Metabolic Syndrome Bryon Allen, MSN, FNP-BC

Objectives Review metabolic syndrome in general How metabolic syndrome impacts HCT recipients Treatment strategies in metabolic syndrome

What is Metabolic Syndrome? Metabolic syndrome is referred to a group of characteristics which occur together, causing an increased risk for a person developing type II diabetes, stroke, and cardiovascular disease.

Prevalence of Metabolic Syndrome in the United States NHANES III data showed overall prevalence in US was 22 percent, which represents ~ 47 million individuals in the United States Approximately 7% of teens Prevalence was nearly 7% among overweight adolescents and 29% among obese adolescents Approximately 40% of people over age 60 meet the criteria

Characteristics of Metabolic Syndrome Obesity High blood pressure Glucose intolerance Elevated triglycerides (atherogenic dyslipidemia) Low HDL-cholesterol

Risk Factors of Metabolic Syndrome Obesity Family history Body fat distribution Socioeconomic factors Physical inactivity Low Vitamin D 25-Hydroxy Excess caloric intake Poor diet Medications (Exposure to antipsychotic medications)

Metabolic Syndrome Criteria for Adults 3 or more of the conditions below is representative of Metabolic syndrome Abdominal obesity (male waist > 40 inches; female waist > 35 inches) (1 point) Triglycerides >= 150 mg/dL or on TG lowering medication (1 point) HDL cholesterol (male < 40; female < 50) or on HDL-C improvement Rx (1 point) Blood pressure >=130/>=85 or on BP medication (1 point) Fasting glucose >= 100 mg/dL or on Glucose lowering medication (1 point) (National Heart, Lung, and Blood Institute and the American Heart Association, International Diabetes Federation, World Heart Federations, International Atherosclerosis Society and International Association for the Study of Obesity joint statement in 2009)

Three or more of the above conditions is representative of Metabolic syndrome

Metabolic Syndrome Criteria in Children and Adolescents As defined by the International Diabetes Foundation Age 6 to <10 years -Obesity > 90th percentile as assessed by waist circumference -Metabolic syndrome cannot be diagnosed, but further measurements should be made if family history of metabolic syndrome, type 2 diabetes mellitus, dyslipidemia, cardiovascular disease, hypertension, or obesity -IDF suggests that a strong message for weight reduction should be delivered for those with abdominal obesity Age 10 to <16 years -Obesity > 90th percentile (or adult cut-off if lower) as assessed by waist circumference and any two of the following conditions -Triglycerides > 150mg/dL (1.7mmol/L) -HDL-cholesterol <40mg/dL (1.03mmol/L) -Blood pressure > 130 mm Hg systolic or > 85 mm Hg diastolic -Fasting Glucose > 100mg/dL (5.6 mmol/L) or known type 2 diabetes mellitus

Why is it important? Linked to insulin resistance Increases risk of diabetes mellitus 5 times Fatty liver Several cancers (Linked to cancers of the breast, colon, gallbladder, kidney, and possibly, prostate gland. Increased risk of cardiovascular disease 2-3 times

Transplant and Metabolic Syndrome Type I diabetes has been transferred in bone marrow from donor to host. Study at FHCRC showed most significant risk factor for development of type 2 diabetes was the patient’s diagnosis at transplant, with leukemia patients at greater risk than patient with other underlying diagnosis. Small studies show 30-50% of HCT survivors develop metabolic syndrome Patients post allogeneic HCT compared to sibling controls. HCT patients are nearly 4 times more likely to develop diabetes and 2 times more likely to have Hypertension. Recipients of autologous HCTs no more likely than siblings to report an of the outcomes studied. Cancer survivors are more likely to be significantly overweight, have higher fasting plasma glucose and insulin levels and decreased serum high-density lipoprotein (HDL-C) cholesterol levels. Combine cancer treatments that re known to be cardiotoxic (radiation therapy, anthracyclines, and cyclophosphamide) with effects of metabolic syndrome and have possible severe late effect Another study showed when siblings compared to HCT survivors (no difference in BMI/waist circumference), More higher percent fat mass, and less lean body mass, more insulin resistance, higher insulin levels, and higher cholesterol/triglycerides.

