Modifiable cardiovascular risk factors include lifestyle-based factors (eg, smoking, exercise, diet) and pathologic conditions (eg, hypertension, diabetes, obesity, dyslipidemia, metabolic syndrome). When 2 or more of these risk factors occur simultaneously, as is often the case, they interact synergistically to increase cardiovascular disease (CVD) risk. The presence of multiple risk factors in asymptomatic, otherwise apparently healthy subjects increases cardiovascular risk by as much as it does in patients with symptomatic CVD. For example, in patients with no cardiovascular history, the 8-year risk for CVD is increased 4-fold in the presence of a single risk factor (hypercholesterolemia). The 1-year cardiovascular event rate in patients with multiple sites of symptomatic arterial disease is increased 5-fold compared with patients with risk factors only (P <.001 for trend). Consequently, it is now considered less important to differentiate between primary and secondary prevention, and more relevant to look at global cardiovascular risk to improve health outcomes. During the 2008 American Heart Association Scientific Sessions, experts convened to discuss refractory risk. They highlighted the multiplicative effect of multiple CVD risk factors and provided clinicians with helpful treatment strategies for patients with refractory risk factors.
The patient case we presented was that of a 57-year-old white woman referred for refractory hypertension. She was asymptomatic, except for daytime fatigue, somnolence, and the presence of diffuse muscle aches, particularly when trying to exercise. Her medical history was remarkable for longstanding hypertension, and she had been taking atenolol (Tenormin) 100 mg for 2 years, amlodipine (Norvasc) 5 mg, and lisinopril (Prinivil) 40 mg for 1 year. She also had a history of poorly controlled diabetes mellitus, which was managed with diet and a sulfonylurea, and dyslipidemia, which was managed with simvastatin (Zocor) 20 mg. There was no history of premature CVD in her family, but her mother and a maternal aunt had type 2 diabetes mellitus. The patient never smoked, reported an approximately 80-lb weight gain since high school, and rare leisure-time physical activity.
The physical examination was remarkable for a heart rate of 82 beats per minute, blood pressure of 158/88 mm Hg, respiratory rate of 16 breaths per minute, weight of 215 lb at a height of 5’ 7”, body mass index of 33 kg/m2, and a waist circumference of 38 inches. She was afebrile, and the remainder of her examination was within normal limits. The electrocardiogram showed normal sinus rhythm with normal axis and intervals. No left ventricular hypertrophy was identified. Fasting labs revealed a glucose of 124 mg/dL, glycosylated hemoglobin A1c (HgbA1c) of 8.5, total cholesterol of 227 mg/dL, triglycerides of 330 mg/dL, high-density lipoprotein (HDL) cholesterol of 35 mg/dL, low-density lipoprotein (LDL) cholesterol of 126 mg/dL, creatinine of 1.4 mg/dL, and glomerular filtration rate of 56 mL/min/1.73 m2.
Global CVD risk stratification approaches
The mainstay of any evaluation includes global CVD risk stratification, and this patient is no exception. Given her multiple risk factors, including age, hypertension, dyslipidemia, diabetes, obesity, and lack of physical activity, she is at high risk for morbidity and mortality from CVD.
One approach to assessing global cardiovascular risk in the clinic is the use of risk charts, such as those jointly issued recently by the European Society of Hypertension/European Society of Cardiology (2007), the World Health Organization/International Society of Hypertension, or the National Cholesterol Education Program. The methods these assessment tools use to calculate risk differ, and, most importantly, these charts appear to be hardly used in clinical practice. In a large European survey of primary care physicians, only 13% always used risk charts to assess a patient’s likelihood of developing CVD, with between 40% and 50% of physicians in different European countries never using them. Regardless of the method used to assess global CVD risk, the underlying premise is the same: multiple risk factors increase the risk for CVD in a multiplicative way.
The Framingham study showed that the presence of 5 risk factors increases risk 60-fold compared with the presence of just 1 risk factor. More recently, INTERHEART, a large international case-control study designed to assess the importance of risk factors for coronary heart disease in 52 countries worldwide, showed that 9 risk factors (abnormal serum lipid levels, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, insufficient intake of fruits and vegetables, consumption of too much alcohol, and lack of physical activity) accounted for 90% of the risk of myocardial infarction (MI). In the case of MI, the most important risk factors were smoking and abnormal lipid levels, which together accounted for about two thirds of the increased risk; smoking alone accounted for 36%.
