not approved by any regulator for type 2 diabetes.

   Source PubMed 1 primary source read for this row

8. Semaglutide

   human RCT Direct outcome Approved for this condition

   Who was studied

   adults with type 2 diabetes on a standard-care regimen, n=3297, 104 weeks; 2735 (83.0%) had established cardiovascular disease, chronic kidney disease, or both; the abstract does not state the HbA1c entry threshold

   SUSTAIN-6 randomised 3297 patients to once-weekly semaglutide 0.5 mg or 1.0 mg or placebo for 104 weeks. The primary endpoint was a cardiovascular composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), not glycaemia; HbA1c was measured and reported as a secondary outcome, which is why this is graded direct_outcome. Semaglutide carries FDA approval for glycaemic control in type 2 diabetes.

   Source PubMed 1 primary source read for this row

9. Survodutide

   human RCT Direct outcome In registered trials

   Who was studied

   adults aged 18-75 with type 2 diabetes, HbA1c 53-86 mmol/mol (7.0-10.0%) and BMI 25-50 kg/m2, on background metformin, n=413 randomised (411 treated), 16 weeks; mean baseline HbA1c 64.7 mmol/mol (8.07%)

   Phase 2 dose-finding trial (NCT04153929) with absolute change in HbA1c at 16 weeks as the primary endpoint and relative bodyweight change as key secondary; open-label semaglutide up to 1.0 mg was an active comparator. Survodutide is not approved by any regulator for type 2 diabetes.

   Source PubMed 1 primary source read for this row

10. Tirzepatide

    human RCT Direct outcome Approved for this condition

    Who was studied

    adults with type 2 diabetes, n=1879, 40 weeks, open-label; mean baseline HbA1c 8.28%, mean age 56.6 years, mean weight 93.7 kg; background therapy not stated in the abstract

    SURPASS-2 randomised 1879 patients 1:1:1:1 to tirzepatide 5, 10 or 15 mg or semaglutide 1 mg once weekly. The primary endpoint was change in HbA1c from baseline to 40 weeks, so glycaemia was the measured outcome rather than a secondary. This is a head-to-head trial against semaglutide; tirzepatide is FDA-approved for type 2 diabetes.

    Source PubMed 1 primary source read for this row

11. Exendin-4

    human case series Surrogate marker Not approved for this condition

    Who was studied

    subjects with type 2 diabetes; study A n=24 dosed twice daily with meals for 5 days, study B n=13 dosed once after an overnight fast with 8 hours of observation; sex, HbA1c range and background therapy not reported in the abstract

    Synthetic exendin-4 (AC2993) reduced postprandial and fasting plasma glucose in two early clinical studies. Both had placebo arms but the abstract does not state that allocation was randomised, so the rung is set conservatively below human_rct. The measured outcomes were plasma glucose, insulin and glucagon concentrations over hours to days; no study on file measured HbA1c for the native venom peptide. The marketed synthetic form of this same molecule is exenatide, which is graded on its own row.

    Source PubMed 1 primary source read for this row

12. GLP-1 (7-36)

    human case series Surrogate marker Not approved for this condition

    Who was studied

    patients with type 2 diabetes in poor metabolic control on diet and sulphonylurea, some with added metformin or acarbose, n=10, HbA1c 11.6 +/- 1.7%, single 4-hour intravenous infusion

    Intravenous GLP-1 (7-36 amide) at 1.2 pmol/kg/min brought fasting plasma glucose to normal fasting concentrations within 4 hours, with placebo as the within-subject comparison; insulin and C-peptide rose and glucagon fell. This is a single-session physiology study of the native hormone, not a treatment trial: no HbA1c or other durable glycaemic outcome was measured. The therapeutic analogues are graded on their own rows.

    Source PubMed 1 primary source read for this row

13. GIP (Gastric Inhibitory Peptide)

    human case series Mechanistic only Not approved for this condition

    Who was studied

    patients with mild type 2 diabetes (fasting plasma glucose 7.8 mmol/L, HbA1c 6.3 +/- 0.6%), n=9, compared with 9 age- and weight-matched normal subjects; single hyperglycaemic clamp sessions

    Recorded, and not evidence for this condition

    Synthetic human GIP infused under hyperglycaemic clamp conditions produced an insulin secretory response 54% lower in the type 2 diabetes group than in matched normal subjects, while GLP-1 retained most of its insulinotropic activity. This characterises the physiology of the native hormone and the loss of GIP responsiveness in the disease; it is not administration of GIP as a treatment, and no study on file measured HbA1c or any durable glycaemic outcome with GIP. GIP receptor agonism as a therapy appears only inside the dual and triple agonists graded on their own rows.

    Source PubMed 1 primary source read for this row

14. MOTS-c

    animal in vivo Mechanistic only Not approved for this condition

    Who was studied

    mice, including high-fat-diet-fed and aged animals; intraperitoneal administration, group sizes and durations as reported in the source; no human participants

    Recorded, and not evidence for this condition

    No study has measured type 2 diabetes in people with MOTS-c: no trial on file has administered it to humans and measured HbA1c, fasting glucose, or any other glycaemic outcome, and this row is mechanistic only. What exists is intraperitoneal administration in mice, where MOTS-c was reported to reduce diet-induced obesity and insulin resistance with glucose infusion rate during clamp as the readout; those figures are murine, and the link to the condition is an argument from rodent physiology rather than a result.

    Source PubMed 1 primary source read for this row

Checked, and nothing recorded

1 compound was checked against type 2 diabetes and produced no gradeable row.

• Amylin — checked, no row on file

A compound is here because someone looked and the sources did not support a row — not because nobody looked. Under the rubric, uncertainty resolves to no row, and a row resting on a vendor page or a clinic blog is worse than no row at all.