update on cardiac risk factors

Educational Objectives

The goal of this program is to improve the management of hypertension in patients with high cardiovascular risk and of lipid control. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe and discuss new and current treatment strategies for hypertension.

2.   Recognize and treat resistant hypertension.

3.   Identify risk factors for metabolic syndrome.

4.   Describe the role of lipid abnormalities in diabetic macrovascular disease and premature cardiovascular mor­tality.

5.   Describe management of dyslipidemia in diabetics and others with metabolic syndrome.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Basile has received grant/research support from the National Heart, Lung and Blood Institute and Novartis; has acted as a consul­tant for Abbott Laboratories, Daiichi-Sankyo, GlaxoSmithKline, Novartis, and Takeda; and has served on the Speakers’ Bu­reaus for Abbott Laboratories, AstraZeneca, Daiichi-Sankyo, Forest Laboratories, GlaxoSmithKline, and Novartis. Dr. Tanenberg and the planning committee reported nothing to disclose.  In his lecture, Dr. Tanenberg presents information re­lated to the off-label or investigational use of a therapy, product, or device.

Acknowledgments

Dr. Basile spoke in Albuquerque, NM, at 2009 Primary Care Update: Improving Patient Care, presented October 31 to No­vember 2, 2009, by the Interstate Postgraduate Medical Association. Dr. Tanenberg spoke in Atlantic Beach, NC, at the 21st Annual Recent Developments in Internal Medicine, presented October 22-24, 2009, by the Brody School of Medicine of East Carolina University. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Hypertension

Jan Basile, MD, Professor of Medicine, Medical University of South Carolina, Charleston

Multiple medications: tolerated in most patients; improve outcome in hypertension; initial therapy not as important as amount of blood pressure (BP) reduction, because cardiovascular disease (CVD) reduction depends on BP level achieved; set BP goal for every patient

Reduction of major CV events: meta-analysis by Blood Pressure Treatment Trialists Collaboration  —  all drugs bet­ter than placebo; angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) appear better for reducing risk for stroke; ACEIs and thiazide diuretics (TDs) appear better for reducing risk for heart fail­ure (HF); no difference in risk for death; use renin-angiotensin system (RAS) blocker in patients with HF or at high risk for HF; use CCB in patients who have had stroke; difficult to show difference in outcome based on single drug, since most trials involve multiple drugs

BP goals: BP <140/<90 mm Hg evidence-based; current recommendations (not based on evidence)  —  BP <130/<80 mm Hg if Framingham risk score ³10%; BP <130/<80 mm Hg in patients with ischemic heart disease; BP <120/<80 mm Hg in patients with HF and reduced ejection fraction

Multiple drugs as initial therapy: most patients require ³2 antihypertensive agents as fixed-dose combination; best fixed-dose combination remains unclear; 2 monotherapies cost-effective and effective; diabetics require more drugs (3-4) to achieve systolic BP <130 mm Hg; Joint National Committee (JNC) 7 guidelines  —  start with fixed-dose combination by 20/10 rule (not evidence–based); if BP 20/10 mm Hg over BP <140/<90 mm Hg, start with 2 drugs; if 20/10 rule not met, start with combination of drugs, including TD

Fixed-dose combinations: all eliminate initial salt and water retention seen in hypertension or concomitant patho­physiologic response to other therapy; all block sympathetic nervous system or RAS; include b-blocker (BB)-TD, ACEI-TD, ARB-TD, direct renin inhibitor (DRI)-TD, ACEI-CCB, and ARB-CCB; given as 2 drugs or fixed-dose combination; ARB up-titration vs ARB-TD  —  choice of up-titration of ARB or addition of TD; adding TD always results in more BP reduction; hydrochlorothiazide (HCTZ) and telmisartan reduce systolic BP 6 mm Hg more than doubling dose of telmisartan; speaker prefers to start with highest ARB dose due to placebo-like tolerability

Food and Drug Administration (FDA) language: after fixed-dose combinations proven safe in stage 2 hyperten­sion, FDA allowed indication of losartan  -HCTZ for severe hypertension unlikely to be controlled on monotherapy; ARB-TD, CCB-ARB, and DRI-HCTZ indicated as initial therapy in patients likely to need multiple drugs

BP control algorithm: for most patients, use RAS blocker and TD (eg, chlorthalidone, HCTZ) or CCB (eg, amlodip­ine); if not at goal, add chlorthalidone or amlodipine as third drug; amlodipine  —  generic now available; efficacious in BP reduction; complements RAS blockers; chlorthalidone  —  more evidence-based than HCTZ; spironolactone  —  add as fourth drug to decrease risk for reactive hyperaldosteronism; modify lifestyle

