What is the best treatment approach for a patient with high cholesterol and type 2 diabetes, considering the use of Repatha (evolocumab) and Mounjaro (tirzepatide)?

Combining Repatha and Mounjaro for High Cholesterol and Type 2 Diabetes

For patients with type 2 diabetes and high cholesterol, initiate Mounjaro (tirzepatide) immediately for its dual benefits on glycemic control and cardiovascular risk factors, while adding Repatha (evolocumab) only if LDL-C remains ≥70 mg/dL on maximally tolerated statin therapy. 1

Prioritize Diabetes Management with Mounjaro First

Mounjaro should be your first-line agent after metformin in patients with type 2 diabetes and cardiovascular risk factors, as it provides superior glycemic control (HbA1c reduction of 1.87-2.59%) and substantial weight loss (6.2-12.9 kg), along with favorable effects on blood pressure, visceral adiposity, and triglycerides. 2, 3

• The 2018 ACC Expert Consensus Decision Pathway explicitly recommends GLP-1 receptor agonists (which includes the dual GIP/GLP-1 agonist tirzepatide) for patients with type 2 diabetes and established ASCVD to reduce cardiovascular events 1
• Tirzepatide demonstrates cardiovascular safety with no increase in major adverse cardiovascular events (MACE) in clinical trials 3
• The drug significantly reduces triglycerides and increases HDL cholesterol, addressing the atherogenic dyslipidemia common in diabetes 3

Statin Therapy Remains the Foundation

Before considering Repatha, ensure the patient is on high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily) to achieve at least a 50% LDL-C reduction. 1

• For patients with diabetes aged 40-75 years without ASCVD, use moderate-intensity statin therapy at minimum 1
• For patients with diabetes and established ASCVD, high-intensity statin therapy is mandatory 1
• Statins provide proven cardiovascular mortality benefit and should never be discontinued 1

When to Add Repatha: The Sequential Approach

Add Repatha 140 mg every 2 weeks or 420 mg monthly only after the patient has been on maximally tolerated statin therapy and LDL-C remains ≥70 mg/dL, particularly if the patient meets "very high-risk" criteria with established ASCVD. 1

Very High-Risk Criteria Requiring PCSK9 Inhibitor Consideration:

• Multiple major ASCVD events (recent acute coronary syndrome, history of MI, ischemic stroke, symptomatic peripheral arterial disease) 1
• One major ASCVD event plus multiple high-risk conditions (age ≥65 years, heterozygous familial hypercholesterolemia, prior coronary bypass surgery or PCI, diabetes, hypertension, chronic kidney disease, current smoking, persistently elevated LDL-C ≥100 mg/dL despite maximal statin therapy) 1

Expected Outcomes with Repatha:

• Evolocumab reduces LDL-C by 55-74% when added to statin therapy 4, 5
• In the FOURIER trial, evolocumab reduced LDL-C from a median of 92 to 30 mg/dL 1
• Evolocumab effectively reduces non-HDL-C by 39-66%, ApoB by 42-57%, and Lp(a) by 35-54% in patients with diabetes 5
• The drug enables 75-80% of patients to achieve both LDL-C <1.4 mmol/L (~54 mg/dL) and ≥50% LDL-C reduction 5

Consider Ezetimibe Before Repatha Due to Cost

If LDL-C remains elevated on high-intensity statin therapy, add ezetimibe 10 mg daily first, as it provides additional 13-20% LDL-C reduction at substantially lower cost than PCSK9 inhibitors. 1

• The 2022 ADA guidelines explicitly state that "the lower cost of ezetimibe may be preferred by many patients" compared to PCSK9 inhibitors 1
• Ezetimibe added to moderate-intensity statin therapy provides additional cardiovascular benefit in patients with recent acute coronary syndrome 1
• Reserve Repatha for patients who cannot achieve LDL-C goals with statin plus ezetimibe, or who have contraindications to ezetimibe 1

Treatment Algorithm for Combined Therapy

Step 1: Optimize Diabetes Management

• Start Mounjaro 2.5 mg weekly, titrate to 5 mg after 4 weeks, then to 10 mg or 15 mg based on glycemic response and tolerability 2
• Target HbA1c <7% for most patients 1
• Monitor for gastrointestinal adverse effects (nausea, vomiting, diarrhea), which are the most common side effects 3

Step 2: Maximize Statin Therapy

• Initiate or intensify to high-intensity statin (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) 1
• Reassess lipid panel 4-12 weeks after statin initiation or dose change 1
• Target LDL-C <100 mg/dL for high-risk patients, <70 mg/dL for very high-risk patients 1

Step 3: Add Ezetimibe if Needed

• If LDL-C remains ≥70 mg/dL on maximally tolerated statin, add ezetimibe 10 mg daily 1
• Reassess lipid panel 4-12 weeks after adding ezetimibe 1

Step 4: Add Repatha Only if Still Not at Goal

• If LDL-C remains ≥70 mg/dL on statin plus ezetimibe, and patient meets very high-risk criteria, add Repatha 140 mg subcutaneously every 2 weeks or 420 mg monthly 1, 4
• Both dosing regimens provide similar LDL-C reductions 4
• Reassess lipid panel 4-12 weeks after initiating Repatha 1

Critical Safety Considerations

Mounjaro is contraindicated in patients with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. 2

Repatha has an excellent safety profile with no increased risk of new-onset diabetes, muscle symptoms, or liver enzyme elevations compared to placebo. 1, 4

• Monitor for injection site reactions with both medications 4, 2
• Adjust Mounjaro dose if hypoglycemia occurs when used with insulin or sulfonylureas 2
• No dose adjustment needed for Repatha based on renal or hepatic function 4

Common Pitfalls to Avoid

Do not add Repatha before maximizing statin therapy and considering ezetimibe—this violates guideline-directed therapy and wastes healthcare resources. 1

Do not discontinue statins when adding Repatha—statins provide proven mortality benefit beyond LDL-C lowering and must be continued. 1

Do not delay Mounjaro initiation while attempting lifestyle modifications alone in patients with HbA1c >7%—pharmacologic therapy should begin immediately alongside lifestyle changes. 1, 2

Do not use Mounjaro as monotherapy without metformin unless metformin is contraindicated or not tolerated—metformin remains first-line therapy for type 2 diabetes. 1

Monitoring Strategy

• Check HbA1c every 3 months until target achieved, then every 6 months 1
• Assess lipid panel 4-12 weeks after any medication change, then annually once at goal 1
• Monitor weight, blood pressure, and cardiovascular symptoms at each visit 2, 3
• Calculate non-HDL-C (total cholesterol minus HDL-C) with target <130 mg/dL 1