Can tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist) be used for patients with a normal hemoglobin A1c (HbA1c) level, morbid obesity, and significant cardiovascular risk?

Can Tirzepatide Be Used in Patients with HbA1c 5.7%, Morbid Obesity, and High Cardiovascular Risk?

Yes, tirzepatide can and should be used in this patient with prediabetes (HbA1c 5.7%), morbid obesity, and significant cardiovascular risk, primarily as weight reduction therapy rather than for glycemic control. This recommendation is based on the 2024 DCRM multispecialty guidelines that explicitly support GLP-1 RA-based therapies (which includes the dual GIP/GLP-1 agonist tirzepatide) for weight reduction in patients with prediabetes and cardiovascular risk, independent of diabetes status. 1

Guideline-Based Rationale for Use

The 2024 DCRM guidelines establish a clear framework for patients with prediabetes and cardiovascular risk:

• All patients with prediabetes are at risk for chronic kidney disease, atherosclerotic cardiovascular disease, and heart failure. 1

• Weight reduction therapies should be initiated if obesity is present and ≥7% weight reduction is not achieved with lifestyle modifications alone. The guidelines specifically list "GLP-1 RA based" agents as the first-line pharmacologic option for weight reduction in this population. 1

• GLP-1 RA-based medications are recommended as part of cardiovascular disease prevention strategies in patients with prediabetes and cardiovascular risk, alongside lipid control and blood pressure management. 1

Why Tirzepatide Is Particularly Appropriate

Tirzepatide demonstrates unprecedented weight loss efficacy that exceeds traditional GLP-1 receptor agonists:

• In the SURMOUNT-1 trial of patients without diabetes but with obesity, tirzepatide 5-15 mg weekly resulted in 16.5-22.4% body weight reduction over 72 weeks—the greatest weight loss ever achieved with a single pharmacologic agent. 2

• In patients with type 2 diabetes, tirzepatide achieved 5.4-12.9 kg weight loss, with 20.7-68.4% of patients losing more than 10% of baseline body weight. 3, 2

• Tirzepatide demonstrated superior weight loss compared to semaglutide 1 mg in head-to-head trials. 3, 4

Cardiovascular Risk Reduction Considerations

While tirzepatide's cardiovascular outcomes trial (SURPASS-CVOT) is still ongoing, preliminary evidence supports cardiovascular safety and potential benefit:

• Meta-analysis of the SURPASS program showed MACE-4 events tended to be reduced over 2 years, with hazard ratios <1.0 versus pooled comparators and upper confidence interval bounds <1.3, fulfilling conventional cardiovascular safety definitions. 3

• Tirzepatide improves multiple cardiometabolic risk factors including blood pressure, visceral adiposity, triglycerides, liver fat, and albuminuria. 4, 2

• The 2024 ESC guidelines recommend GLP-1 RAs with proven cardiovascular benefit in patients with peripheral arterial disease and type 2 diabetes to reduce cardiovascular events, independent of baseline or target HbA1c. 1 While this guideline addresses established diabetes, the principle of cardiovascular risk reduction independent of glycemic status is relevant.

Practical Implementation Strategy

Initiation approach:

• Start tirzepatide at 2.5 mg weekly and titrate every 4 weeks (2.5 mg → 5 mg → 7.5 mg → 10 mg → 12.5 mg → 15 mg) based on tolerability and weight loss response. 5, 3

• No need to discontinue other medications since the patient doesn't have diabetes and presumably isn't on sulfonylureas or insulin. 1

• Educate regarding gastrointestinal side effects (nausea, vomiting, diarrhea, constipation), which are dose-dependent and typically improve with gradual titration. 3, 2

Monitoring parameters:

• Weight and waist circumference every 4-12 weeks to assess efficacy. 1

• Blood pressure and lipid profile as tirzepatide improves these cardiovascular risk factors. 4, 2

• HbA1c every 6-12 months to monitor for progression to diabetes (though tirzepatide will likely prevent this). 1

• Comprehensive metabolic panel including liver enzymes at baseline and periodically, as tirzepatide reduces liver fat and transaminases. 6, 7

Critical Pitfalls to Avoid

Do not wait for diabetes to develop before initiating therapy. The 2024 DCRM guidelines explicitly support early intervention in prediabetes with obesity and cardiovascular risk. 1

Do not combine tirzepatide with DPP-4 inhibitors (sitagliptin, saxagliptin, etc.) as they work through redundant incretin pathways. 8

Avoid in patients with:

• Active gallbladder disease or gastroparesis 1
• Recent heart failure decompensation 8
• Personal or family history of medullary thyroid carcinoma or MEN2 syndrome (standard GLP-1 RA contraindication)

Monitor for diabetic ketoacidosis symptoms (nausea, vomiting, abdominal pain) even though this patient doesn't have diabetes, as rare euglycemic DKA has been reported with GLP-1 RAs. 1

Expected Outcomes

Based on the SURMOUNT-1 trial in patients without diabetes:

• Expect 15-20% total body weight reduction with tirzepatide 10-15 mg over 12-18 months. 2

• Cardiovascular risk factor improvements including blood pressure reduction of 5-10 mmHg systolic, triglyceride reduction of 20-30%, and HDL increase. 4, 2

• Prevention of progression to type 2 diabetes, as 23-62% of patients in SURPASS trials achieved HbA1c <5.7% (normoglycemia). 3

The evidence strongly supports tirzepatide use in this clinical scenario, with the primary indication being obesity management and cardiovascular risk reduction rather than glycemic control, fully aligned with current multispecialty guideline recommendations. 1