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ROLE OF DIABETES AS COMORBIDITY IN CARDIOVASCULAR DISEASE
OVERVIEW
The future of our health care system is in jeopardy because of the increasing prevalence of obesity and type
2 diabetes mellitus. The current National Health and Nutrition Examination Survey (NHANES), which was conducted from 1999-2002, estimated that 9.3% of adults have diabetes and 26% have an impaired fasting glucose
level (Cowie, 2006). Thus, 73.3 million adults in the United States have diabetes or are at risk for the development of diabetes. The prevalence of diagnosed diabetes is higher among African Americans (11%) and Hispanic persons (10.4%) than white persons (5.2%). As the incidence and prevalence of diabetes increase, the progression to morbidity from commonly associated conditions such as hypertension and dyslipidemia will also escalate.
Diabetes mellitus is a recognized risk factor for cardiovascular and
end-stage renal disease. Approximately 65% of patients with diabetes
mellitus die from cardiovascular disease (Thom, 2006). Cardiovascular
mortality among adults with diabetes is 2-4 times higher compared to
that of adults without diabetes. African Americans are
disproportionately affected; they have a 27% higher death rate than
white persons. The presence of diabetes among women doubles the
age-adjusted prevalence of major cardiovascular disease. Compared to
that of patients without diabetes, the relative risk for a first
myocardial infarction is 1.5-4.5 times higher among women with diabetes
and 1.5-2 times higher among men with diabetes. Similarly, the relative
risk of a first stroke is 2-6.5 times higher among women with diabetes
and 1.5-2 times higher among men with diabetes. The presence of diabetes
raises the risk of a stroke between 1.8 and about 6 times. Compared to the incidence of stroke in nondiabetic individuals, ischemic strokes in patients with diabetes are more likely to occur in younger patients and in African Americans who have hypertension, myocardial infarction, and elevated cholesterol levels. Diabetes is the most potent risk factor for the development of heart failure among women with coronary heart disease, especially in women with an elevated body mass index or depressed creatinine clearance. Diabetes and cigarette smoking are robust risk factors for the development of peripheral arterial disease.
Diabetes is the leading cause of end-stage renal disease in the United States, and cardiovascular disease is the leading cause of death among patients with chronic kidney disease. Microalbuminuria is an early marker for the development of end-stage renal disease in persons with diabetes. Furthermore, microalbuminuria is associated with a greater risk of cardiovascular mortality, stroke, coronary heart disease events, and an increased severity of coronary artery disease.
In the United Kingdom Prospective Diabetes Study, the traditional risk factors associated with coronary artery disease are increased levels of low-density lipoprotein (LDL) cholesterol,
decreased levels of high-density lipoprotein (HDL) cholesterol, increased
triglyceride levels, increased glycosylated hemoglobin A1C (HbA1C) concentration,
increased systolic blood pressure, increased fasting plasma glucose concentration, and a history of smoking (Turner, 1998). The question that may arise is whether modifying these risk factors alters cardiovascular events.
LIPID STUDIES
The atherogenic dyslipidemia of diabetes is characterized by an increase in triglyceride levels, low HDL levels, and small dense LDL particles. Thus, one might predict that treatment with fibrates to lower triglyceride levels and raise HDL levels would reduce cardiovascular events. The Fenofibrate Intervention and Event Lowering in Diabetics (FIELD) study was designed to assess cardiovascular events in 9795 patients aged 50-70 years who had type
2 diabetes, a total cholesterol level of 116-251 mg/dL, and a ratio of total cholesterol to HDL cholesterol greater than 4 or plasma triglyceride levels of 89-443 mg/dL (Keech, 2005). The trial was a randomized double-blind study comparing 200 mg of micronized fenofibrate to placebo. Enrollment began in 1998. The primary end point was the first occurrence of either a nonfatal myocardial infarction or coronary heart disease death. The median follow-up was 5 years. A 19% increase was seen in coronary heart disease mortality (P = .22), as was a 24% reduction in nonfatal myocardial infarction (P = .01). Total mortality was increased by 11% (P = .18), but coronary revascularizations were reduced by 11% (P = .003). Over the course of the trial, 17% of the placebo group and 8% of the fenofibrate group used other lipid-lowering drugs. Thus, the mixed results of this trial could be due to concomitant statin therapy.