Simplified Treatment Intervention to Control Hypertension (STITCH) study: compared 2 strategies to reach BP <140/<90 mm Hg in 6 mo;  first strategy started with 1 drug, up-titrated dose, and added more drugs; second strat­egy started with ACEI-TD or ARB-TD, up-titrated dose, and added more drugs; subjects  —  similar baseline BPs; few had diabetes; few on fixed-dose combinations at entry; no BPs <140/<90 mm Hg at entry; results  —  65% BP control in patients on fixed-dose combination; patients felt better (by questionnaire) and physicians pleased be­cause BP control achieved in 6 mo

Avoiding Cardiovascular events in COMbination Therapy in Patients LIving with Systolic Hypertension (AC­COMPLISH) trial: design  —  ³11,000 high-CV-risk hypertensives; age ³55 yr; 60% diabetic; 23% postmyocardial infarction (MI); 36% postcoronary revascularization; 13% poststroke; double-blind comparison of benazepril-HCTZ to benazepril-amlodipine; 2 primary morbidity and mortality end points; no free period without drugs; on day of randomization, subjects crossed over and HCTZ and amlodipine doses increased; 1 mo later, free add-on of other antihypertensive drugs (could not add ACEI, ARB, CCB, or TD); results  —  for either combination, rate of BP reduction to <140/<90 mm Hg in normal patients or to <130/<80 mm Hg in diabetics 73%; ACEI-CCB arm achieved more reduction of composite CV morbidity and mortality and of morbidity and mortality in patients with­out CV revascularization; no difference in death; in diabetics, perhaps amlodipine better partner than HCTZ; amlo­dipine very good in patients with underlying CVD and reduces risk for stroke; chlorthalidone  —  1.5 to 2 times more potent than HCTZ; lasts for >24 hr, while HCTZ lasts for »17 hr; HCTZ effective in BP reduction, but no ev­idence for outcome improvement; HCTZ effective against placebo for outcome, not against comparators

ACEI and ARB combination treatment: ACEI and ARB equivalent in patients with underlying CVD or in high-risk diabetics; fewer side effects with ARB; using ACEI and ARB together in same population does not improve outcome over either alone, and associated with more side effects

RAS blockade: ONTARGET trial  —  studied 25,000 high-risk patients; evaluated telmisartan, ramipril, and telmisar­tan and ramipril together; found little additive BP reduction with ARB and ACEI together; 2.4/1.4 mm Hg total BP improvement in combination group over ramipril alone; add either TD or CCB to ACEI or ARB to achieve maxi­mum BP reduction; less cough and angioedema in telmisartan group; more hypotension and renal dysfunction in combination group; in renal disease group, proteinuria reduced at expense of reduction in glomerular filtration rate (GFR); ACEI and ARB together not beneficial over either agent alone

b-blockers: heterogeneous; atenolol  —  most widely prescribed b-blocker; should be used twice daily; poor perfor­mance, compared to other antihypertensive agents; effect less than optimal; increased risk for stroke, compared to placebo; in patients with left ventricular hypertrophy (LVH), losartan-based therapy more effective than atenolol-based therapy; newer b-blockers (eg, carvedilol, nebivolol) differ from traditional b-blockers

Resistant hypertension: defined as high BP uncontrolled on ³3 drugs, including TD; exclude pseudoresistance; identify and reverse adverse lifestyles (eg, obesity, physical inactivity, drinking, bad diet); minimize use of nonste­roidal anti-inflammatory drugs; screen for secondary causes, including  —  obstructive sleep apnea; primary aldoste­ronism; chronic kidney disease; renal artery stenosis; pheochromocytoma; Cushing's disease; coarctation of the aorta; pharmacologic intervention  —  maximize TD treatment (eg, ³25 mg HCTZ, 25 mg chlorthalidone); aldoste­rone antagonist (eg, spironolactone, eplerenone); use agents with different mechanisms of action; if estimated GFR <40 mL/min, consider loop diuretic (eg, furosemide, torsemide); consider referral to specialist; in patients on spi­ronolactone, monitor potassium; replace HCTZ with same dose of chlorthalidone in uncontrolled or resistant pa­tients

Lipids: The Skinny On Fats, Diabetes, And Risk For Cardiovascular Disease  

  Robert J. Tanenberg, MD, Professor of Medicine, Division of Endocrinology, Brody School of Medicine, and Director, Diabetes and Obesity Center, East Carolina University, Greenville, NC

