Question explored with the scientific record
Which version of glp1 drugs is the best to use
The short version: no version of these drugs has been tested in a long-term head-to-head trial that measures death or disability, so "best" depends on which surrogate endpoint you care about and how much GI distress you can tolerate.
The evidence you have is almost entirely from manufacturer-funded trials that last 26 to 104 weeks and measure lab values (HbA1c, weight) rather than hard outcomes like heart attack, stroke, or death in a general population. The SUSTAIN trials for injectable semaglutide [1, 2, 3] and the PIONEER trials for oral semaglutide [7, 8] show HbA1c drops of about 1.2% to 1.8% and weight loss of 3 to 6 kg. Tirzepatide, the dual GIP/GLP-1 agonist, shows larger effects: HbA1c reductions up to 2.6% and weight loss up to 12.4 kg in SURPASS-2 [14, 17]. Retatrutide, the triple agonist, is still in phase 2 but shows weight loss up to 24% at 48 weeks in an obesity trial [13]. All three cause frequent nausea (20-60% of patients), vomiting, and diarrhea, and about 8-17% of people stop the drug because of side effects [6, 8, 13].
The pancreatitis risk is the one safety signal that has been studied systematically. A meta-analysis of seven cardiovascular outcome trials with nearly 28,000 patients on GLP-1 agonists found 92 cases of acute pancreatitis versus 88 in placebo, a difference that is not statistically significant [22]. The ABCD liraglutide audit found an incidence of 0.027 per 100 patient-years for cases with no other cause [25]. But case reports of necrotizing pancreatitis exist [24, 26], and the trials were not designed or powered to detect rare harms. The retinopathy signal in SUSTAIN-6 (3.0% vs 1.8% with placebo, HR 1.76) [32] is a real warning that these drugs may have organ-specific risks that the short trial windows miss.
| Drug | HbA1c reduction | Weight loss | Nausea rate | Discontinuation due to AEs |
|---|---|---|---|---|
| Semaglutide (injectable) | 1.2-1.8% [1] | 3.5-6.5 kg [2] | 20-24% [6] | ~8% [8] |
| Semaglutide (oral) | 1.0-1.4% [7] | 3.7-4.7 kg [7] | ~20% [8] | 11-13% [8] |
| Tirzepatide | 2.0-2.6% [14] | 7.8-12.4 kg [14] | 17-22% [14] | 6-8.5% [14] |
| Retatrutide (phase 2) | 0.4-2.0% [13] | 8.7-24.2% [13] | 14-60% [13] | 16-17% [13] |
My call: if you need a GLP-1 drug, tirzepatide has the strongest evidence for glycemic control and weight loss in the short term, but no version has long-term safety data beyond 2 years, the pancreatitis question is not settled, and the retinopathy signal with semaglutide is a specific reason to pause. Confidence: moderate for short-term efficacy, low for long-term safety.
Sources used 14
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Pharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist
This review article evaluates the pharmacokinetics, efficacy, and safety of semaglutide, a new GLP-1 receptor agonist for managing type 2 diabetes mellitus, highlighting its potential for glycemic control and weight loss with a low risk of hypoglycemia.
DOI: 10.1007/s40262-018-0668-z -
Semaglutide: Review and Place in Therapy for Adults With Type 2 Diabetes
This review discusses the efficacy and safety of semaglutide, a GLP-1 receptor agonist, in managing type 2 diabetes, highlighting its superior effects on glycemic control and weight loss compared to other treatments, as well as its cardiovascular benefits.
DOI: 10.1016/j.jcjd.2018.05.008 -
Semaglutide for the Treatment of Type 2 Diabetes Mellitus
This study reviews the efficacy and safety of semaglutide, a GLP-1 receptor agonist, in treating type 2 diabetes mellitus, highlighting its significant reductions in HbA1c and body weight compared to other treatments, along with cardiovascular benefits and potential risks of ret…
DOI: 10.1177/8755122518790925 -
Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial
The SUSTAIN 1 trial demonstrated that once-weekly semaglutide monotherapy significantly improves glycaemic control and reduces body weight in treatment-naive patients with type 2 diabetes compared to placebo, with a safety profile similar to existing GLP-1 receptor agonists.
