approach , management and diagnosis of journal

journal presentation

1. JOURNAL CLUB MEDICINE :IV Dr. Santosh Pokhrel Department of Internal Medicine

2. Maridebart Cafraglutide demonstrated significant and dose-dependent weight loss. In the multiple ascending dose cohorts, participants saw a mean body weight loss of 14.5% by day 85 at the highest dose. This weight loss was maintained for up to 150 days after the last dose, with maximum weight loss maintained for two months after the final dose.

3. Trial Name Patient Population Duration Weight Loss (%) Key Takeaway Tirzepatide – SURMOUNT-1 Obesity, no diabetes 72 weeks −15.0 to −20.9 Strong efficacy in non-diabetics Tirzepatide – SURMOUNT-2 Obesity + T2D 72 weeks −12.8 to −14.7 Effective in diabetes subset Tirzepatide – SURMOUNT-3 Lifestyle lead-in 84 weeks ∼ −21.1 (from lead-in) Incorporates behavioral program Tirzepatide – SURMOUNT-4 Maintenance tracking 52 weeks Maintained loss Cessation = weight regain Tirzepatide – SURMOUNT-5 Head-to-head vs Semaglutide — 20.2 vs 13.7 Superior to Semaglutide

4. Background & Why This Study? Global health crisis: >1 billion people affected Associated with T2DM, cardiovascular disease, NAFLD, OSA, cancer Current management: GLP-1 receptor agonists (e.g., semaglutide) → significant weight loss Tirzepatide (GLP-1 + GIP agonist) → superior efficacy Limitations: frequent dosing, GI side effects, long-term adherence Maridebart cafraglutide (MariTide) Long-acting: once-monthly injection Designed to improve weight reduction, glycemic control, and adherence

5. PICO Model Population Intervention Control Outcome Age ≥ 18 years Adults with obesity (BMI ≥30 kg/m², or ≥27 with comorbidity)and HbA1c < 6.5% Type 2 Dm and HbA1c ≥ 7% and ≤ 10% Long-acting GLP-1 receptor agonist + GIP receptor antagonist S/C Doses: 140, 280, or 420 mg Every 4 or 8 weeks, with or without dose escalation Placebo injection (matching schedule) Primary outcome: % change in body weight at 52 weeks Secondary outcomes: Change in HbA1c (in diabetes cohort) Safety and tolerability (GI side effects, adverse events)

6. Study Design Multination Multicenter Phase 2 Randomized Controlled Trial Placebo-controlled Double blinded

7. Inclusion Criteria Age ≥18 years Obesity cohort :  • BMI ≥30 OR BMI ≥27 + comorbidity (HTN, dyslipidemia, OSA, CVD)  • HbA1c <6.5%, no diabetes Obesity + Diabetes cohort :  • Type 2 DM ≥6 months  • HbA1c 7–10%  • On stable therapy (diet/exercise, metformin, SU, or SGLT2i)

8. Exclusion Criteria Type 1 diabetes mellitus Cardiovascular & Organ Health: recent history of heart attack, stroke, or uncontrolled hypertension , severe liver or kidney problems Psychiatric Conditions: history of major depressive disorder, suicide attempts, or severe psychiatric conditions like schizophrenia or bipolar disorder. Disease-Related: history of medullary thyroid carcinoma, pancreatitis, or other endocrine disorders that cause obesity.

9. Medication & Treatment History: recently used any weight-loss medications, bariatric surgery, or weight-loss devices. Women's & Men's Health: All participants had to be non-pregnant. Both men and women of childbearing potential were required to use specified contraception methods throughout the trial for safety reasons. General Exclusions: Excluded participants with a significant recent weight change (> 5 kg), or other conditions that could pose a risk to their safety or interfere with study procedures.

10. Study design

11. Bias Type How Addressed in Study Selection Bias Randomization was used to evenly distribute patient characteristics among the treatment groups. Performance Bias The study was double-blinded, so neither patients nor researchers knew who was getting the drug. Reporting Bias Pre-specified endpoints and public registration ensured all results were reported transparently. Attrition Bias A dose escalation strategy and intention-to-treat analysis minimized dropouts and accounted for any that occurred. Ascertainment Bias A rigorous patient reporting tool was used to systematically and objectively track side effects. Temporal Bias An ongoing extension study was designed to evaluate the long-term effects of the drug beyond the initial trial period.

12. Results: 17 August 2025 21

13. ADVERSE EVENTS

14. Discussion New Monthly Therapy: Maridebart cafraglutide is a promising once-monthly treatment that led to significant weight loss. Safety Profile: Side effects were consistent with other drugs in this class, and a dose escalation strategy was found to improve tolerability. Novel Mechanism: The drug is a GIP receptor antagonist, introducing a new way to achieve weight loss compared to existing GIP receptor agonists. Future Direction: The findings support advancing to Phase 3 trials, with an emphasis on the dose escalation strategy to improve the side-effect profile.

15. Strength Randomized design with placebo controlled Long term follow up Methodical Side Effect Reporting Novel Mechanism Clinical Efficacy result

16. Limitations Small Group Sizes: The overall trial size was divided among many groups, limiting the power to statistically compare them. Incomplete Efficacy Data: The trial ended before a weight loss plateau was reached, so the maximum potential of the drug is still unknown. Complex Analysis: The use of two different statistical analysis methods (treatment policy estimand vs. efficacy estimand) could make the results confusing to interpret.

17. Conclusion Clinical Efficacy: The drug resulted in substantial weight reduction (up to 16.2% in one cohort) and improved glycemic control in participants with type 2 diabetes. Long-Term Potential: A weight plateau was not reached at 52 weeks, indicating a need for longer-term studies to assess its full efficacy. Patient Convenience: Its once-monthly administration offers a key advantage, potentially improving patient adherence . Next Steps: The ongoing Part 2 extension study will provide more data on maximum weight loss .

18. C ritical appraisal

19. Was the study design appropriate for the research question ? Multination (12 nations and 4 continent) Multicenter Double blinded Phase 2 Randomized Controlled Trial Placebo-controlled

20. Is the study population clearly described and representative of the target population? Study population is clearly described obesity and obesity + T2DM cohorts

21. Were the inclusion and exclusion criteria clearly defined and applied consistently? Clearly defined and applied

22. Were the outcomes clinically relevant and important ? Primary: % change in body weight at 52 weeks Secondary: HbA1c, waist circumference, BP , body composition All relevant to obesity and metabolic health

23. What are the implications and limitations for clinical practice? • Once-monthly dosing may improve adherence • Strong efficacy for weight and HbA1c reduction • Limitations: short-term safety, phase 2 only, limited generalizability • Needs phase 3 for definitive evidence

24. Were follow-up and data collection adequate? • 52-week follow-up, regular monitoring • 72% trial completion rate • Acceptable but attrition could bias results

25. Were the outcomes measured in a valid and reliable way? Standardized weight and lab measurements DXA for body composition in sub-study HbA1c, BP measured using validated tools

26. Conclusion • Maridebart cafraglutide showed substantial weight loss and HbA1c reduction • Safe in short term, but long-term safety unknown • Promising therapy; Phase 3 needed for confirmation

27. Thank You