Therapeutic Objectives To reduce the underlying causes of metabolic syndrome: Overweight and obesity Physical inactivity Treat lipid and non-lipid risk factors Dyslipidemia Hypertension Cardiovascular complication prevention

Dietary Goals Decrease total calories Increase whole grains Limit total fat to 25 to 35% of calories per day, and saturated fat to <7% of calories per day. Recommended types of diet: Mediterranean and DASH Consider consult to nutritionist

Activity Goals Physical activity. At least 30 minutes continuous or intermittent moderate intensity, 5 times/week initially. Increase up to 1 hour a day, 6 times/week Try to determine behaviors your patient(s) can and will do

Glucose control For impaired fasting glucose, encourage weight reduction and exercise. Drug therapy for hyperglycemia in patients with metabolic syndrome typically begins with an insulin- sensitizing agent, such as metformin. For type 2 Diabetes, goal A1C <7 percent

Atypical Antipsychotics Metformin and lifestyle interventions both have proven effective at reducing weight gain and insulin resistance in patients taking atypical antipsychotics

Management – LDL-C and HDL-C levels Management of elevated LDL-C includes consideration of statins (coenzyme A [HMG-CoA] reductase inhibitors) at indicated ranges, as there are several formulations available with different doses and potencies. Management of reduced HDL-C remains controversial, however, starts with diet/exercise modifications and may include niacin. Certain statins may help, although this is not a widely accepted indication. Niacin raises low HDL-C levels and reduces cardiovascular events, however, may exacerbate hyperglycemia, especially in high doses (>1500 mg/day), so monitoring is recommended

Management HDL-C continued Fibrate therapy may serve as an important adjunct in overweight patients with elevated triglyceride and low HDL-C levels Elevated triglyceride levels: Niacin, fibrates, and omega-3 fatty acids

Management-Hypertension Should proceed according to the recommendations of the JNC-7 guidelines, to achieve a goal blood pressure of less than 140/90 mm Hg or, in patients meeting diagnostic criteria for diabetes mellitus, less than 130/80 mm Hg JNC-7 -Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

Treatments Lower BP –agents will be reviewed shortly Decreased HDL-C levels: Niacin Elevated triglyceride levels: Niacin, fibrates, and omega- 3 fatty acids Hyperglycemia: Insulin-sensitizing agent, such as metformin

Cardiovascular preventive therapy Aspirin therapy may be helpful in the primary prevention of cardiovascular complications, particularly in patients with at least an intermediate risk of suffering a cardiovascular event (e.g., >6% 10 y risk). Aspirin therapy also recommended for all patients in the (AIM-HIGH) trial. ATP III Guidelines, available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/dskref. htm Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglycerides. People with metabolic syndrome are in a pro-inflammatory and pro- thrombotic state.

Review of Goals Decrease calorie intake/change type of calorie intake Increase activity Lower BP Increase HDL-C Lower elevated triglyceride levels Control hyperglycemia

Management via ABCDE A – Assess cardiovascular risk and aspirin therapy B – Blood pressure control C – Cholesterol management D – Diabetes prevention and diet therapy E – Exercise therapy

ATPIII At a glance, quick reference: available at: http://www. nhlbi STEP 1: Determine lipoprotein levels - obtain complete lipoprotein profile after 9- to 12-hour fast. LDL Cholesterol - Primary Target of Therapy <100 Optimal 100-129 Near Optimal/Above Optimal 130-159 Borderline High 160-189 High greater than or equal to190 Very high Total Cholesterol <200 Desirable 200-239 Borderline High greater than or equal to240 High HDL Cholesterol <40 Low greater than or equal to60 High

Symptomatic carotid artery disease Peripheral arterial disease STEP 2: Identify presence of clinical atherosclerotic disease that confers high risk for coronary heart disease (CHD) events (CHD risk equivalent): Clinical CHD Symptomatic carotid artery disease Peripheral arterial disease Abdominal aortic aneurysm.

STEP 3: Determine presence of major risk factors (other than LDL): Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goals Cigarette smoking Hypertension (BP greater than or equal to140/90 mmHg or on antihypertensive medication) Low HDL cholesterol (<40 mg/dl)* Family history of premature CHD (CHD in male first degree relative <55 years; CHD in female first degree relative <65 years) Age (men greater than or equal to45 years; women greater than or equal to55 years) * HDL cholesterol greater than or equal to60 mg/dL counts as a "negative" risk factor; its presence removes one risk factor from the total count. Note: in ATP III, diabetes is regarded as a CHD risk equivalent.