DOI: 10.1016/s2213-8587(17)30013-x -
<p>Oral Semaglutide In The Management Of Type 2 Diabetes: A Report On The Evidence To Date</p>
This article reviews the development, pharmacology, and clinical evidence for oral semaglutide in type 2 diabetes, detailing its efficacy (glycemic control and weight loss), cardiovascular safety (non-inferiority with potential mortality benefits in PIONEER-6), safety profile (G…
DOI: 10.2147/DMSO.S229802 -
Efficacy, safety and cardiovascular outcomes of once‐daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme
Oral semaglutide reduces HbA1c and body weight across diverse type 2 diabetes populations and demonstrates cardiovascular safety, providing an oral GLP-1 receptor agonist option alongside injections.
DOI: 10.1111/dom.14054 -
Retatrutide as a Novel Treatment for Obesity and Type 2 Diabetes
Retatrutide, a weekly triple agonist of GLP-1, GIP, and glucagon receptors, produced dose-related weight loss and HbA1c reductions in two phase 2 trials (obesity and type 2 diabetes) but showed notable GI and cardiovascular safety signals, underscoring the need for phase 3 confi…
DOI: 10.19080/crdoj.2023.16.555949 -
Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction
Dual GIP/GLP-1 receptor co-agonist tirzepatide achieves unprecedented glycemic control and substantial weight loss in type 2 diabetes, with favorable cardiovascular safety signals across the SURPASS trials and potential for obesity/NAFLD indications.
DOI: 10.1186/s12933-022-01604-7 -
Management of Early-Onset Type 2 Diabetes in Adults: Current Evidence and Future Directions
A comprehensive narrative review synthesizing current evidence on the management of early-onset type 2 diabetes (EOT2D) in adults, outlining weight loss and β-cell preservation targets, cardiometabolic risk management, psychological wellbeing, and emerging interventions (tirzepa…
DOI: 10.4093/dmj.2025.0561 -
Risk of acute pancreatitis with incretin-based therapy: a systematic review and updated meta-analysis of cardiovascular outcomes trials
This systematic review and updated meta-analysis of cardiovascular outcomes trials in type 2 diabetes shows GLP-1 receptor agonists do not increase acute pancreatitis risk, while DPP-4 inhibitors are associated with a higher pancreatitis risk.
DOI: 10.1080/17512433.2020.1736041 -
Semaglutide induced Pancreatitis
This case report discusses a 48-year-old male patient who developed acute pancreatitis after starting semaglutide, a glucagon-like peptide-1 receptor agonist, highlighting the potential risks associated with its use.
DOI: 10.36948/ijfmr.2024.v06i04.26238 -
Liraglutide pancreatitis: The ABCD nationwide liraglutide audit
Very low incidence of pancreatitis among liraglutide-treated patients in the ABCD nationwide audit; most pancreatitis cases have alternative etiologies; rates fall within expected ranges for type 2 diabetes pancreatitis
DOI: 10.1177/1474651413502685 -
Case Report of Acute Necrotizing Pancreatitis Associated with Combination Treatment of Sitagliptin and Exenatide
This case report describes a 76-year-old woman with type 2 diabetes who developed necrotizing pancreatitis after adding sitagliptin to chronic exenatide therapy, suggesting a possible causal link between GLP-1 receptor agonists and DPP-4 inhibitors (alone or in combination) and …
DOI: 10.4158/EP11264.CR -
Cardiovascular safety and benefits of GLP-1 receptor agonists
A narrative expert opinion reviewing cardiovascular safety and potential benefits of GLP-1 receptor agonists (GLP-1RAs) for type 2 diabetes, highlighting neutral to favorable CV outcomes in several CVOTs (e.g., liraglutide and semaglutide) with varying effects on CV risk factors…
DOI: 10.1080/14740338.2017.1281246