KATHERINE WERNER, PHARMD, CDE, CACP, CGPPHARMACY CLINICAL COORDINATOR

PORTLAND VETERANS AFFAIRS MEDICAL CENTER (PVAMC)

PORTLAND, OREGON

Metabolic Syndrome & Prediabetes

WHAT DIFFERENTIATES METABOLIC SYNDROME FROM PRE-DIABETES?

Objectives

Differentiate between metabolic

syndrome and prediabetes

Discuss risk factors and screening for prediabetes and metabolic syndrome

ID Treatment goals for both metabolic

syndrome and prediabetes

Be familiar with the clinical trials supporting medication use in

prediabetes

DEFINED BY 2 KEY ORGANIZATIONS 1) NATIONAL CHOLESTEROL EDUCATION

PROGRAM(ATP I I I REPORT)2) NIH’S NATIONAL HEART, LUNG &

BLOOD INSTITUTE

What is Metabolic Syndrome?

What is Metabolic Syndrome?

Metabolic Syndrome term defined by ATP III: Abdominal obesity Atherogenic dyslipidemia

Raised blood pressure

Insulin resistance ± glucose intolerance

Proinflammatory state Prothrombotic state

Metabolic Syndrome per ATP III

Underlying risk factors for CVD: Obesity (especially abdominal obesity) Physical inactivity Atherogenic diet

Major risk factors: Cigarette smoking Hypertension Elevated LDL cholesterol Low HDL cholesterol Family history of premature coronary heart disease

(CHD) Aging

Metabolic Syndrome per ATP III

Emerging risk factors Elevated triglycerides Small LDL particles Insulin resistance/

glucose intolerance Proinflammatory state Prothrombotic state

Emerging risk factors are now known as risk factors for metabolic syndrome aka. Syndrome X!

What is Metabolic Syndrome?

Definition: National Heart, Lung & Blood InstituteAnother name for a group of risk factors that

raises your risk for heart disease and other health problems such as diabetes and stroke. Metabolic refers to the biochemical processes involved in

the body's normal functioning. Risk factors are traits, conditions, or habits that increase

your chance of developing a disease. A person must have 3 of the 5 identified risk

factors to be classified as having Metabolic Syndrome

http://www.nhlbi.nih.gov/health/health-topics/topics/ms/

Metabolic Syndrome’s 5 Risk Factors

Abdominal obesity. Waist circumference in Men>40”, Women>35”

High triglyceride level (or if on medicine to treat). TG>150 mg/dL

Low HDL cholesterol level (or if on medicine). HDL<40mg/dL Men, <50mg/dL Women

High Blood Pressure or Diagnoses of HTN >130/85 mmHg

High fasting blood sugar Fasting BG >100 mg/dL or higher

http://www.nhlbi.nih.gov/health/health-topics/topics/ms/diagnosis.html

Metabolic Syndrome: Treatment Goals

Aim is to reduce the risk of heart diseasePossible to prevent or delay metabolic syndrome

with therapeutic lifestyle changes (TLC) Dietary changes, exercise, weight management

Primary goal is directed at ↓LDL cholesterol and ↓high BP, & controlling DM (if applicable)

Secondary goal is to prevent the onset of DM2 & or DM complications Heart & kidney disease, vision loss, and foot or leg

amputation.

Metabolic Syndrome & Therapeutic Lifestyle Changes (TLC)

Healthy food choice encouraged with high fiber diet containing fruit, nuts, vegetables, whole grains, fish

Saturated fats replaced with monosaturated or polysaturated fats with saturated fats<7%, trans<1%

Lower salt intake (DASH diet)Alcohol in moderation

Men<20-30g, Women<10-20gLimit beverages & foods with added sugarPhysical activity 30”/day every dayAvoid tobacco products

ESC/EAS Guidelines for the management of dyslipidaemias. European Heart Journal (2011) 32, 1769-1818.

HOW IS PREDIABETES DEFINED?HOW IS IT DIFFERENT FROM DIABETES?HOW IS PREDIABETES DIFFERENT FROM

METABOLIC SYNDROME?

What Is Prediabetes?

Prediabetes: Definition

Fasting Plasma Glucose (FPG) test or 2-h Oral Glucose Tolerance Test (OGTT) can be used to screen for pre-diabetes Impaired Fasting Glucose (IFG) Impaired Glucose Tolerance (IGT)

Defined as IGT or IFG with microvascular changes associated with diabetes

A1C now utilized in diagnoses of prediabetes

Prediabetes: An epidemic

57 million Americans >20 years of age have prediabetes; ~70% of Americans >65 yrs too!

