What are the beneficial effects of Glucagon-like peptide-1 (GLP-1) therapy?

Beneficial Effects of GLP-1 Therapy

GLP-1 receptor agonists provide substantial cardiovascular mortality reduction, weight loss, and glycemic control with the lowest risk of hypoglycemia among glucose-lowering medications, making them a preferred therapeutic option for patients with type 2 diabetes, particularly those with established cardiovascular disease or obesity. 1

Cardiovascular Benefits

GLP-1 receptor agonists demonstrate proven mortality and morbidity reduction in major cardiovascular outcomes trials:

• Liraglutide reduced cardiovascular death, non-fatal MI, or stroke by 13% (13% vs 14.9%, p=0.01) in the LEADER trial 2
• Semaglutide showed cardiovascular outcomes of 6.6% vs 8.9% (RR 0.74,95% CI 0.58-0.95) in SUSTAIN 6 2
• In non-diabetic patients with cardiovascular disease and BMI >27, semaglutide 2.4 mg weekly reduced cardiovascular events to 6.5% vs 8.2% (p=0.001) in the SELECT trial 2
• The 2024 ESC Guidelines recommend GLP-1 receptor agonists with proven cardiovascular benefit for all patients with type 2 diabetes and chronic coronary syndromes (Class I, Level A evidence) 2

The cardiovascular protection extends beyond glucose control through multiple anti-inflammatory mechanisms, including reduction of systemic inflammation, decreased platelet aggregation, anti-atherosclerotic properties, and suppression of inflammatory cytokines 2

Weight Loss and Metabolic Effects

GLP-1 therapy produces clinically meaningful weight reduction that rivals bariatric surgery outcomes:

• GLP-1 agonists result in mean weight reduction compared with usual care, while insulin and sulfonylureas cause weight gain 1
• Tirzepatide (dual GIP/GLP-1 agonist) achieved mean weight loss of 15% at 72 weeks in non-diabetic obese patients, with reductions up to 20.9% at the 15 mg dose 3
• Weight loss ranges from 6.1-17.4% body weight reduction depending on the specific agent and dose, with liraglutide 3.0 mg daily or semaglutide 2.4 mg weekly providing maximal effects 4
• This degree of weight loss was previously only achievable with bariatric surgery 3

Glycemic Control

GLP-1 receptor agonists provide potent glucose-lowering effects through multiple mechanisms:

• The greatest reductions in A1C level occur with specific GLP-1 RAs (particularly semaglutide) and tirzepatide, comparable to or exceeding insulin efficacy 1
• Glucose-dependent insulin secretion enhancement occurs only when blood glucose is elevated, with insulin secretion subsiding as glucose approaches euglycemia 5
• Glucagon suppression occurs in a glucose-dependent manner, preventing hypoglycemia risk 5
• Delayed gastric emptying reduces the rate at which postprandial glucose appears in circulation 5, 6

Hypoglycemia Risk Reduction

GLP-1 agonists consistently reduce severe hypoglycemia compared with either usual care or other medication classes such as sulfonylureas and insulin 1

• The glucose-dependent mechanism of action means GLP-1 agonists do not independently cause hypoglycemia 1
• Hypoglycemia incidence is low but increases when combined with insulin secretagogues or insulin, requiring dose reduction of these agents 1, 7

Anti-Inflammatory Effects

GLP-1 receptor agonists provide systemic anti-inflammatory benefits beyond metabolic effects:

• Reduction of epicardial adipose tissue thickness by 36% at 6 months with liraglutide, associated with decreased inflammation and improved cardiac outcomes 2
• Improved endothelial function through anti-inflammatory mechanisms in arterial walls 2
• Reduction of hepatic steatosis and inflammation in NAFLD/NASH, with the LEAN trial demonstrating more frequent resolution of NASH and less fibrosis progression with liraglutide 2
• The European Association for the Study of the Liver recommends GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide) as preferred pharmacological options for treating MASLD/MASH without cirrhosis (F0-F3) 2

Renal Protection

• GLP-1 receptor agonists reduce serious adverse events compared with usual care 1
• Studies demonstrate positive impact on kidney outcomes in patients with type 2 diabetes compared to placebo 8

Blood Pressure and Lipid Benefits

GLP-1 therapy improves multiple cardiovascular risk factors:

• Systolic blood pressure reduction of 4.13 mm Hg and diastolic blood pressure reduction of 1.39 mm Hg 9
• Significant improvements in lipid profiles including reduced triglycerides (SMD -0.99 mg/dL), total cholesterol (SMD -0.73 mg/dL), VLDL (SMD -1.11 mg/dL), and LDL (SMD -0.27 mg/dL) 9
• Increased HDL levels (SMD 0.11 mg/dL) 9

Important Clinical Considerations

Start at low doses and titrate slowly to minimize gastrointestinal side effects while achieving therapeutic benefit, with expectations of 4-6 months for meaningful clinical improvement 4

• Gastrointestinal adverse events (nausea, vomiting, diarrhea, abdominal pain, constipation) are the most common side effects, occurring in ≥5% of patients, but abate over time with continued treatment 10, 7
• Use with caution in patients with history of pancreatitis, though acute pancreatitis remains rare 2, 4
• Avoid if recent heart failure decompensation has occurred 2
• Contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 10
• Discontinue in women at least 2 months before planned pregnancy due to long washout period 10
• Never share pens between patients even if needle is changed 10