Approaching Statin Therapy in Adults with and without Diabetes

Quick Takes

  • Modifying multiple cardiovascular risk factors is the best way to reduce cardiovascular risk in patients with diabetes.
  • Managing dyslipidemia is essential to reducing cardiovascular events.
  • We have limited data in how to approach statin initiation in elderly patients.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in patients with diabetes mellitus (DM).1 For patients with DM, morbidity and mortality from cardiovascular related conditions cost $37.3 billion per year, according to American Diabetes Association (ADA). More aggressive risk factor modifications for patients with DM have decreased ASCVD events.2

There has been a shift towards a more comprehensive approach of controlling multiple cardiovascular risk factors.3 The pooled cohort equation (PCE) risk estimator, which takes into account both total and HDL cholesterol (HDL-C), has been used to guide treatment of hyperlipidemia.

The PCE tends to overestimate ASCVD risk in patients <75 years of age who are well-educated and have a higher socioeconomic status (SES).4 However, the PCE is only validated for men and women 40 to 79 years of age and not for individuals ≥80 years. We do not have clear evidence and guidelines for older patients, especially those ≥75 years.

Clinicians often are unclear whether to start statin therapy in older patients as well as what intensity of statin to start.5 The 2018 AHA/ACC Cholesterol Guideline recommends starting moderate intensity statin in adults with diabetes by age 40. According to a prospective Veteran Affairs (VA) study in patients with DM, the current model tends to overestimate ASCVD risk in patients with diabetes compared to a novel VA-fitted model.6 Similarly, in a large contemporary "real world" population without DM, the PCE generally overestimated 5-year risk.7

Study Design
Raghavan et al. recently studied VA patients from 2002-2007 with diabetes who had at least one primary care encounter during the baseline period; this was defined as the date of first lipid measure following the primary care visit that included blood pressure measurement. Patients with baseline cardiovascular disease were excluded.

DM was defined as the use of outpatient diabetic medication during the baseline period. The primary outcome was the development of a first ASCVD event over 5 years. Secondary outcomes examined in analyses of the Risk Equations for Complications of Diabetes equations (RECODe) were acute myocardial infarction (MI) and acute ischemic stroke.

The study included 183,096 individuals with a mean follow-up interval of 4.6 years; 11,814 individuals experienced an ASCVD events within 5 years (6.5%). The mean age was 61 years, nearly all participants were men (97.6%), and 80.5% were White. The PCE over-predicted ASCVD risk across all deciles of risk, whereas the novel VA-fitted models over-predicted ASCVD risk in only the highest deciles of predicted risk.

It is not clear if the authors were able to fully account for the introduction of preventive pharmacotherapy during the follow-up. The concordance classification between PCE and the VA-derived models 2 and 3 was only about 30%, respectively. Model 2 represents the PCE with a coefficient fitted to the study population, and model 3 has the added variables: eGFR, HbA1c, and DM medications.

The VA-derived models rarely classified individuals at higher risk than the PCE. On the other hand, 65.6% (on model 2) or 60.9% (on model 3) of veterans with DM would meet a guideline indication for high-intensity statin therapy based on the PCE but not using VA-fitted models. The VA-derived model reclassified a substantial proportion of the study population from high risk (defined as 10-year ASCVD risk ≥20%) to low or intermediate, which could affect the prescribed intensity of statin therapy.6

A recent retrospective analysis by Orkaby and colleagues examined VA patients on statin therapy without a history of ASCVD who were older than 75; there was a decrease in all-cause mortality and cardiovascular death. They were less likely to sustain a nonfatal ASCVD event or undergo coronary revascularization.8 Statin treatment appeared to show greater benefit with vascular disease and some degree of cognitive impairment.9

Future directions
There are two ongoing clinical trials focusing on statin therapy in elderly patients. The Statin Therapy for Reducing Events in the Elderly (STAREE) is a randomized controlled trial comparing atorvastatin 40 mg daily versus placebo. It examines whether treatment with statin will prolong survival or disability free survival in healthy people >70 years of age. The primary outcome is a composite of death, development of death or development of disability or cardiovascular event.10

The Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE) is a multi-center randomized controlled study randomizing community dwelling older adults without cardiovascular disease or dementia to atorvastatin or placebo. The primary outcome is death, dementia, and persistent disability; secondary composite outcomes include mild cognitive impairment and cardiovascular events.

Although the above studies will give us helpful insight on the importance of initiation of statin in the elderly, they are not exclusive to individuals with DM. Further studies may be considered specifically with a focus on older patients with DM. Meanwhile, there is a need to implement existing knowledge in cardiovascular disease prevention to address all modifiable risk factors using a comprehensive ABCDEF approach.11


  1. Huang ES, Meigs JB, Singer DE. The effect of interventions to prevent cardiovascular disease in patients with type 2 diabetes mellitus. Am J Med 2001;111:633–42.
  2. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007;30:162–72.
  3. Norgaard CH, Mosslemi M, Lee CJY, Torp-Pedersen C, Wong ND. The importance and role of multiple risk factor control in type 2 diabetes. Curr Cardiol Rep 2019;21:35.
  4. DeFilippis AP, Young R, Carrubba CJ, et al. An analysis of calibration and discrimination among multiple cardiovascular risk scores in a modern multiethnic cohort. Ann Intern Med 2015;162:266-75.
  5. Mortensen MB, Falk E. Primary prevention with statins in the elderly. J Am Coll Cardiol 2018;71:85-94.
  6. Raghavan S, Ho YL, Vassy JL, et al. Optimizing atherosclerotic cardiovascular disease risk estimation for veterans with diabetes mellitus. Circ Cardiovasc Qual Outcomes 2020;Aug 31[Epub ahead of print].
  7. Rana JS, Tabada GH, Solomon MD, et al. Accuracy of the atherosclerotic cardiovascular risk equation in a large contemporary, multiethnic population. J Am Coll Cardiol 2016;67:2118-30.
  8. Orkaby AR, Driver JA, Ho Y-K, et al. Association of statin use with all-cause and cardiovascular mortality in US veterans 75 years and older. JAMA 2020;324:68-78.
  9. Nichols JS, Nelson AJ. Statins for primary prevention in the elderly: the importance of rigorous evidence. JAMA 2020;324:45-6.
  10. Gurwitz JH, Go AS, Fortmann SP. Statins for primary prevention in older adults: uncertainty and the need for more evidence. JAMA 2016;316:1971-2.
  11. Feldman DI, Dudum R, Alfaddagh A, et al. Summarizing 2019 in cardiovascular prevention using the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease's ABC's Approach. Am J Prev Cardiol 2020;Jun 6[Epub ahead of print].

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Prospective Studies, Cholesterol, HDL, Retrospective Studies, Risk Factors, Cardiovascular Diseases, Veterans, Hemoglobin A, Hyperlipidemias, Stroke, Independent Living, Outpatients, Follow-Up Studies, Blood Pressure

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