Primary Prevention- Diabetes

Introduction

The 2018 multi-society (including American College of Cardiology and American Heart Association (ACC/AHA)) cholesterol guideline considers patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) aged 40-75 and LDL-C of 70-189 mg/dL a statin benefit group. Based extensive randomized trial evidence, both the multi-society cholesterol guideline and the American Diabetes Association (ADA) standards of care recommend that patients in this group should receive statin therapy to reduce their near-term and high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). Primary prevention of ASCVD is of even greater importance in individuals with diabetes since they experience greater morbidity and worse survival following an ASCVD event.

Clinical Highlight I

• All primary prevention patients with diabetes aged 40-75 years should receive at least a moderate-intensity statin.
• Consider a high-intensity intensity statin if aged 40-75 years and multiple ASCVD risk factors are present.
• Primary prevention diabetes age <40 or >75 years, or LDL-C <70 mg/dL with risk factors— may consider moderate-intensity statin.
• Nonstatins: Ezetimibe is first choice addition to achieve a ≥50% LDL-C reduction, and may be considered if 10-year ASCVD risk is ≥20%. Most patients with diabetes have fairly low LDL-C levels at baseline, and on high-intensity statins most reach LDL-C levels <70 mg/dL.
• Other nonstatins may be considered for selected patients with diabetes
• Encourage healthy lifestyle habits and risk factor control.

Initiating Statin Therapy: Primary Prevention Diabetes Diabetes: Age 40-75 Years

Both the 2018 multi-society cholesterol guideline and the 2023 American Diabetes Association (ADA) standards of care recommend statin therapy for all persons with diabetes 40-75 years of age (Tables 12-1 and 12-2). Several cardiovascular disease (CV) outcomes trials have evaluated moderate-intensity statin therapy in primary prevention populations with diabetes aged 40-74 years. A similar reduction in the relative risk of CVD occurred as in populations without diabetes, and in those with CVD (CTT) (Figure 12-1). Some patients with type 1 diabetes (T1D) were included in the statin trials, and they had a similar magnitude of risk reduction as those with type 2 diabetes (T2D). Similar relative reductions occurred across other subgroups as well, including those with chronic kidney disease (CKD).

The 2018 multi-society cholesterol guideline therefore made a strong recommendation (Class of Recommendation [COR] I) for moderate-intensity statin therapy for those with diabetes aged 40-75 years with LDL-C 70-189 mg/dL. No primary prevention trials of high-intensity statin therapy have been performed in individuals with diabetes. However, the evidence that the high-intensity statin rosuvastatin 20 mg reduced CV events in the lower risk population without diabetes in JUPITER supports the 2018 multi-society cholesterol guideline recommendation to consider (COR IIa) a high-intensity statin in patients with multiple ASCVD risk factors, whether general or specific to diabetes (Table 12-3). This recommendation is concordant with the primary prevention recommendation for those without diabetes and LDL-C <190 mg/dL. 

The 2023 ADA guideline recommends a moderate-intensity statin for those aged 40-75 years without a risk factor and a high-intensity statin for those with one or more risk factors, including family history of premature ASCVD, dyslipidemia, CKD/albuminuria, high blood pressure, smoking and overweight/obesity.

Comparing the two sets of recommendations, consider a 40-year old patient with diabetes, LDL-C of 100 mg/dL, who is a normotensive nonsmoker, has an estimated 10-year ASCVD risk of <2% using the Pooled Cohort Equations, and a lifetime risk of 39% (ACC/AHA risk estimator app). While high-intensity statins do not appear to worsen diabetes control and reduce ASCVD risk about 20% more than moderate-intensity statins, a moderate-intensity statin would also be appropriate for this patient since the incremental benefit from a high-intensity statin may be low for this patient. A clinician-patient discussion eliciting patient preferences may be helpful when the choice of statin intensity is less clear.

The maximally tolerated statin intensity should be used if a patient cannot tolerate a moderate- or high-intensity statin.