Prediabetes does not inevitably lead to diabetes however raises short-term absolute risk of developing diabetes 3- to 10-fold

DPP trial showed us that people who lost 5 to 7% of their body weight via healthy food choices, being physically active 30 minutes/day x 5 days/week reduced the onset of type 2 diabetes by 58%

Prediabetes: Diagnoses

Fasting plasma glucose >100 but <126 mg/dl – typically confirmed on 2 separate occasions

Impaired glucose tolerance test result >140mg/dl but <199 mg/dl post 75 gram load of glucose.

A1C 5.7-6.4%Remember the terminology is Impaired

fasting glucose (IFG) or impaired glucose tolerance (IGT) depending on test results.

Diabetes Care January 2012 35:S64-S71; doi:10.2337/dc12-s064

Prediabetes: Who should be tested?

Asymptomatic & Age >44 + Overweight with BMI >25

Overweight (BMI>25kg/m2)+ 1 Risk factor Physically inactive Previous A1C>5.7%, IGT or IFP Parent, brother or sister with diabetes (1st degree relative) High risk ethnicity: African American, American Indian, Asian

American, Hispanic/Latino or Pacific Islander PMH of GDM or having given birth to baby weighing >9lbs High Blood Pressure (HTN) (>140/90) HDL<35 (0.90 mmol/L) or TG>250(2.82 mmol/L) Women with polycystic ovarian syndrome (PCOS) PMH CVD or comorbidities associated with insulin resistance

Diabetes Care January 2012 35:S64-S71; doi:10.2337/dc12-s064

Prediabetes: Who should be tested?

In absence of meeting testing criteria screening for DM should begin at 45 years of age

If results are normal then may repeat screening at 3-year intervals but may consider more frequent testing based on initial lab results and risk status

All patients with prediabetes should be tested annually at a minimum!

Diabetes Care January 2012 35:S64-S71; doi:10.2337/dc12-s064

Prevention/Delay of DM2

Per new ADA Guidelines, refer patients with IGT, IFG, or A1C 5.7-6.4% to ongoing support program that targets weight loss (7% body weight), and increasing activity to minimum of 150 min/week

Follow up counseling important for success!Consider metformin for prevention of DM2 in

those with BMI>35% kg/m2, <60 years or GDM history

At a minimum annual monitoring for Prediabetes patients should be performedDiabetes Care January 2012 35:S11-S63; doi:10.2337/dc12-s011

Prediabetes: Treatment Recommendations

Screening & TreatmentMacrovascular Complication Prevention:

THE ABC’s A1C: blood glucose control Blood pressure control Cholesterol /Coronary heart disease

THE “A” IN THE ABCS OF TREATMENT

A1C Control

Therapeutic Lifestyle Modification/Change (TLC)

Prediabetes: Treatment TLC

TLC is the corner-stone of treatment for prediabetes Address at every visit! Goal is to reduce weight 5-10% Moderate-intensity exercise 30 minutes daily 5 days Diet – calorie restriction, increased fiber intake, and

limiting carbohydrates For cholesterol control – low fat diet (NCEP &

ECS/EAS ) For BP control – low sodium(DASH) & avoiding

alcohol(JNC7)

Prediabetes: Treatment

Increase success by: Patient self-monitoring Realistic & step-wise goal setting Stimulus control Cognitive strategies Social support Appropriate reinforcement

Prediabetes Treatment

Medical Nutrition Therapy (MNT)Results both in cost-savings and improved

outcomesPhysical Activity

150 min/week at 50-70% of maximum heart rate Spread over at least 3 days of the week No more than 2 consecutive days without exercise

Resistance training should be encouraged 2x/week in the absence of contraindications

Medical Weight Loss Strategies: Pharmacologic

Pharmacologic Treatments for obesity: Orlistat & Sibutramine reduce weight while improving

lipid profile and glycemic control but can increase BP Cannabinoid receptor antagonists reduce weight &

improve glycemic control but promote anxiety and depression --- not approved in US

Locaserin is a serotonin antagonist Bariatric surgery for morbidly obese

(BMI>40) can reduce the likelihood of developing DM2 however not recommended in pre-diabetes

Pharmacotherapy in Prediabetes: ABCs

Extrapolate data for DM2 & apply ABCs to reduce risk of CVD & other complications associated with hyperglycemia

No agent has been approved by the FDA for the treatment of pre-diabetes therefore any use is considered “Off-label” Consider individual risk to benefit Goal to normalize glucose levels, delay diabetes, and

prevent microvascular complications Best outcomes were lifestyle interventions not

medication

Clinical Trials & Prediabetes

Clinical trials with metformin, acarbose, or thiazolidinediones (TZD)STOP-NIDDM TrialCANOE TrialDREAM TrialACT-NOW