Dr Byron Hoogwerf discussed glucose-lowering considerations in patients at high risk for CVD. Recent data have highlighted the importance of glucose lowering, but questioned just how low to go when it comes to glucose. Concerns regarding hypoglycemia remain paramount, and recent clinical trials, such as ACCORD (Action to Control Cardiovascular Risk in Diabetes), VADT (Veterans Affairs Diabetes Trial), and ADVANCE (Action on Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), have failed to demonstrate improvement in outcomes when HgbA1c levels below 7.0 mg/dL are aggressively targeted. Overall, when one considers whether an HgbA1c target below 7.0 mg/dL is warranted, Dr Hoogwerf asserts that the answer is probably “yes,” despite there being no assurance of reduced CVD risk. With respect to glucose-lowering agents, he emphasized using those that keep the risk for hypoglycemia and weight gain low. In view of the patient’s marginal elevation in creatinine, caution with agents such as metformin is warranted, and dose adjustment with gliptins is essential. Finally, caution regarding heart failure with thiazolidinedione and metformin are necessary.
Blood pressure evaluations and treatment
Given these data, the aggressive reduction of risk is essential to mitigating cardiovascular events. Dr George Bakris reviewed what evaluation measures and treatment steps are required for managing our patient’s blood pressure. Clearly, based on multiple clinical trials, the aggressive lowering of blood pressure in this woman is known to be associated with significant improvement in cardiovascular events, particularly stroke. She is already on a multidrug regimen, but not at optimal doses.
Resistant hypertension is defined as failure to achieve goal blood pressure when a patient adheres to the maximum tolerated doses of 3 antihypertensive drugs including a diuretic. Although the exact prevalence of resistant hypertension is currently unknown, indirect evidence from population studies and clinical trials suggests that it is a relatively common clinical problem. The prevalence of resistant hypertension is projected to increase, owing to the aging population and increasing trends in obesity, sleep apnea (as is likely the case in this individual), and chronic kidney disease. Management of resistant hypertension must begin with a careful evaluation of the patient to confirm the diagnosis and exclude factors associated with “pseudo-resistance,” such as improper blood pressure measurement technique, the white-coat effect, and poor patient adherence to lifestyle changes and/or antihypertensive medications. Education and reinforcement of lifestyle issues that affect blood pressure, such as sodium restriction, reduction of alcohol intake, and weight loss in obese individuals, are critical in treating resistant hypertension. Exclusion of preparations that contribute to true blood pressure treatment resistance, such as use of nonsteroidal anti-inflammatory agents, cold formulas, and certain herbs, is also important. Lastly, blood pressure control can be achieved only if an antihypertensive treatment regimen is used that focuses on the genesis of the hypertension. An example is volume overload, a common but unappreciated cause of treatment resistance. Use of the appropriate dose and type of diuretic provides a solution to overcome treatment resistance in this instance.
Beta blockers were used in our patient. These drugs can be effective antihypertensive agents in the diabetic population as part of a multidrug regimen. They also can be used in patients with diabetes and concomitant evidence of coronary artery disease, such as anginal symptoms, including anginal equivalents, or after MI. The effectiveness of beta blockers was demonstrated in the UKPDS (United Kingdom Prospective Diabetes Study Group), where atenolol was comparable with captopril in reducing CVD outcomes. Although these agents have been associated with adverse effects on glucose and lipid profiles and implicated in new-onset diabetes in obese patients, they are not absolutely contraindicated for use in diabetic patients. In fact, carvedilol, which has both alpha- and beta-receptor blocking properties, has been shown to induce vasodilatation and improve insulin sensitivity.
Thiazides have been shown to cause electrolyte imbalances, metabolic changes, and volume contraction. Nevertheless, the ALLHAT (Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial) study, which compared a thiazide (chlorthalidone) with a calcium channel blocker (amlodipine) or an angiotensin-converting enzyme (ACE) inhibitor (lisinopril), found that the thiazide was less expensive and superior to the ACE inhibitor or calcium channel blocker in lowering the incidence of CVD in hypertensive populations. Therefore, ALLHAT suggests that thiazides could be considered as a first-line therapy for many diabetic patients with hypertension, despite the fact that they may adversely affect insulin resistance and potassium balance in some individuals. Indeed, using a thiazide diuretic in the antihypertensive repertoire has consistently been shown to improve cardiovascular outcomes, even in those with diabetes. Treating volume expansion with thiazide diuretics can increase the activity of the renin-angiotensin-aldosterone system (RAAS); thus, combining a diuretic with an ACE inhibitor or an angiotensin receptor blocker can be an effective blood pressure-lowering combination.