Risk factors in population: National Health and Nutrition Examination Survey (NHANES) data  —  17% have total cholesterol >240 mg/dL; 15% have BP >140/90 mm Hg; smoking prevalence 26%; diabetes and obesity increasing; Bogalusa Heart Study  —  at autopsy, coronary artery dissection found fatty streaks in coronary arteries of children 2 to 15 yr of age and coronary artery disease (CAD) in 50% of young adults 25 yr of age; CAD present in almost all transplanted donor hearts

Modifiable risk factors in diabetes: glucose levels; BP; lipids; insulin resistance through weight loss; smoking  —  risk for CVD mortality doubled in diabetic smoker; increased risk for kidney disease, retinopathy, and neuropathy; secondhand smoke  —  also increases CVD risk; if parent smokes 1 pack/day for 5 yr, equivalent of child smoking 102 packs

Diabetes and CVD: diabetes sixth leading cause of death in United States; CVD  —  causes 80% of diabetic mortality; CAD and peripheral vascular disease cause 75% of hospitalizations of diabetics; 50% of people newly diagnosed with type 2 diabetes already had complications, including CVD

Coronary heart disease (CHD) in women: in last 30 yr, 20% decrease in death from CHD in nondiabetic women, but 23% increase in diabetic women (who lose cardioprotective effect of being premenopausal); risk for recurrent MI in diabetic women 3 to 4 times greater than in nondiabetic women

Glycemic control and CVD: trial data mixed; 4 large trials, including United Kingdom Prospective Diabetes Study (UKPDS), found that improved glycemic control lowers risk for CVD mortality in diabetes; Action to Control Car­diovascular Risk in Diabetes (ACCORD) trial did not show this, but participants treated with rosiglitazone; Veter­ans Affairs Diabetes Trial (VADT)  —  found reduced CV mortality in newly diagnosed type 2 diabetics treated aggressively in first 15 yr; effect of glycemic control equivocal during years 15 to 20; glycemic control after 20 yr not shown to reduce CVD risk

Atherosclerosis: CAD does not result from progressive narrowing; first 40% of plaque deposits affect vessel endo­thelium, not lumen; plaque in vessel walls; the more fat in plaque the more unstable the vessel; statins work by re­ducing fat in vessel wall; arterial intima  —  exposed to high hydrostatic pressure; lacks lymphatics to clear excess plasma macromolecules, eg, low-density lipoprotein (LDL); contains 10 times more LDL than other connective tis­sue

Lipid measurement: standardized conditions  —  overnight fast; no alcohol consumption for 24 hr, because alcohol alters plasma triglycerides; direct LDL  —  more expensive; widely available; useful when triglycerides ³400 mg/dL (carrying more chylomicrons); calculation of non–high-density lipoprotein (HDL) cholesterol  —  total cholesterol minus HDL; measures non-HDL lipoproteins that contribute to CVD; fasting state not required; inexpensive

Causes of abnormal lipids: uncontrolled diabetes elevates LDL and triglycerides; if triglycerides ³400 mg/dL, cho­lesterol ³260 mg/dL, and hemoglobin (Hb) A_1c  ³12%, place patient on insulin; after blood glucose (BG) con­trolled, prescribe statin; lipemic syndrome  —  patients with triglycerides >1000 mg/dL may have eruptive xanthomata and “tomato soup” fundus; associated with acute pancreatitis, memory loss, mental confusion, and hepatosplenomegaly; type 2 diabetes as CAD equivalent  —  19% risk for second MI in 7 yr in nondiabetics with 1 MI; 20% risk for first MI in 7 yr in type 2 diabetic

Metabolic syndrome: defined as any 3 of following risk factors  —  waist circumference ³40” in men or ³35” in women (>36” in Asian men or >32” in Asian women); elevated cholesterol; low HDL; hypertension (BP ³130/³85 mm Hg); diabetes (fasting BG ³100 mg/dL); lipid abnormality; 87% of type 2 diabetics meet criteria; insulin resistance  —  can lead to type 2 diabetes, polycystic ovary disease, hepatic steatosis, abnormal lipids, hypertension, and hyperuricemia; skin markers for insulin resistance  —  acanthosis nigricans; skin tags in neck and axillae; meta­bolic syndrome predicts type 2 diabetes and CHD  —  CHD prevalence 9% in patients without diabetes or metabolic syndrome, 7.5% in patients with diabetes but no metabolic syndrome, 14% in patients with metabolic syndrome but no diabetes, 19% in patients with both diabetes and metabolic syndrome