STOP NIDDM Trial

International study on the efficacy of an alpha-glucosidase inhibitor to prevent DM2 in IGT

Multicenter, placebo-controlled, randomized intension to treat trial -> acarbose 100mg tid

Results: 221 (32%) patients randomized to acarbose and 285 (42%)

randomized to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015)

Acarbose increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001)

Treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to DM2

CANOE Trial

Canadian Normoglycemia Outcomes Evaluation (CANOE) Investigated if low-dose combination therapy with

rosiglitazone plus metformin could affect the development of DM2 in IGT patients

Randomized rosiglitazone 2mg +metformin 500mg or placebo

Treatment group: DM2 occurred in significantly fewer individuals in the active treatment group (n=14 [14%]) than in the placebo group (n=41 [39%]; p<0·0001)

THE “B” IN THE ABCS OF TREATMENT

Blood Pressure Management

Blood Pressure Management: Screening/Diagnoses

Different goals from non-diabetic populationMeasure routinely at every visitGoal is a systolic BP< 130 and diastolic<80

mmHgIf above goal then confirm the readings on a

separate visit prior to diagnosing with hypertension

Consider 24 hour Blood Pressure monitor for patients with “white coat” syndrome

Blood Pressure Management

To treat or not to treat? When do we really need medication & is lower

better? According to JNC 7 and the American Diabetes

Association it is better to treat in these higher risk populations versus not to treat in hopes of preventing diabetic complications

According to the ESH/HYVET trial no added benefit seen when you treat BP <140/85 in the elderly unless end organ damage (EOD) present or severe Individualize therapy to maximize benefit while balancing

minimizing SE of therapy Could aim for lower BP goal if EOD evident

Hypertension: Treatment

If systolic BP 130-139 mm Hg or diastolic BP 80-89 mm Hg lifestyle therapy alone may be considered for a maximum of 3 months

If systolic BP > 140 mmHg or if the diastolic BP is > 90 mmHg pharmacological therapy in addition to lifestyle therapy should be initiated

Hypertension: Drug Therapy

Drugs of Choice: ACE inhibitor or Angiotensin receptor blockers (ARB)

If not tolerated then substitute If not at goal with ACE inhibitor or ARB then

add on a thiazide diuretic (GFR > 30ml/min) or a loop diuretic (GFR <30mL/min)

Multiple drug therapy is typically required Monitor kidney and serum potassium levels

with ACE inhibitors and ARBs

BP Management in the Elderly

BP Management in the Elderly

Drug therapy provide significant CV risk reduction Degree of BP reduction more important than drug usedHigher incidence of resistant hypertension Combination antihypertensive therapy is usually

indicated ACE-inhibitor with diuretic or CCB Combination products preferred once dose determined

Greater tendency for SESubclinical CV organ damage earlier onset of drug

therapy leads to a reduction of the total CV riskExtreme elderly (>80 years) treat early but monitor SE

per HYVET (Hypertension in the Very Elderly Trial)

Causes of Resistant HTN

False positive or pseudoresistance

Incorrect technique in measuring blood pressure

Pseudohypertension

Lack of adherence to life style modifications

Lack of patient adherence to antihypertensive therapy

Suboptimal therapy

True resistant hypertension

Sleep apnea

Hypertension related to secondary etiology

BP Goals & Therapy in Pregnant Women

Both ACE inhibitors and ARBs are contraindicated in pregnant women

BP goals are lower for long-term maternal health and to minimalize impaired fetal growth Systolic BP 110-129 Diastolic BP 65-79

THE “C” IN THE ABCS OF TREATMENT

Cholesterol Management

Lipid Management

Screening: Measure fasting lipid profiles at least annually In adults with low-risk lipid profiles screening can be

every 2 years Actual goals:

LDL cholesterol <100 mg/dL HDL cholesterol >50 mg/dL Triglycerides (TG) < 150 mg/dL

Lipid management: Goals

LDL-C goal < 100 mg/dL in patients without overt CV disease

LDL-C goal <70 mg/dL in patients with overt CV disease or high risk patients with >1 risk factor for heart disease

Both the ADA and ACE agree with ATP III recommendations

Lipid management: Goals

Although there are listed targets for both HDL and TG in both the ADA and ATP III, LDL-C targeted therapy still remains the primary strategy in reducing risk for CV events

