What are the current indications for the use of tirzepatide (dual GIP and GLP-1 receptor agonist) in adults with type 2 diabetes, particularly those with a history of cardiovascular disease or multiple cardiovascular risk factors?

Current Indications for Tirzepatide

Tirzepatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, with particular value for patients requiring substantial HbA1c reduction and weight loss, those with metabolic dysfunction-associated steatotic liver disease (MASLD), and those with established cardiovascular disease or multiple cardiovascular risk factors. 1, 2

Primary FDA-Approved Indication

• Glycemic control in type 2 diabetes: Tirzepatide is approved as adjunctive therapy to diet and exercise for improving glycemic control in adults with type 2 diabetes mellitus 2, 3
• The drug achieves marked HbA1c reductions of 1.87% to 3.02% across clinical trials 3, 4

Preferred Patient Populations Based on Guidelines

First-Line Consideration After Metformin

• The American Diabetes Association recommends considering tirzepatide as a first-line treatment for patients with newly diagnosed type 2 diabetes requiring medication beyond metformin, especially those with obesity or overweight 1
• The American College of Physicians recommends adding either an SGLT-2 inhibitor or GLP-1 agonist (including tirzepatide) to metformin and lifestyle modifications in adults with inadequate glycemic control (strong recommendation; high-certainty evidence) 1

Cardiovascular Disease Context

• In patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) or multiple cardiovascular risk factors, GLP-1 receptor agonists with demonstrated cardiovascular benefit are recommended to reduce major adverse cardiovascular events 5
• Tirzepatide showed no increased risk of major adverse cardiovascular events in pooled analyses (HR 0.80,95% CI 0.57-1.11 for MACE-4) 1, 6
• The 2025 ADA Standards recommend that combined therapy with an SGLT2 inhibitor and a GLP-1 RA may be considered for additive reduction of cardiovascular and kidney events in patients with established ASCVD or multiple risk factors 5

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

• Tirzepatide is preferred for glycemic management in patients with MASLD or high risk for liver fibrosis due to its benefits in reducing hepatic steatosis 1
• The American Diabetes Association recommends dual GIP/GLP-1 receptor agonists for patients with type 2 diabetes, MASLD, and overweight/obesity 1

Chronic Kidney Disease

• In patients with eGFR <30 mL/min/1.73 m², GLP-1 receptor agonists (including tirzepatide) are preferred over SGLT-2 inhibitors for glycemic management due to lower hypoglycemia risk and cardiovascular event reduction 1
• Emerging evidence suggests kidney protection through albuminuria reduction and eGFR preservation 7

Weight Management Indication

• Tirzepatide achieved unprecedented weight loss of 15-22.4% in adults with obesity or overweight without diabetes over 72 weeks, representing the most substantial pharmacologic weight reduction documented outside of bariatric surgery 7
• Mean weight reduction of 8.47 kg compared to usual care in diabetic populations, with up to 67% of participants achieving ≥10% weight reduction 1

Clinical Scenarios Where Tirzepatide is Preferred

Over Insulin Therapy

• Tirzepatide is preferred over insulin in adults with type 2 diabetes without evidence of insulin deficiency, as it provides greater glycemic effectiveness and beneficial effects on weight and hypoglycemia risk 1

Substantial Glycemic Reduction Needed

• Consider tirzepatide when target glycemic control is not achieved with current therapy, especially for patients requiring substantial HbA1c reduction 1
• Superior to dulaglutide 0.75 mg and semaglutide 1 mg in head-to-head trials 1, 2

Hypoglycemia Risk Minimization

• Tirzepatide minimizes hypoglycemia risk with low rates of severe hypoglycemia when used as monotherapy or with metformin 1
• When combined with SGLT2 inhibitors compared to sulfonylureas, reduces severe hypoglycemia by 90% (RR 0.10) 1

Important Prescribing Considerations

Medication Adjustments

• When adding tirzepatide to insulin therapy, reduce insulin dose to minimize hypoglycemia risk 1
• Reassess the need for and/or dose of sulfonylureas, meglitinides, and insulin when initiating tirzepatide 1
• Do not use DPP-4 inhibitors concurrently with tirzepatide due to lack of additional glucose lowering 1

Contraindications and Exclusions

• Do not use tirzepatide in pregnant adults 1
• Monitor for signs of insulin overbasalization when combined with insulin: basal dose exceeding 0.5 units/kg/day, significant glucose differentials, hypoglycemia, and high glycemic variability 1

Safety Profile

• Generally well tolerated with a safety profile consistent with GLP-1 receptor agonists 2, 3
• Most common adverse events are gastrointestinal (nausea, diarrhea, decreased appetite, vomiting), typically mild to moderate in severity 1, 2
• Serious adverse events occurred less frequently with tirzepatide compared to insulin (RR 0.79) 1
• Delayed gastric emptying is a class effect that may persist with chronic use 1

Emerging Indications Under Investigation

• Heart failure management, particularly heart failure with preserved ejection fraction 3, 8
• Nonalcoholic steatohepatitis (NASH) 7, 3
• Chronic weight management in obesity without diabetes 7, 4