Volume 01, Issue 03
May 6, 2010
Beyond Metabolic Syndrome
Peter Sheehan, MD, President, Sheehan Health Management Consulting, LLC, New York, NY
Definition of risk
Although many clinicians have become familiar with the term “metabolic syndrome,” the definition does not adequately encapsulate the various factors that contribute to risk for cardiovascular disease (CVD). Therefore, the American Diabetes Association (ADA) promotes using the term “cardiometabolic risk.”
A person is considered to have the metabolic syndrome if he or she has ³3 of the following risk factors:
Overweight or obesity
• Glucose intolerance
• High level of triglycerides
• Low level of high-density lipoprotein (HDL) cholesterol
Additional cardiometabolic risk factors
• Family history
• Smoking status
• Physical inactivity
Gestational diabetes (GDM)
Women with histories of GDM are not only at increased risk of developing overt type 2 diabetes, but also are at increased risk of developing CVD. Furthermore, it appears that children of these women also have elevated risk of developing metabolic abnormalities (eg, central obesity; high levels of triglycerides) at a young age.
Risk factor management
Focus: smoking cessation; lipid control; blood pressure (BP) control, glycemic control; antiplatelet therapy; (see issues 01 and 02 for updated clinical practice guidelines).
Smoking cessation: A variety of pharmacologic agents are available (eg, varenicline; nicotine replacement therapy) and help improve quit rates.
LDL-cholesterol: Therapy — primarily statin therapy. Targets — low-density lipoprotein (LDL) cholesterol <100 mg/dL for individuals with ³2 cardiometabolic risk factors; LDL cholesterol <70 mg/dL for those with diabetes and established CVD.
Apolipoprotein B (Apo B): Measurement provides an indication of the number of atherogenic lipid particles, because it occurs in a one-to-one ratio with LDL and very-low density lipoprotein (VLDL) cholesterol. Targets — <80 mg/dL for patients with high cardiometabolic risk; <90 mg/dL for those at moderate risk. Implications — LDL particles are not uniform in size or density. For a given level of LDL cholesterol, a high density of particles (ie, small, dense particles) is associated with a high degree of atherogenicity, whereas a low density of particles (ie, large, “fluffy” particles) is associated with a low degree of atherogenicity.
Non–HDL-cholesterol: Total cholesterol minus HDL-cholesterol seems to be more closely correlated with risk for CVD than is LDL-cholesterol.
Prioritizing management approaches to reduce cardiometabolic risk
• Primary: Physical activity (eg, 30 min/day of walking) and dietary interventions are critical components in the management of cardiometabolic risk — especially in patients who are overweight or obese and have multiple risk factors. In patients with type 2 diabetes, weight loss may have a greater impact on cardiometabolic risk than does glycemic control.
• Secondary: BP control; lipid control; smoking cessation.
• Tertiary: Glycemic control (Although glycemic control is strongly correlated with microvascular complications, its impact on cardiometabolic risk is relatively small, compared to the risk conferred by hypertension, dyslipidemia, and smoking.)
Coming in June … Motivating and Empowering Patients in the Self-Management of Diabetes.
Race, Sex, and Cardiometabolic Risk
Robert Eckel, MD, Professor of Medicine and Charles A. Boettcher II Chair in Atherosclerosis, University of Colorado Health Sciences Center, Denver, CO
HDL-cholesterol: In premenopausal women, levels are generally higher than in men, contributing to lower risk for CVD.
Hypertension: Somewhat lower prevalence, compared to men.
Diabetes: Women with diabetes have the same risk for CVD as do men with diabetes (ie, the “gender benefit” seems to disappear).
Obesity: Most data suggest that central (ie, visceral) obesity confers greater risk for CVD than does lower-body obesity. Women are more likely than men to exhibit lower-body obesity (ie, “pear shape”). However, when women increase body fat, their levels of C-reactive protein (CRP) seem to increase more dramatically than in men with increasing body fat. This relationship and its implications are under investigation.
Role of estrogen: The lower risk for CVD in premenopausal women has been attributed to estrogen, but the relationship may be more complex. Before puberty, girls and boys have similar levels of HDL-cholesterol, but those levels decrease after puberty (with the onset of increased androgen production) in boys. After menopause, not only do estrogen levels decrease, but the relative concentration of androgens increases.
Hypertension: Higher prevalence among blacks.
HDL-cholesterol: Latinos tend to have lower levels than whites, who tend to have somewhat lower levels than blacks.