TG < 150 mg/dLHDL > 45 mg/dL men and >50 mg/dL women

Blood Pressure Cholesterol

Same targets as DM2

ACE-i/ARB 1st lineCCB 2nd lineThiazides & Beta-

blockers increase blood sugar – use cautiously

Goals same as DM2Statin preferred

agentColesevelam

approved for DM2Niacin increases

blood glucose

ABCs of Pre-Diabetes: “B” & “C”

Prediabetes: Treatment Recommendations

Recent studies have shown that once IGT has been identified & if the ABCs remain untreated, this population has a more rapid progression to diabetes and has a higher incidence of both micro- & macro-vascular complications upon diabetes diagnoses versus patients treated once IGT was identified

Apply ABCs of diabetes management to prediabetes

WHAT IS THE IMPACT OF THESE CONDITIONS ON THE HEALTH?

Why are we spending an hour discussing differences between

MS & prediabetes?

CVD Rates in US 2013

Even though rates of death attributable to CVD have declined in the past decade, the burden of disease remains high.

CVD #1 killer of men & women in the US!!!People with DM2 & potentially pre-dm/MS

are at equal risk of CVD. Rate of death attributable to CVD was 236.1 per

100,000. More than 2150 Americans die of CVD each day

average of 1 death every 40 seconds Stroke accounted for ≈1 of every 19 deaths in the US.

Prevalence of risk factors in US 2013 Data

~154.7 million US adults of overweight or obese

~23.9 million children (age 2-19) have BMI>25% & ~12.7 million are obese

~78 million adults or 33.0% of US adults have hypertension

~ 31.9 million adults have total serum cholesterol≥240 mg/dL.

~19.7 million Americans had diagnosed diabetes mellitus, representing 8.3% of the adult population.

Prevalence of meeting the 2008 Federal Physical Activity Guidelines among adults ≥18 years of age by race/ethnicity and sex (National Health Interview Survey: 2010).

Go A S et al. Circulation 2013;127:e6-e245

Copyright © American Heart Association

Modifiable – Can Change

Not Modifiable – Can’t Change

Weight/Body Mass Index

Blood PressureBlood sugarCholesterolActivity Level

AgeSex EthnicityFamily history

Risk Factors for Heart Disease

Weight/ BMI

Body Mass Index= BMI

Usually listed as % 15-25% HEALTHY 25-29.9% Overweight >30% Obese

Blood Pressure

Awareness, treatment, and control of high blood pressure by race/ethnicity National Health and Nutrition Examination Survey: 2007–2010

Go A S et al. Circulation 2013;127:e6-e245

Blood Sugar

Healthy blood sugar reading <100 mg/dl Fasting blood sugar

100-125 pre-diabetic Fasting blood sugar

>126 diabetes Controlled Uncontrolled

Diabetes mellitus awareness, treatment, and control National Health and Nutrition Examination Survey: 2007–2010

Go A S et al. Circulation 2013;127:e6-e245

Copyright © American Heart Association

Cholesterol

Screening tool: Total Cholesterol <200 mg/dL LDL = “bad cholesterol”

Personalized goal HDL= “good cholesterol”

>50 TG= triglycerides

<150

ActivityLevel

Regular, moderate intensity physical activity can keep your heart in good shape!

70% Americans don’t get the activity they need!

Adults: 150 minutes/ week

Kids: 60 minutes/day

Make the time!

Start with walking!

Prevalence of meeting the 2008 Federal Physical Activity Guidelines among adults ≥18 years of age by race/ethnicity and sex (National Health Interview Survey: 2010).

Go A S et al. Circulation 2013;127:e6-e245

Copyright © American Heart Association

Cardiovascular disease

Number one killer of men & women in U.S.!What is CVD?

Heart & blood vessel disease: Hypertension/High blood pressure Heart disease/Heart Attack/MI Congestive Heart Failure CHF Stroke/ TIA Peripheral vascular disease PVD/stents

Deaths attributable to heart disease (United States: 1900–2009).

Go A S et al. Circulation 2013;127:e6-e245

Copyright © American Heart Association

Deaths due to cardiovascular disease (United States: 2009).

Go A S et al. Circulation 2013;127:e6-e245

Copyright © American Heart Association

Rate of heart disease in adults ≥20 years of age by age and sex National Health and Nutrition Examination Survey: 2007–2010

Go A S et al. Circulation 2013;127:e6-e245

Copyright © American Heart Association

Health impact pyramid.

Pearson T et al. Circulation 2013;127:1730-1753

Copyright © American Heart Association

American Heart Association Initiative

January 2010 goal to reduce CVD by 20% by 2020 & improve the health of America by 20%!