The Heart Protection Study randomly assigned 5963 patients with diabetes, aged 40-80 years, to simvastatin 40 mg or matching placebo (Collins, 2003). To be eligible for randomization, study participants needed a nonfasting plasma cholesterol level of 135 mg/dL or higher and coronary disease, occlusive disease in noncoronary arteries, or treated hypertension. The mean duration of follow-up was 4.8 years. All-cause mortality was reduced by 15% (P = .02), and vascular deaths were reduced by 21% (P = .006). Furthermore, the number of strokes was significantly (22%) lower. The beneficial effect was seen regardless of baseline
HbA1C level or obesity. The profound benefits of this study caused the American Diabetes Association (ADA) to recommend a 30% reduction of LDL cholesterol levels with statins, regardless of baseline value, for
patients with diabetes who are older than 40 years.
HYPERTENSION
The Losartan Intervention For Endpoint (LIFE) reduction hypertension study assessed 1195 diabetic hypertensive patients
aged 55-80 years with left ventricular hypertrophy (Lindholm, 2002). The
goal of the randomized double-blind trial was to use losartan or
atenolol, in combination with other antihypertensive drugs, to reduce
blood pressure to less than 140/90 mm Hg. Compared to atenolol, losartan reduced total mortality 40% (P = .001) and reduced cardiovascular mortality 38% (P = .019) after a mean follow-up of 4.7 years. Although the Heart Outcomes Prevention Evaluation (HOPE) study was not designed as a hypertension study, the 3577 patients with diabetes (≥55 y) treated with 10 mg of ramipril experienced a 37% (P = .0001) reduction in cardiovascular death, a 33% (P = .0074) reduction in stroke, a 22% (P = .01) reduction in myocardial infarction, and a 24% (P = .004) reduction in total mortality (HOPE Study Investigators, 2000).
GLUCOSE CONTROL
A prospective double-blind study randomized 5238 patients with type 2 diabetes (aged 35-75 y) to pioglitazone 15-45 mg or placebo if the
HbA1C concentration exceeded 6.5% (Dormandy, 2005). The average time for follow-up was 34.5 months. Although the primary composite end point was not achieved, the secondary composite end point of total mortality, nonfatal myocardial infarction, and stroke was reduced by 16% (P = .027).
GUIDELINESES
The ADA favors achieving the following lipid goals, in sequence:
- LDL level less than 100 mg/dL
- HDL level more than 40 mg/dL in men and more than 50 mg/dL in women
- Triglyceride level less than 150 mg/dL
The National Cholesterol Expert Panel and the American Heart Association/American College of Cardiology suggested an LDL level lower than 70 mg/dL as an optional or reasonable target. To achieve the composite goals requires a combination of hypolipidemic drugs. The ADA, the National Kidney Foundation, and the Joint National Committee Report are concordant with a blood pressure goal of less than 130/80 mm Hg. To achieve this target in diabetic patients with or without chronic renal insufficiency, multiple antihypertensive drugs are needed. Hypoglycemic therapies should achieve a
HbA1C concentration less than 7%. Aspirin is appropriate therapy for diabetic adults with or without vascular disease. Pharmacological treatment is concomitant with lifestyle interventions.
REFERENCESES
Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
Lancet. 2003;361:2005-16.
Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the US population: National Health And Nutrition Examination Survey 1999-2002.
Diabetes Care. 2006;29:1263-8.
Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
Lancet. 2005;366:1279-89.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy.
Lancet. 2000;355:253-9.
Keech A, Simes RJ, 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;366:1849-61.
Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Lancet. 2002;359:1004-10.
Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics--2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
Circulation. 2006;113:e85-151.
Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23).
BMJ. 1998;316:823-8.
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