What the best evidence shows: impressive short-term results, but gaps remain
The most comprehensive long-term human evidence comes from a 2025 study of over 215,000 people taking GLP-1 receptor agonists (the core of dual and triple drugs) compared to over 1.2 million people on other diabetes medications [2]. This study found that GLP-1 use was linked to lower risks of 42 health outcomes including heart disease, dementia, and substance use disorders, but also higher risks of gastrointestinal problems, pancreatitis, and kidney stones [2]. This gives us a solid picture of what happens over several years of use, but it only covers the GLP-1 component, not the newer dual or triple combinations.
For the actual dual and triple drugs, the longest human data comes from phase 3 trials lasting 1-2 years. Tirzepatide (a dual GLP-1/GIP drug) produced up to 22.5% average weight loss in these trials [1], while retatrutide (a triple GLP-1/GIP/glucagon drug) showed even greater weight loss in early phase 3 data [1][5]. A 2025 network meta-analysis of randomized trials found retatrutide achieved the greatest weight reduction (about 8.6 kg more than standard therapy) and tirzepatide was best for blood sugar control (lowering HbA1c by nearly 2 percentage points) [5]. But the same analysis noted that study durations were short and sample sizes small, limiting confidence in long-term safety [5].
The safety concern that needs longer data: thyroid cancer risk
One specific long-term safety question is thyroid cancer risk. A 2022 study using French national health data found that people using GLP-1 drugs for 1-3 years had a 58% higher risk of all thyroid cancers and a 78% higher risk of medullary thyroid cancer compared to non-users [3]. This is a real signal that needs longer follow-up, especially since dual and triple drugs contain even more potent GLP-1 activity. The study included over 2,500 thyroid cancer cases, making it the largest analysis of this specific risk [3].
This doesn't mean the drugs are unsafe—the absolute risk is still low—but it does mean we need 5-10 year data to know whether this risk grows or stabilizes. The 2025 comprehensive study [2] didn't specifically report thyroid cancer, so we can't yet cross-check this finding in a different large population. This gap is exactly why experts say we need longer-term evidence before declaring these drugs fully proven for lifelong use [1][5].
What experts say about the evidence gap: promising but not yet proven long-term
Across all five papers, the consistent message is that dual and triple incretin drugs are 'promising' and 'attractive' options, but the evidence base is still building [1][4][5]. A 2024 review of the obesity drug pipeline notes that while these drugs approach the weight loss seen with bariatric surgery, the data comes from phase 3 trials that typically last 1-2 years [1]. A 2024 review of liver disease treatments similarly says these drugs are 'becoming' a treatment option, not that they are established [4].
The 2025 network meta-analysis is the most direct comparison of dual vs triple drugs, but it explicitly states that 'small sample sizes, short study durations, and reliance on indirect comparisons' limit certainty [5]. The authors call for direct head-to-head trials lasting several years to confirm the results [5]. So the honest answer is: we have strong short-term evidence for efficacy, moderate evidence for common side effects, but limited long-term human evidence for rare or delayed risks. That's typical for new drug classes, but it means patients and doctors should weigh the known benefits against the unknown long-term profile.
About These Sources
This answer is built on 5 peer-reviewed studies — published from 2022 to 2025, 4 from 2024 or later, 4 in Q1 journals, collectively cited 737 times — selected as the most relevant from 5 studies that passed quality screening, drawn from 42 papers retrieved from a database of over 500 million.
Sources used in this answer
What is the pipeline for future medications for obesity?
A 2024 review of obesity treatments reports that tirzepatide (dual GLP-1/GIP) achieved up to 22.5% weight loss in phase 3 trials, while retatrutide (triple agonist) and cagrisema (GLP-1/amylin) have progressed to phase 3 with early data suggesting even greater weight loss, but all data comes from trials lasting 1-2 years.
Mapping the effectiveness and risks of GLP-1 receptor agonists
A 2025 cohort study of over 215,000 GLP-1 users vs 1.2 million controls found reduced risks for 42 health outcomes (including heart disease and dementia) but increased risks for gastrointestinal disorders, pancreatitis, and kidney stones, providing the largest long-term safety atlas for GLP-1 drugs.
GLP-1 Receptor Agonists and the Risk of Thyroid Cancer
A 2022 nested case-control study using French national data (2,562 thyroid cancer cases) found that 1-3 years of GLP-1 use was associated with a 58% increased risk of all thyroid cancers and a 78% increased risk of medullary thyroid cancer.
Recent advances in incretin-based therapy for MASLD: from single to dual or triple incretin receptor agonists
A 2024 review of incretin-based therapies for liver disease (MASLD/MASH) states that dual and triple agonists are 'becoming' an attractive treatment option based on phase 2 trials showing histological improvements, but notes long-term efficacy data is still emerging.
Beyond GLP-1: efficacy and safety of dual and triple incretin agonists in personalized type 2 diabetes care—a systematic review and network meta-analysis
A 2025 network meta-analysis of randomized trials found retatrutide achieved the greatest weight reduction (8.6 kg more than standard therapy) and tirzepatide was best for lowering HbA1c (by nearly 2 percentage points), but noted small sample sizes and short study durations limit certainty.