AHA defined ideal cardiovascular health as life’s simple 7 simple measures the average person can do to keep a healthy heart

Life’s Simple 7 Campaign

AMERICAN HEART ASSOCIATIONJANUARY 2010

GOAL: REDUCE CV DEATHS BY 20% BY 2020

Life’s Simple 7

S M O K I NG S TAT U SB M I / W E I G H T

H E A LT H Y D I E T S C O R ET O TA L C H O L E S T E R O L

B L O O D P R E SS U R EFA S T I N G P L A S M A G LU C O S E

P H Y S I C A L A C T I V I T Y

Criteria for Ideal Heart Health

Stop Smoking

Plan to quit!

Talk to your doc!

Talk to your friends!

Highest success rates are with support from family/friends plus nicotine replacement & medication

Life’s Simple 7 Defined

Never smoked, or quit more than a year ago.Having a BMI (body mass index) of less than 25

kg/m2.Exercising at a moderate level for at least 150

minutes, or at an intense level for 75 minutes per week.

Meeting four to five of the key components of a healthy diet in line with current AHA guidelines.

Having a total cholesterol of less than 200 mg/dL.Blood pressure below 120/80 mm Hg.Fasting blood glucose below 100 mg/dL.

Trends for Ideal Cardiovascular (Heart) Health among US adults aged ≥20 years

Go A S et al. Circulation 2013;127:e6-e245

Lose Weight

EAT HEALTHY DIET

• Low in saturated & trans fats

• Low in cholesterol

• Low in sodium <1500mg/day

• High in whole grains

• High in lean proteins

• High in fruit & vegetables

Control Cholesterol

Personalized goal based on risk factors Modifiable (weight, activity level, BP) Not modifiable (age, sex, family history)

Manage Blood Pressure

What is high blood pressure?

What is my goal blood pressure?

Depends on your individual risk factors

What is the benefit of having controlled blood pressure?

Be an active participant in your health care!

Reduce Blood Sugar

Fasting blood sugar <100 is considered healthy

Reduce simple sugar intake

Get regular exerciseTake medications as

prescribed

G E T A C T I V E !C O N T R O L C H O L E S T E R O L !

E AT B E TT E R !M A NA G E B L O O D P R E SS U R E !

L O S E W E I G H T !R E D U C E B L O O D S U G A R !

S T O P S M O K I NG !

The Simple 7

Children 6-19 years of age who exercised ≥60 minutes per day on 5 or more of the last 7 days

Go A S et al. Circulation 2013;127:e6-e245

Considerations in the Child/Adolescent

Incidence of MS on the rise due to childhood obesity and decrease in activity levels associated with modernization & risk for MS based on ethnicity, weight, age, & sex Hispanic>White>African American

Primary goal is prevention of progression to DM2

NHANES 99-02 & NHANES III demonstrate the risk for progression to DM2 proportionate to BMI

Proposed MS Criteria in Children

BMI <85th percentileWaist circumference by age

8 yr- 70 cm 12 y - 83 cm 15 y – 92 cm 17y – 99 cm

HDL > 35 mg/dL, TG <110 mg/dLInsulin level <15 uU/LFasting glucose <100 mg/dLGlucose (2h OGT) <140 mg/dLSystolic BP <120 mm HgDiastolic BP <75mm Hg

Treatment of MS in Children/Adolescents

Focus on lifestyle change & improving insulin resistance Increase activity level 60 minutes/day goal Nutritional intervention Pharmacological intervention: insulin sensitizers, BP

medications, and cholesterol medicationsSuccessful interventions are typically family-

based & school-basedGuidelines for treating blood pressure &

cholesterol established but pharmacotherapy use requires caution due to the effect on growth

Metabolic Syndrome versus Prediabetes

Is there a difference?

YES!

Summary

References

www.nhlbi.nih.gov/guidelines/hypertension/express.pdfwww.heart.orgwww.americanheart.org/presenter.jhtml?identifier=4756Am Heart J. 2006 Jul;152(1):27-38.http://www.nhlbi.nih.gov/health/health-topics/topics/ms/Diabetes Care January 2012 35:S64-S71; doi:10.2337/dc12-

s064.http://circ.ahajournals.org/content/121/4/586.full.pdf+htmlhttp://circ.ahajournals.org/content/127/1/e6.full.pdf+html ESC/EAS Guidelines for the management of dyslipidaemias.

European Heart Journal (2011) 32, 1769-1818.http://pamw.pl/sites/default/files/PAMW1-2-2010_inv-Fagard.pdfhttps://www.aace.com/files/prediabetesconsensus.pdf