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Diabetes: Age < 40 Years

Although no CV outcomes trials have included individuals <40 years of age, patients with long-standing type 1 or 2 diabetes are likely to benefit from moderate-intensity statin therapy. Although the 10-year ASCVD risk may be low, their lifetime risk of ASCVD is ≥39% (ACC/AHA risk estimator app), even in the absence of other risk factors. The 2018 multi-society cholesterol guideline states that statin therapy may be reasonable (COR IIb) in adults 20-39 years of age with diabetes and at least one diabetes-specific ASCVD risk factor (Table 12-3).

Diabetes: Age > 75 Years

Few individuals >75 years were included in the primary prevention statin trials that included individuals with diabetes. Individuals >75 years with diabetes are at high 10-year ASCVD risk even in the absence of other risk factors (>30% using the ACC/AHA risk estimator app), and the relative reductions in CV risk from moderate-intensity statin therapy in persons >65 years appear to be similar to those <65 years . The 2018 multi-society guideline states that while it may be reasonable (COR IIb) to initiate statin therapy in persons with diabetes >75 years, comorbidities that may influence safety, quality of life considerations and patient preferences should all be considered before initiating a statin for primary prevention. The guideline considers it reasonable (COR IIa) to continue statin therapy in patients >75 years who were already on a statin before.

In patients >75 years with diabetes, it would be reasonable to start with a moderate-intensity statin and increase to a high-intensity statin if tolerated. In the IDEAL secondary prevention trial, those >70 years had somewhat higher rates of atorvastatin 80 mg discontinuation than younger patients, suggesting adverse effects may have occurred more frequently in the older group. On the other hand, the incremental 20% relative risk reduction in a person >75 years would result in at least a 6% reduction in absolute ASCVD risk for a number-needed-to-treat (NNT) to prevent one CV event of 16 or less.

A clinician-patient discussion eliciting patient preference may be helpful when deciding to initiate or intensify statin therapy in patients >75 years of age.

Nonstatin Therapy

Although at higher ASCVD risk, patients with diabetes tend to have lower LDL-C and higher non–HDL-C than otherwise comparable patients without diabetes. It therefore seems reasonable to maximize therapy to achieve a ≥50% LDL-C reduction in those at higher risk (e.g., for whom a high-intensity statin is considered) than to titrate to a specific LDL-C goal of <100 or <70 mg/dL (which could result in using a less than evidence-based statin intensity).

If a <50% reduction in LDL-C occurs on the maximally tolerated intensity of statin therapy, higher risk patients with diabetes may benefit from the addition of a nonstatin to achieve a ≥50% reduction in LDL-C:

• Ezetimibe is the preferred choice for additional LDL-C lowering, based on CV risk reduction benefit in IMPROVE-IT. The 2018 multi-society guideline considers the addition of ezetimibe to maximally tolerated statin therapy potentially reasonable (COR IIb). The 2022 ACC Expert Consensus Decision Pathway agrees with this recommendation, stating that ezetimibe may be considered in patients with diabetes whose 10-year ASCVD risk is ≥20% and whose LDL-C reduction on maximally tolerated statin therapy is <50% and LDL-C level is ≥70 mg/dL.
• Fenofibrate is an alternative in patients with LDL-C <35 mg/dL and triglycerides >250 mg/dL on a moderate-intensity statin (ACCORD), although it is not clear whether this is an appropriate strategy in women with diabetes.
• Colesevelam has been shown to modestly reduce LDL-C and HbA1C in patients with diabetes but has not been evaluated in CV outcomes trials. Bile acid sequestrants can worsen hypertriglyceridemia and are contraindicated when triglycerides are ≥300 mg/dL (and should probably be avoided when triglycerides are ≥250 mg/dL).
• The PCSK9 inhibitors alirocumab, evolocumab and inclisiran have similar LDL-C lowering efficacy of 50-65% in patients with diabetes. Alirocumab and evolocumab also demonstrated a CV outcome benefit in the ODYSSEY OUTCOMES and FOURIER trials, in which 27-37% of patients had diabetes. The FDA at the time of this writing has not approved a PCSK9 inhibitor for use in primary prevention patients unless they have primary hypercholesterolemia.