Fat: visceral fat  —  found around intestine, liver, and kidney; present in metabolic syndrome; metabolically active part of endocrine system; high risk; contains macrophages that produce cytokines; ectopic fat  —  found in obese people with relative adipose tissue deficiency; deposits of fat in viscera, muscle (causing insulin resistance), liver (causing fatty liver, cirrhosis, and death), beta cells, and heart (cardiac steatosis); subcutaneous fat  —  formation stimulated by thiazolidinediones; improves fatty liver by providing site for fat; visceral obesity  —  associated with insulin resis­tance and high free fatty acids in plasma; leads to high hepatic triglyceride-rich very-low-density lipoprotein (VLDL), low HDL, more dense LDL, and increased CV risk; VLDL  —  forms buoyant LDL and small dense LDL; oxidized small dense LDL taken up by scavenger receptors on macrophages which transform it into foam cells and fatty streaks

Dyslipidemia in type 2 diabetes and metabolic syndrome: low HDL; non-HDL cholesterol; elevated triglycerides; high small dense LDL (more particles; endothelial complications more likely); decreased HDL increases CV risk; triglycerides increase as LDL levels off but particle number increases

Risk assessment: family history of CHD  —  first-degree male relative <55 yr of age; first-degree female relative <65 yr of age; evaluation  —  laboratory work-up; physical examination; exclude secondary causes of abnormal lipids (eg, hypothyroidism); evaluate for genetic causes, eg, familial hypercholesterolemia; follow National Cholesterol Education Program guidelines for determining when to treat; assessing risk  — CHD or equivalent; 10-yr risk using Framingham model; CHD risk equivalents  —  type 2 diabetes; peripheral arterial disease; carotid artery disease; an­eurysm; lipids  —  normal total cholesterol £150 mg/dL; optimal LDL <100 mg/dL; in patients with highest risk, goal LDL <70 mg/dL and non-HDL cholesterol <100 mg/dL; high HDL removes 1 risk factor

Treatment: statins  —  primary and secondary prevention of CHD; simvastatin reduced more risk in diabetics than in nondiabetics; study showed atorvastatin reduces risk for CVD events in patients with LDL <130 mg/dL, at high risk without any CHD events; treat all type 2 diabetics with statins, unless intolerant; statins not enough  —  »20% of type 2 diabetics given simvastatin had CV event in 5 yr; 97% of those given simvastatin and niacin event-free for 3 yr; treat high-risk patients with statins and niacin; in patients with triglycerides ³200 mg/dL, treat to achieve non-HDL cholesterol <130 mg/dL; in those with triglycerides ³200 mg/dL, treat to achieve LDL <70 mg/dL and non-HDL cholesterol <100 mg/dL

Classes of drugs: LDL reduction  —  statin best; niacin; colesevelam; ezetimibe; raising HDL  —  niacin (best); weight loss; fibrates; triglyceride reduction  —  low glycemic diet (best); weight loss; fish oil; fibrates; niacin; class comparison    — nicotinic acid best for lowering triglycerides and LDL and raising HDL; fibrates effective and well-tolerated

Suggested Reading

ADVANCE Collaborative Group et al: Intensive blood glucose control and vascular outcomes in patients with type 2 dia­betes. N Engl J Med 24:358, 2008; Baker WL et al: Systematic review: comparative effectiveness of angiotensin-convert­ing enzyme inhibitors or angiotensin II-receptor blockers for ischemic heart disease. Ann Intern Med 12:151, 2009; Calhoun DA et al: Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation 25:117, 2008; Chobanian AV et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 19:289, 2003; Davidson MH et al: Efficacy and tolerability of adding prescription omega-3 fatty acids 4g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, random­ized, double-blind, placebo-controlled study. Clin Ther 7:29; 2007; Feldman RD et al: A simplified approach to the treat­ment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension 4:53, 2009; Holman RR et al: Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med 15:359, 2008; Holman RR et al: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 15:359, 2008; Karas RH et al: Long-term safety and efficacy of a combination of niacin extended release simvastatin in patients with dyslipidemia: the OCEANS study. Am J Cardiovasc Drugs 2:8, 2008; Jamerson K et al: Benazepril plus amlodipine or hydrochlorothiazide for hyper­tension in high-risk patients. N Engl J Med 23:359, 2008; Levitzky YS et al: Impact of impaired fasting glucose on cardio­vascular disease: the Framingham Heart Study. J Am Coll Cardiol 3:51, 2008; Lindholm LH, Carlberg B, Samuelsson O: Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 366:9496, 2005; Nguyen NT et al: Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: find­ings from the National Health and Nutrition Examination Survey, 1999 to 2004. J Am Coll Surg 6:207, 2008; ONTARGET Investigators et al: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 15:358, 2008; Patel A et al: Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370:9590, 2007; Pol­dermans D et al: Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan com­pared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension. Clin Ther 2:29, 2007.