From the Guidelines
The long-term effects of GLP-1 receptor agonists include sustained weight loss, improved glycemic control, and potential cardiovascular benefits, with a reduction in major adverse cardiovascular events by 12-26%, as demonstrated in the LEADER trial with liraglutide 1. The LEADER trial, a randomized, double-blind trial, assessed the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, versus placebo on cardiovascular outcomes in 9,340 patients with type 2 diabetes at high risk for cardiovascular disease or with cardiovascular disease, and showed that the primary composite outcome (MI, stroke, or cardiovascular death) occurred in fewer participants in the treatment group (13.0%) when compared with the placebo group (14.9%) (HR 0.87; 95% CI 0.78–0.97; P < 0.001 for noninferiority; P = 0.01 for superiority) 1. Some key points to consider when using GLP-1 receptor agonists include:
- Sustained weight loss, with some patients experiencing up to 20% weight loss with newer agents like tirzepatide
- Improved glycemic control
- Potential cardiovascular benefits, including a reduction in major adverse cardiovascular events by 12-26%
- Common side effects that may persist, such as gastrointestinal symptoms like nausea and constipation
- Rare but serious long-term concerns, including increased risk of medullary thyroid cancer (based on animal studies), pancreatitis, and gallbladder disease
- The importance of resistance training during treatment to mitigate muscle loss accompanying weight reduction
- The need for indefinite treatment to maintain benefits, making these medications a long-term commitment rather than a short-term intervention More recent studies, such as the SUSTAIN-6 trial with semaglutide 1, have also demonstrated the potential cardiovascular benefits of GLP-1 receptor agonists, with a reduction in the primary outcome of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.74; 95% CI 0.58–0.95; P < 0.001). Overall, the use of GLP-1 receptor agonists, such as liraglutide and semaglutide, can provide sustained weight loss, improved glycemic control, and potential cardiovascular benefits, making them a valuable treatment option for patients with type 2 diabetes.
From the FDA Drug Label
In a 2-year trial involving patients with type 2 diabetes and high cardiovascular risk, more events of diabetic retinopathy complications occurred in patients treated with OZEMPIC (3.0%) compared to placebo (1.8%). The effect of long-term glycemic control with semaglutide on diabetic retinopathy complications has not been studied. There have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis, in patients treated with GLP-1 receptor agonists. Cholelithiasis and cholecystitis In adult glycemic control trials of liraglutide injection, the incidence of cholelithiasis was 0.3% in both liraglutide injection-treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both liraglutide injection-treated and placebo-treated patients. The following additional adverse reactions have been reported during post-approval use of liraglutide injection: Gastrointestinal: Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus Renal and urinary: Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis
The long-term effects of GLP-1 receptor agonists include:
- Increased risk of diabetic retinopathy complications 2
- Acute kidney injury and worsening of chronic renal failure 2
- Cholelithiasis and cholecystitis 3
- Acute pancreatitis, hemorrhagic and necrotizing pancreatitis 3 It is essential to monitor patients carefully for signs and symptoms of these potential long-term effects when using GLP-1 receptor agonists.
From the Research
Long-term Effects of GLP-1 Receptor Agonists
The long-term effects of Glucagon-Like Peptide-1 (GLP-1) receptor agonists have been studied in various research papers. Some of the key findings include:
- Reduction in cardiovascular risk factors, microvascular and macrovascular complications, and mortality in patients with type 2 diabetes 4
- Decrease in the rates of cardiovascular events and mortality among patients with type 2 diabetes 5, 6
- Improvement in glycemic control, weight loss, and reduced risk of hypoglycemia 7, 8
- Increased gastrointestinal events causing treatment discontinuation 4
Cardiovascular Benefits
The cardiovascular benefits of GLP-1 receptor agonists have been consistently shown in randomized controlled trials (RCTs) and real-world studies (RWS). Some of the key findings include:
- Reduction in major adverse cardiovascular events (MACE) such as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke 5, 4
- Decrease in the rates of cardiovascular events and mortality among patients with type 2 diabetes 6
- Confirmation of cardiovascular benefits in RWS, which provide highly informative information on treatment with GLP-1RAs 6
Comparison with Other Anti-Hyperglycemic Medications
GLP-1 receptor agonists have been compared with other anti-hyperglycemic medications in several studies. Some of the key findings include:
- Reduction in cardiovascular risk factors and increase in gastrointestinal events compared to placebo and other anti-hyperglycemic medications 4
- Better cardio-renal outcomes with GLP-1RAs than with DPP-4i, while initial findings from RWS described a weaker cardiovascular protection compared to SGLT-2i 6
Real-World Studies
Real-world studies (RWS) have provided new opportunities to complement the information obtained from RCTs. Some of the key findings include:
- Different clinical characteristics between subjects enrolled in RCTs versus those attending real-world clinics and receiving a GLP-1RA 6
- Overall consistency in subgroups of patients less represented in RCTs 6
- Identification of modifiable factors (eg, titration or adherence) that might guide physicians towards better GLP-1RAs use 6