Treating the Common Dyslipidemia in Patients with Type 2 Diabetes: Insights from FIELD on the Effects of Fenofibrate on CVD Risk
Current Indications for Statin and Fibrate Therapy
The evidence of cardiovascular protection afforded by statins has recently extended beyond patients with hypercholesterolemia.With the publication of several trials,1-7 bold extrapolations of the power of statin therapy in cardiovascular prevention have been offered:
- Statins equally reduce risk in subjects with or without hypercholesterolemia
- Statins may be the first choice in patients with diabetes; and
- The guideline goal for LDL-cholesterol may need to be lowered to 70mg/dL. Thus, it seems that statin therapy may become necessary in high-risk individuals, even in the absence of dyslipidemia and possibly even when LDL-cholesterol levels are <100mg/dL. However, it should be emphasized that the optional goal of LDL-cholesterol levels <70mg/dL applies only to individuals who are very high-risk (i.e. established CVD plus multiple major risk factors), as there are potential side effects of using high statin doses to reduce LDL-cholesterol to very low levels.8
Similar momentum has been building for fibrates. These agents were originally indicated for patients with severely high triglyceride levels. However, the benefit of fibrates has recently been extended to treat the atherogenic dyslipidemia that afflicts most patients with type 2 diabetes, which is characterized by high levels of triglycerides, LDL particles that are small and dense, and low levels of HDL-cholesterol.9-11 The FIELD study, discussed in detail below, provides important data regarding the potential for fenofibrate to reduce cardiovascular risk in patients with type 2 diabetes both with and without dyslipidemia.
Treatment of Atherogenic Dyslipidemia to Reduce Cardiovascular Risk
The current guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)10 and the American Diabetes Association (ADA)12 highlight the importance of LDL-cholesterol reduction in high risk patients, but at the same time encourage physicians to position all patients with type 2 diabetes and insulin resistance in the high cardiovascular risk category. Because patients with type 2 diabetes and insulin resistance are commonly affected by the atherogenic dyslipidemia, characterized by high triglycerides and low HDL-cholesterol, one could argue that the optimal lipid intervention in these patients should be one targeting these abnormalities. Triglyceride and HDL-cholesterol levels have been shown to predict coronary event rates independently from LDL-cholesterol levels in populations from Europe and the US.13-15 The knowledge that the ratio of total cholesterol to HDL-cholesterol is the most sensitive index of cardiovascular disease progression highlights the important contribution of atherogenic dyslipidemia to cardiovascular risk, given that this ratio is mostly determined by abnormalities of triglyceride metabolism.
- Heart Protection Study Collaborative Group, “MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial”, Lancet (2002);360: pp. 7–22
- Sever P S, Dahlof B, Poulter N R et al.,“Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial”, Lancet (2003);361: pp. 1,149–1,158.
- Colhoun H M, Betteridge D J, Durrington P N et al.,“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);364: pp. 685–696.
- Rader D J, Davidson M H, Caplan R J, Pears J S,“Lipid and apolipoprotein ratios: association with coronary artery disease and effects of rosuvastatin compared with atorvastatin, pravastatin, and simvastatin”, Am J Cardiol (2003);91: pp. 20C-23C; discussion 23C–24C.
- LaRosa J C, Grundy S M,Waters D D et al.,“Intensive lipid lowering with atorvastatin in patients with stable coronary disease”, N Engl J Med (2005);352: pp. 1,425–1,435.
- Pedersen T R, Faergeman O, Kastelein J J et al.,“High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial”, JAMA (2005);294: pp. 2,437–2,445.
- de Lemos J A, Blazing M A,Wiviott S D et al., “Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial”, JAMA (2004);292: pp. 1,307–1,316.
- Grundy S M, Cleeman J I, Merz C N et al.,“Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines”, Circulation (2004);110: pp. 227-239.
- Haffner S M, “Management of dyslipidemia in adults with diabetes”, Diabetes Care (2003);26 (suppl. 1): pp. S83–S86.
- Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report”, Circulation (2002);106: pp. 3,143–3,421.
- Fazio S, Linton M F, “The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy”, Current Atherosclerosis Report, (2004);6: pp. 148–157.
- American Diabetes Association. Standards of medical care in diabetes – 2006”, Diabetes Care (2006);29 (suppl. 1): pp. S4-S42.
- Austin M A, Hokanson J E, Edwards K L, “Hypertriglyceridemia as a cardiovascular risk factor”, Am J Cardiol (1998);81: pp. 7B–12B.
- Castelli W P, “Cholesterol and lipids in the risk of coronary artery disease – the Framingham Heart Study”, Can J Cardiol (1988);4 (suppl. A): pp. 5A–10A.
- Gordon T, Castelli W P, Hjortland M C, Kannel W B, Dawber T R, “High density lipoprotein as a protective factor against coronary heart disease.The Framingham Study”, Am J Med (1977);62: pp. 707–714.
- Scandinavian Simvastatin Survival Study Group,“Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study (4S)”, Lancet (1994);344: pp. 1,383–1,389.
- Sacks F M, Pfeffer M A, Moye L A et al.,“The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators”, N Engl J Med (1996);335: pp. 1,001–1,009.
- Keech A, Colquhoun D, Best J et al., “Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial”, Diabetes Care (2003);26: pp. 2,713–2,721.
- Manninen V,Tenkanen L, Koskinen P et al.,“Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment”, Circulation (1992);85: pp. 37–45.
- Koskinen P, Manttari M, Manninen V et al., “Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study”, Diabetes Care (1992);15: pp. 820–825.
- Rubins H B, Robins S J, Collins D et al., “Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group”, N Engl J Med (1999);341: pp. 410–418.
- Rubins H B, Robins S J, Collins D et al.,“Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT)”, Arch Intern Med (2002);162: pp. 2,597–2,604.
- Field Study Investigators,“The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [ISRCTN64783481]”, Cardiovasc Diabetol (2004);3: p. 9.
- Keech A, Simes R J, Barter P et al., “Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial”, Lancet (2005);366: pp. 1,849–1,861.
- Jones P H, Davidson M H,“Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin”, Am J Cardiol (2005);95(1): pp. 120–122.
- Davidson M H, “Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions”, Expert Opin Drug Saf (2006);5: pp. 145–156.