Three levels of 10-year risk: >20% -- CHD risk equivalent 10-20% STEP 4: If 2+ risk factors (other than LDL) are present without CHD or CHD risk equivalent, assess 10-year (short-term) CHD risk (see Framingham tables). Three levels of 10-year risk: >20% -- CHD risk equivalent 10-20% <10%

STEP 5: Determine risk category: Establish LDL goal of therapy Determine need for therapeutic lifestyle changes (TLC) Determine level for drug consideration Risk Category LDL Goal LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) LDL Level at Which to Consider Drug Therapy CHD or CHD Risk Equivalents (10-year risk >20%) <100 mg/dL greater than or equal to100 mg/dL greater than or equal to130 mg/dL (100-129 mg/dL: drug optional)* 2+ Risk Factors (10-year risk less than or equal to20%) <130 mg/dL greater than or equal to130 mg/dL 10-year risk 10-20%: greater than or equal to130 mg/dL 10-year risk <10%: greater than or equal to160 mg/dL 0-1 Risk Factor** <160 mg/dL greater than or equal to160 mg/dL greater than or equal to190 mg/dL (160-189 mg/dL: LDL-lowering drug optional) * Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory. ** Almost all people with 0-1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in people with 0-1 risk factor is not necessary.

STEP 6: Initiate therapeutic lifestyle changes (TLC) if LDL is above goal. TLC Features TLC Diet: Saturated fat <7% of calories, cholesterol <200 mg/day Consider increased viscous (soluble) fiber (10-25 g/day) and plant stanols/sterols (2g/day) as therapeutic options to enhance LDL lowering Weight management Increased physical activity

Consider drug simultaneously with TLC for CHD and CHD equivalents STEP 7: Consider adding drug therapy if LDL exceeds levels shown in Step 5 table: Consider drug simultaneously with TLC for CHD and CHD equivalents Consider adding drug to TLC after 3 months for other risk categories. Drugs Affecting Lipoprotein Metabolism

STEP 8: Identify metabolic syndrome and treat, if present, after 3 months of TLC Clinical Identification of the Metabolic Syndrome - Any 3 of the Following: Risk Factor Defining Level Abdominal obesity* Men Women Waist circumference** >102 cm (>40 in) >88 cm (>35 in) Triglycerides greater than or equal to150 mg/dL HDL cholesterol Women <40 mg/dl <50 mg/dl blood pressure greater than or equal to130/greater than or equal to85 mmHg Fasting glucose greater than or equal to110 mg/dL * Overweight and obesity are associated with insulin resistance and the metabolic syndrome. However, the presence of abdominal obesity is more highly correlated with the metabolic risk factors than is an elevated body mass index (BMI). Therefore, the simple measure of waist circumference is recommended to identify the body weight component of the metabolic syndrome. ** Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased, e.g., 94-102 cm (37-39 in). Such patients may have a strong genetic contribution to insulin resistance. They should benefit from changes in life habits, similarly to men with categorical increases in waist circumference.

STEP 9: Treat elevated triglycerides. ATP III Classification of Serum Triglycerides (mg/dL) < 150 Normal 150-199 Borderline high 200-499 High greater than or equal to500 Very high Treatment of elevated triglycerides (greater than or equal to150 mg/dL) Primary aim of therapy is to reach LDL goal. Intensify weight management. Increase physical activity. If triglycerides are greater than or equal to200 mg/dL after LDL goal is reached, set secondary goal for non-HDL cholesterol (total -) HDL-C 30 mg/dL higher than LDL goal. Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals for Three Risk Categories Risk Category LDL Goal (mg/dL) Non-HDL-C Goal (mg/dL) CHD and CHD Risk Equivalent (10-year risk for CHD >20%) <100 <130 Multiple (2+) Risk Factors and 10-year risk less than or equal to20% <130 <160 0-1 Risk Factor <160 <190 If triglycerides 200-499 mg/dL after LDL goal is reached, consider adding drug if needed to reach non-HDL-C goal: intensify therapy with LDL-lowering drug, or add nicotinic acid or fibrate to further lower VLDL. If triglycerides greater than or equal to500 mg/dL, first lower triglycerides to prevent pancreatitis: very low-fat diet (less than or equal to15% of calories from fat) weight management and physical activity fibrate or nicotinic acid when triglycerides <500 mg/dL, turn to LDL-lowering therapy. Treatment of low HDL cholesterol (<40 mg/dL) First reach LDL goal, then: Intensify weight management and increase physical activity. If triglycerides 200-499 mg/dL, achieve non-HDL-C goal. If triglycerides <200 mg/dL (isolated low HDL-C) in CHD or CHD equivalent, consider nicotinic acid or fibrate.