Cardiovascular Outcomes Trials

The IMPROVE-IT, FOURIER and to a lesser extent ACCORD trials have demonstrated an incremental ASCVD event risk reduction benefit of a nonstatin added to background statin therapy in patients with diabetes (seeNonstatins for further discussion).

ACCORD

In patients with well-controlled diabetes with and without CVD, fenofibrate did not further reduce CV events when added to background moderate-intensity statin therapy in the ACCORD trial overall. Mean achieved LDL-C was approximately 80 mg/dL at year 3 in both treatment groups. HDL-C increased by about 1 mg/dL at year 1 and triglycerides were reduced by about 17% at year 3 in the fenofibrate group. A trend toward a CV event reduction benefit was observed in the subgroup of patients with HDL-C <34 mg/dL and triglycerides ≥204 mg/dL (P = .06). However, there was evidence of significant harm in women (P = .01).

IMPROVE-IT

IMPROVE-IT evaluated very high-risk patients with a recent acute coronary syndrome (within 10 days) and an additional high-risk characteristic such as diabetes (n = 18,144). Baseline LDL-C was 50-125 mg/dL if not on lipid-lowering therapy and 50-100 mg/dL if on lipid-lowering therapy. Patients were treated with moderate-intensity statin therapy (simvastatin 40-80 mg) with or without ezetimibe 10 mg daily. LDL-C was reduced to a mean of 54 mg/dL in the ezetimibe-statin group compared to 70 mg in the statin-placebo group. A 10% reduction in ASCVD events (nonfatal MI, stroke and CVD death) and a 6% reduction in major cardiovascular events (additionally including revascularization and unstable angina requiring rehospitalization) occurred over the average 6 years of follow-up. Ezetimibe appears to reduce major CV events across prespecified subgroups, with evidence of particular benefit in those with diabetes or age ≥75 years.

FOURIER

The anti-PCSK9 monoclonal antibody (mAb) evolocumab significantly reduced the incidence of the primary endpoint (a composite of CV death, myocardial infarction [MI], stroke, hospitalization for unstable angina, or coronary revascularization) in patients with ASCVD in the FOURIER trial. In a pre-specified analysis, evolocumab treatment also significantly reduced the incidence of the primary endpoint in patients with diabetes (hazard ratio [HR] 0.83, 95% CI 0.75-0.93; P = 0.0008) and without diabetes (HR 0.87, 95% CI 0.79-0.96; P = .0052).

ODYSSEY OUTCOMES

The anti-PCSK9 mAb alirocumab demonstrated CV outcome efficacy in the ODYSSEY OUTCOMES trial, significantly reducing the incidence of the primary endpoint (a composite of death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) in patients with ASCVD. When stratified by baseline glycemic status in a pre-specified analysis, alirocumab treatment reduced the incidence of the primary endpoint in patients with diabetes (HR 0.84, 95% CI 0.74-0.97), prediabetes (HR 0.86, 95% CI 0.74-1.00) and normoglycemia (HR 0.85, 95% CI 0.70-1.03).

Healthy Lifestyle Habits and Risk Factor Control

All patients should be counseled to adhere to healthy lifestyle habits and control weight (see Lifestyle and Blood Pressure). Participants in randomized trials were counseled on healthy lifestyle habits, and the ASCVD risk reduction benefit of statins added to this. Healthy lifestyle habits are crucial for persons with diabetes to maintain or improve diabetes control (Look AHEAD).

ASCVD risk factors should be treated aggressively in individuals with diabetes, because they markedly increase ASCVD risk. Smoking is particularly detrimental when combined with diabetes. Aggressively work with patients to encourage immediate smoking cessation. Randomized trials have shown that aggressive control of risk factors improves outcomes in patients with diabetes.

The 2023 ADA guideline states that a daily aspirin dose of 75-162 mg may be considered as a primary ASCVD prevention strategy in patients with diabetes, following a comprehensive risk-benefit discussion with the patient, including discussion around increased bleeding risk. However, the use of aspirin for primary prevention is still controversial.