Module 4: Cardiometabolic Risk in Diabetes

The American Diabetes Association (ADA) standards of care recommend that statin therapy be added to lifestyle Rx for all diabetic patients (no matter the level of LDL) who have CVD, are over age 40, and have one or more CVD risk factors (almost all do). For patients under age 40, the decision is based on CVD risk. Several clinical trials have demonstrated that statins have significant benefit for primary and secondary prevention of CVD and coronary artery disease (CAD) death in patients with diabetes.

1. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care.2006 Jun;29(6):1220-6.
2. Sever PS, Poulter NR, Dahlöf B, Wedel H, Collins R, Beevers G, Caulfield M, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT-LLA). Diabetes Care. 2005 May;28(5):1151-7.
3. Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care. 2006 Jul;29(7):1478-85.
4. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004 Aug 21-27;364(9435):685-96.

Hepatic toxicity is rare with statin use. First evaluate the patient for outer causes of elevated enzymes. Less than 1% of patients on statins have enzyme elevation. This elevation is most like due to fatty liver that is associated with diabetes, usually goes up and down dependent on how well the diabetes is controlled, and usually is mild and dose-dependent. In the TNT study, enzyme elevation for 10 mg of atorvastatin was 0.2% and for 80 mg was 1.2%. If the enzymes remain elevated, consider changing to another statin or reducing the dose. The National Lipid Association’s Statin Safety Task Force questions the need for routine evaluation of liver enzymes and has asked that regulatory agencies re-examine the requirement. The Task Force recommends direct bilirubin measurement because it is more indicative of liver damage than liver enzymes.

1. Hou R, Goldberg AC. Lowering low-density lipoprotein cholesterol: statins, ezetimibe, bile acid sequestrants, and combinations: comparative efficacy and safety. Endocrinol Metab Clin North Am. 2009 Mar;38(1):79-97. Review.
2. Cohen DE, Anania FA, Chalasani N; National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006 Apr 17;97(8A):77C-81C. Epub 2006 Feb 3.

The 2011 ADA Standards of Medical Care in Diabetes states the following: “In asymptomatic patients, routine screening for CAD is not recommended, as it does not improve outcomes as long as CVD risk factors are treated.” Intensive medical therapy has an increasing evidence base for providing equal outcomes to invasive revascularization. A recent trial demonstrated no clinical benefit to routine screening of asymptomatic patients with type 2 diabetes and normal EKGs. After a baseline EKG, no other tests can be recommended unless the clinical situation indicates a need.

1. BARI 2D Study Group, Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, Orchard TJ, Chaitman BR, Genuth SM, Goldberg SH, Hlatky MA, Jones TL, Molitch ME, Nesto RW, Sako EY, Sobel BE. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009 Jun 11;360(24):2503-15. Epub 2009 Jun 7.
2. Wackers FJ, Chyun DA, Young LH, Heller GV, Iskandrian AE, Davey JA, Barrett EJ, Taillefer R, Wittlin SD, Filipchuk N, Ratner RE, Inzucchi SE; Detection of Ischemia in Asymptomatic Diabetics (DIAD) Investigators. Resolution of asymptomatic myocardial ischemia in patients with type 2 diabetes in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study. Diabetes Care. 2007 Nov;30(11):2892-8. Epub 2007 Aug 6

The ACCORD Lipid study demonstrated that the addition of a fibrate to a statin in a high-risk group provided no additional benefit compared to the stain alone. But a subanalysis of those patients with high triglycerides and low HDL indicated a reduction in cardiovascular events. Fenofibrate (Tricor) was used in this study. Gemfibrozil (Lopid) is not recommended in combination with a statin. This combination is associated with a higher degree of rhabdomyolysis. After you have reached your LDL target with a statin, significant residual risk remains if the triglycerides remain high and HDL low. If this is the case, I would suggest you add fenofibrate or niacin (Niaspan) to further reduce the residual cardiovascular risk that remains, especially in a diabetic patient.

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus The ACCORD Study Group N Engl J Med. 2010;362:1563-1574

There are three types of niacin (nicotinic acid) available. Fast-acting or immediate-release niacin is an over-the-counter product. It is almost always associated with flushing, and this makes it difficult for patients to use. Sustained-release (SR) nicotinic acid, also known as "timed-release" nicotinic acid, is also an OTC product. It is associated with less flushing but has an increased risk of liver toxicity. Extended-release (ER) nicotinic acid (Niaspan) is released slowly into the body, has low incidence of flushing, and no associated liver toxicity reported. Several studies indicate decreased CV events when Niaspan is added to a statin.

Zhao XQ, Krasuski RA, Baer J, Whitney EJ, Neradilek B, Chait A, Marcovina S, Albers JJ, Brown BG. Effects of combination lipid therapy on coronary stenosis progression and clinical cardiovascular events in coronary disease patients with metabolic syndrome: a combined analysis of the Familial Atherosclerosis Treatment Study (FATS), the HDL-Atherosclerosis Treatment Study (HATS), and the Armed Forces Regression Study (AFREGS). Am J Cardiol. 2009 Dec 1;104(11):1457-64

Fish oil or omega-3 fatty acids have several positive effects. The key to choosing fish oil is the amount of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) you ingest. It takes 750 mg of the two ingredients to obtain any effect. Sudden death is decreased at doses of 750 mg daily, and doses of over 2500 mg are needed to reduce triglycerides. HDL levels do not change, and LDL may increase (with DHA, not EPA). If over-the-counter formulations are used, it is important to review the amount of EPA and DHA on the label. To be effective, the label should read the amount of each in the tablet. Some labels read 1000 mg of fish oil concentrate but the amount of EPA and DHA varies from 100 to 500 mg. It may take 2 to 6 tablets to reach the 750 mg dose. Lovaza is the only prescription product available. One gram of Lovaza contains 465 mg of EPA and 375 mg of DHA, so 4 tablets are needed for triglyceride reduction. Several good-tasting liquid products that contain high levels of EPA and DHA are available for online purchase. Some studies indicate that fish oil added to statins may provide added CV reduction.

1. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18;296(15):1885-99. Review. Erratum in: JAMA. 2007 Feb 14;297(6):590.
2. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007 Mar 31;369(9567):1090-8. Erratum in: Lancet. 2007 Jul 21;370(9583):220.

Statin therapy lowers plasma concentrations of CoQ, but there is no evidence this is of any clinical significance. Randomized studies do not indicate that it decreases muscle aches and pains associated with statin use. Muscle aches and pains are common in diabetes and the elderly population, so it is difficult to know if statins are to blame for the symptoms. Lowering the dose or changing statins may help. Obtain a CPK to be sure it is not 10 times greater than normal. Remember, CPK can be elevated from exercise and other causes.

Rosenson RS. Current overview of statin-induced myopathy. Am J Med. 2004 Mar 15;116(6):408-16. Review.

Elevated triglycerides are common in diabetes, especially type 2 diabetes. Most but not all diabetics will have elevations of triglycerides when their diabetes is not in good control. Triglycerides can be elevated from excess alcohol and sedentary lifestyle, genetic hyperlipidemia disorders, and hypothyroidism. Insulin resistance contributes to the elevation of triglycerides. One of the roles of insulin is to drive fatty acids into the fat cells for energy storage. With insulin-resistance, fatty acids increase, and this leads to increased triglycerides.

Oh RC, Lanier JB. Management of hypertriglyceridemia. Am Fam Physician. 2007 May 1;75(9):1365-71. Review.