Management: In general, targets (eg, BP, lipids, blood glucose) are the same, regardless of race/ethnicity.
Hypertension: Diagnosis and Management
Sheila Garris, MD, Clinical Hypertension Specialist and Associate Professor of Clinical Internal Medicine, Eastern Virginia Medical School, Norfolk, VA
• BP should be measured twice, taken ³5 min apart.
• Patients should avoid eating or drinking for ³30 min before measuring BP.
• Patients should be in a sitting position with both feet flat on the floor.
• »80% of the upper arm must be covered by the bladder of the BP cuff. If the cuff is too small, the BP reading will be artificially high (potentially leading to inappropriate treatment).
• The patient’s arm should be approximately at the level of the heart.
• Before diagnosing a patient with hypertension, measure the BP in both arms.
Treatment approach: patients without diabetes
• First-line therapy: thiazide diuretic (in most patients)
• Two agents are recommended for patients with BP ³160/100 mm Hg. If the first agent is a drug that affects actual blood volume (eg, a diuretic) or relative blood volume (eg, a vasodilator), then the second agent should be a drug that affects the renin-angiotension-aldosterone system (eg, an angiotension-converting enzyme [ACE] inhibitor or angiotension-II receptor blocker [ARB]).
• If BP remains high, up-titrate medications or add a third agent.
• Consider secondary sources of hypertension — the most common being use of nonsteroidal anti-inflammatory drugs (NSAIDs). Other common causes of secondary hypertension are sleep apnea and idiopathic hyperaldosteronism (IHA).
• To work up a patient for IHA, order an aldosterone-to-renin ratio or refer to a clinical hypertension specialist.
Note: Initiating a low-sodium diet can reduce systolic BP by 6 to 8 mm Hg (similar effect as a diuretic).
Complete guidelines for the management of hypertension are available in the 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7).
Patients with diabetes: Thiazide diuretics may worsen glycemic control. Therefore, a better first choice is an ACE inhibitor or ARB. If a second agent must be added, consider a calcium-channel blocker.
Women of childbearing age: ACE inhibitors and ARBs are associated with fetal abnormalities. Therefore, women taking these agents must be protected from pregnancy. Although oral contraceptives (OCs) may increase BP, they may be used as long as the BP is adequately controlled. Some antihypertensive agents (eg, vasodilating b-blockers [eg, labetalol], methyldopa) are safe for women who are planning pregnancies.
Action for Health in
Diabetes (Look AHEAD) Trial
Table 1: Look AHEAD Trial
Prospective, randomized, controlled trial
Intensive lifestyle intervention (designed to achieve and maintain weight loss) vs diabetes education and support
Composite outcome: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke
>5000 adults, 45-75 yr of age, who are overweight or obese and have type 2 diabetes
Up to 13.5 yr
10% of initial body weight
Show Me the Data!
Table 2: Results at 1 yr
-6.8 mm Hg
-2.8 mm Hg
-3.0 mm Hg
-1.8 mm Hg
Jeffrey Curtis, MD, Coinvestigator, Action for Health in Diabetes (Look AHEAD) Trial; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Phoenix, AZ
Results from baseline
• Patients reported no symptoms
• 22.5% of tests showed
• 12% of participants were unable to achieve ³5 METs.
• ST segment depression was seen in 7.6%.
• 0.5% of participants demonstrated abnormal recovery of heart rate.
• Angina occurred in 1.1%.
• Detectable arrhythmia occurred in 0.71%.
• The variable that best predicted abnormal results was age.
Overweight or obese adults with type 2 diabetes have 22% likelihood of having abnormal results on stress tests. Although it is not yet known whether these abnormalities will prove clinically significant, they have been associated with increased cardiovascular mortality in other studies. The authors do not broadly recommend stress testing for all overweight patients with diabetes, but they note that clinicians should be mindful that even asymptomatic patients may be at increased risk for cardiovascular events, especially with increasing age.
in Patients with
Type 1 Diabetes
Trevor Orchard, MBBCh, MMedSci, FAHA, Professor of Epidemiology, Pediatrics, and Medicine, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA
Predictors of risk
Data from the Pittsburgh Epidemiology of Diabetes Complications Study shows that cardiovascular autonomic neuropathy (CAN) is a predictor of future development of arterial stiffness. Other predictors were smoking status and level of HDL cholesterol.
Cardiac autonomic nerve function: Heart rate variability (R-R interval) during deep breathing, expressed as the expiration-to-inspiration (E/I) ratio.