It has been shown that nondihydropyridine (ND) calcium channel blockers, such as verapamil and diltiazem, decrease proteinuria in diabetics. While not to the degree of ACE inhibitors alone, ND calcium channel blockers used in combination with ACE inhibitors have been shown to have additive effects in reducing albuminuria. The Syst-Eur (Systolic Hypertension in Europe) trial with nitrendipine demonstrated that intensive antihypertensive therapy for older patients with type 2 diabetes and isolated systolic hypertension eliminated the additional risk for CVD events and stroke associated with diabetes. In the HOT (Hypertension Optimal Treatment) trial, there was a reduction in major CVD events with diastolic blood pressure control in patients with diabetes when felodipine was used as first-line therapy. These trials indicate that calcium channel blockers are not harmful or contraindicated in hypertensive patients with diabetes, and the combination of an ACE inhibitor and a calcium antagonist is effective for the management of hypertension in diabetic patients.
Therapy aimed at improving insulin sensitivity and RAAS blockade seems to offer survival benefits to diabetics with hypertension. Further work in identifying the mechanisms of hypertension, diabetes, and insulin resistance would shed more light on the missing link that connects these seemingly different disease processes.
Dr Evan Stein concluded the session with a review of what alternatives exist regarding the management of the patient’s dyslipidemia. A controversy in the lipid community is whether to increase the dose of a statin or add adjunctive therapy for further LDL cholesterol reduction. Proponents of increasing the statin dose indicate that keeping the regimen simple will improve adherence, be more cost-effective, and that adjunctive agents may not provide additional pleiotropic effects (eg, C-reactive protein reduction) comparable to higher statin doses. Conversely, others argue that doubling the statin dose may result in only a 6% further reduction in LDL cholesterol with increased side effect potential, whereas the addition of ezetimibe or a bile acid sequestrant (BAS) may result in an approximately 20% reduction in LDL cholesterol levels. In reality, each side of the controversy has valid points. While increasing the statin dose may be the simplest option in certain cases, statins do have dose-dependent side effects, particularly when titrated to the highest doses. For example, the incidence rates of myopathy and elevated transaminases increase 4- to 5-fold when titrating simvastatin or atorvastatin from 40 mg to 80 mg daily. In cases such as this, adding a second agent (ie, ezetimibe, colesevelam) with a different site of action will not only provide more LDL cholesterol reduction, but will also limit potential side effects.
The use of fixed-combination lipid-altering products (ie, ezetimibe/simvastatin and lovastatin/extended-release niacin) offers potential advantages, and, in certain cases, may be preferential to adding a separate second agent or titrating the statin. The attributes of these products compared with statin monotherapy include an overall improved effect on the lipid profile and the possibility of greater cost-effectiveness. These advantages may be especially true when targeting LDL cholesterol with the ezetimibe/simvastatin combination. There is less controversy surrounding additional agents for other types of dyslipidemia. Among patients with low HDL cholesterol levels, attaining the LDL cholesterol goal is the first priority followed by achieving the non-HDL cholesterol goal and maximizing therapeutic lifestyle changes. If HDL cholesterol still remains a concern, therapy with niacin or fibrates may then be considered. Although side effects can limit niacin use, when added to a statin, only moderate doses (1000 mg/day) are required to significantly raise HDL cholesterol (24%) while minimizing adverse events.
The potential for increased adverse events must be considered with the use of more aggressive lipid-altering therapies, including higher statin doses and combination therapy. The risk of additional serious adverse events appears to be extremely low when using agents with excellent safety profiles (ie, cholesterol absorption inhibitor, BAS) in combination with statins; however, cases of rhabdomyolysis with ezetimibe alone or in combination with other agents associated with muscle toxicity (eg, statins) have been reported. Additionally, fibrate monotherapy is associated with a risk for muscle toxicity similar to that of statin monotherapy. As a result, concerns regarding an increased incidence of adverse effects are valid and must be monitored appropriately when using statins in combination with other agents (ie, ezetimibe, fibrates, niacin).