The GRADE Trial: Liraglutide Led Weight Loss While Weight Gain on Other Diabetes Drugs Worsened Heart and Kidney Outcomes | Research

The takeaway

In 4,980 patients over 5 years, liraglutide produced the most first-year weight loss (-3.5 kg) among four diabetes drugs, and weight gain on any medication was independently associated with worsening blood sugar, cardiovascular disease, and kidney disease.

-3.5 kg with liraglutide
Liraglutide produced the most weight loss at 1 year among four diabetes drugs, while each kg of weight gain on any drug was independently associated with 3-5% increased risk of cardiovascular, kidney, and glycemic complications

What the researchers found

In 4,980 participants followed for 5 years (mean age 57, BMI 34.3, HbA1c 7.5%):

First-year weight changes:

• Liraglutide: -3.5 kg (95% CI: -3.8 to -3.2)

• Sitagliptin: -1.07 kg (-1.4 to -0.78)

• Insulin glargine: +0.45 kg (+0.16 to +0.74)

• Glimepiride: +0.89 kg (+0.60 to +1.2)

• All groups P significant for differences

Weight gain consequences (per kg, independent of drug):

• HbA1c >7.5%: HR 1.05 (95% CI: 1.04-1.07)

• Cardiovascular disease: HR 1.03 (1.005-1.06)

• Kidney disease: HR 1.03 (1.01-1.06)

• Lower diabetes treatment satisfaction

• Baseline weight (not weight gain) predicted new-onset neuropathy

Why it matters

This is landmark evidence from one of the largest head-to-head diabetes drug trials ever conducted. It demonstrates two things: first, that liraglutide (a GLP-1 peptide) produces significantly more weight loss than three other major diabetes drug classes. Second, that weight gain — regardless of drug — independently worsens the very complications diabetes drugs are meant to prevent. This fundamentally supports prioritizing weight-reducing medications like GLP-1 agonists in diabetes management.

How the study worked

The GRADE study was a large, multicenter, randomized controlled trial comparing four diabetes medications added to metformin in patients with type 2 diabetes. 4,980 participants were followed for up to 5 years. Weight was measured over the study period, and hazard ratios were calculated per kilogram of weight change for glycemic, cardiovascular, kidney, neuropathy, and treatment satisfaction outcomes.

What this study cannot tell us

Weight change was not a pre-specified primary outcome of the GRADE trial. The analysis is observational within a randomized framework — while treatment assignment was randomized, the weight change-outcome associations are adjusted but not randomized. Liraglutide doses in GRADE may differ from those used in current obesity practice. The study population (BMI 34.3, early diabetes) may not represent all type 2 diabetes patients. Neuropathy was not associated with weight gain, suggesting the relationship is not universal across complications.

How to read the evidence

This is a secondary analysis of the GRADE randomized controlled trial — one of the largest comparative effectiveness studies in diabetes. The weight change data are from a randomized trial, but the outcome associations are observational within that framework. The large sample size (4,980) and 5-year follow-up provide strong, high-quality evidence.

When this study was published

Published in 2025, this analysis draws from the GRADE trial which enrolled patients from 2013-2017. The findings are directly relevant to current diabetes treatment decisions and support the growing preference for GLP-1 agonists in clinical guidelines.

The bigger picture

The GRADE trial has been one of the most influential diabetes studies of the decade, and this weight analysis adds to its impact. The data provide objective, comparative evidence supporting guidelines that now recommend GLP-1 agonists as preferred second-line therapy for type 2 diabetes. The finding that weight gain independently drives complications — not just blood sugar levels — represents a paradigm shift from glucose-centric to weight-centric diabetes management.

Questions still open

Would newer, more potent GLP-1 drugs like semaglutide or tirzepatide produce even larger weight loss benefits in this study population?
Is there a threshold of weight gain below which the cardiovascular and kidney risks are negligible?
Should weight change be a primary outcome in all future diabetes drug comparison trials?

Common questions

Does weight gain on diabetes medication really make outcomes worse?

Yes — this large trial of nearly 5,000 patients found that for every kilogram of weight gained, the risk of losing blood sugar control increased by 5%, and the risk of cardiovascular and kidney disease each increased by 3%. This was true regardless of which medication caused the weight gain, suggesting that weight management should be a central consideration when choosing diabetes drugs.

How much weight loss does liraglutide produce compared to other diabetes drugs?

In the GRADE trial, liraglutide users lost an average of 3.5 kg in the first year, compared to 1 kg loss with sitagliptin and slight weight gain with insulin glargine (+0.45 kg) and glimepiride (+0.89 kg). While 3.5 kg may seem modest, it contrasts sharply with weight gain on alternative drugs, and the study showed that even small amounts of weight gain predict worse long-term outcomes.

Read the original research

Weight Gain Was Associated With Worsening Glycemia and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes Independent of Diabetes Medication in the GRADE Randomized Controlled Trial.

Diabetes care, 48(6), 935-944

View on PubMed ↗Publisher’s paper ↗

Citation

Wexler, Deborah J; Garvey, W Timothy; Ghosh, Alokananda; Kazemi, Erin J; Krause-Steinrauf, Heidi; Ahmann, Andrew J; Brown-Friday, Janet; Casula, Sabina; Cherrington, Andrea L; Elasy, Tom A; Fortmann, Stephen P; Krakoff, Jonathan A; Mudaliar, Sunder; Tiktin, Margaret; Younes, Naji. (2025). Weight Gain Was Associated With Worsening Glycemia and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes Independent of Diabetes Medication in the GRADE Randomized Controlled Trial.. Diabetes care, 48(6), 935-944. https://doi.org/10.2337/dc24-2825