Arterial stiffness: Pulse wave analysis was measured using a SphygmoCor Px system. Pulse pressure is another useful measure, but data by Prince and colleagues show that augmentation pressure and subendocardial viability ratio (SEVR) are somewhat better predictors.
Reducing cardiometabolic risk
Pharmacogenetics: Risk for CVD is reduced with vitamin E therapy in individuals with type 2 diabetes who have the haptoglobin 2-2 genotype. Emerging data also suggest a relationship between haptoglobin genotype and risk for CVD in patients with type 1 diabetes.
Management of standard risk factors: It is very important to control BP and lipids. For example, statin therapy should be considered for all patients with type 1 diabetes who are >30 yr of age. Risk assessment — Individuals with type 1 diabetes should be evaluated for cardiometabolic risk on a regular basis, beginning at puberty. Targets — smoking cessation; LDL cholesterol <100 mg/dL; BP £120/80 mm Hg **.
** Note, the above recommendations are based on expert opinion and extrapolations from data in type 2 diabetes.
“Our data suggest that [risk for CVD in individuals with type 1 diabetes] is strongly related to renal disease. However, we’ve seen a nice decline in renal disease and not as big a decline in CVD. That partly reflects the fact that we’ve been too focused on renal disease and not on cardiovascular risk.”
Articles Featured in the June Issue of Diabetes Care
Abbott CA: Explanations for the lower rates of diabetic neuropathy in Indian Asians versus Europeans
The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group: The cost-effectiveness of continuous glucose monitoring in type 1 diabetes
Knip M: Prediction of Type 1 Diabetes in the General Population
Redmon JB: Effect of the Look AHEAD Study Intervention on medication use and related cost to treat cardiovascular disease risk factors in individuals with type 2 diabetes
Rosenstock J: Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without prediabetes
Sawada SS: Long-term trends in cardiorespiratory fitness and the incidence of type 2 diabetes
Abbott CA: Explanations for the lower rates of diabetic neuropathy in Indian Asians versus Europeans; American Diabetes Association: Standards of medical care in diabetes – 2010. Diabetes Care 33 (Suppl 1):S11, 2010; Asleh R et al: Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype. Diabetes 57:2794, 2008; Blonde L: Current antihyperglycemic treatment guidelines and algorithms for patients with type 2 diabetes mellitus. Am J Med 123 (3 Suppl):S12, 2010; Blum S et al: The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Atherosclerosis Feb 21, 2010 [Epub ahead of print]; Cignarella A et al: Emerging role of estrogen in the control of cardiometabolic disease. Trends Pharmacol Sci 31:183, 2010; Curtis JM et al: Prevalence and predictors of abnormal cardiovascular responses to exercise testing among persons with type 2 diabetes. The Look AHEAD Study. Diabetes Care 33:901, 2010; Danaei G et al: The promise of prevention: the effects of four preventable risk factors on national life expectancy and life expectancy disparities by race and county in the United States. PLoS Med 7:e1000248, 2010; Homko CJ et al: Gender differences in cardiovascular risk factors and risk perception among individuals with diabetes. Diabetes Educ Apr 1, 2010 [Epub ahead of print]; Patel MR et al: Low diagnostic yield of elective coronary angiography. N Engl J Med 362:886, 2010; The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group: The cost-effectiveness of continuous glucose monitoring in type 1 diabetes; Knip M: Prediction of Type 1 Diabetes in the General Population; Persell SD et al: Medication reconciliation and hypertension control. Am J Med 123:182, 2010; Poulsen MK et al: Identification of asymptomatic type 2 diabetes mellitus patients with a low, intermediate, and high risk of ischaemic heart disease: Is there an algorithm? Diabetologia 53:659, 2020; Prince CT et al: Cardiovascular autonomic neuropathy, HDL cholesterol, and smoking correlate with arterial stiffness markers determined 18 years later in type 1 diabetes. Diabetes Care 33:652, 2010; Redmon JB: Effect of the Look AHEAD Study Intervention on medication use and related cost to treat cardiovascular disease risk factors in individuals with type 2 diabetes; Rosenstock J: Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without prediabetes; Shivu GN et al: Relationship between coronary microvascular dysfunction and cardiac energetics impairment in type 1 diabetes mellitus. Circulation 121:1209, 2010; Sawada SS: Long-term trends in cardiorespiratory fitness and the incidence of type 2 diabetes; The Look AHEAD Research Group: Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes. Diabetes Care 30:1374, 2007.
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