Guidelines for Prediabetes Diagnosis and Management http www

Guidelines for Pre-diabetes Diagnosis and Management http: //www. bluenile. com/ Ali A. Rizvi, MD Department of Medicine University of South Carolina School of Medicine

TYPE 2 DIABETES. . . A PROGRESSIVE DISEASE Natural History of Type 2 Diabetes Postmeal glucose Plasma Glucose 126 mg/d. L Fasting glucose Insulin resistance Relative -Cell Function 20 10 0 10 Years of Diabetes 20 30 Insulin secretion

What is pre-diabetes? When a person's blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes “Borderline diabetes” “A touch of sugar” PRE-DIABETES

A 1 c Derived Average Glucose (ADAG) Study Diabetes Care, August 2008 Translating the A 1 c assay into estimated average glucose • Increased accuracy of Hb. A 1 c in reflecting the true average glycemia • Results reported as A 1 cderived average glucose “estimated average glucose” – e. AG A 1 C % 6 6. 5 e. AG mg/dl 126 140 7 7. 5 8 8. 5 9 9. 5 10 154 169 183 197 212 226 240

Role of A 1 c Testing to Diagnose Diabetes: Joint Recommendations from IDF, EASD, and ADA June 2009 • • • Advantages of A 1 c over FPG or OGTT: better indicator of overall glycemic exposure less variability, unaffected by outside factors like stress not a timed test, requires no fasting; more convenient Better at predicting complications ≥ 6. 5% seems to be a reasonable cut-point to avoid overdiagnosis. An A 1 c 5. 7 -6. 4% indicates high risk for developing diabetes: “pre-diabetes”

ADA Diagnostic Criteria for Diabetes Clinical Practice Recommendations 2010 1. A 1 C ≥ 6. 5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay. * OR 2. FPG ≥ 126 mg/dl. Fasting is defined as no caloric intake for at least 8 h. * OR 3. 2 -h plasma glucose ≥ 200 mg/dl during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. * OR 4. Random plasma glucose ≥ 200 mg/dl in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis. In the absence of unequivocal hyperglycemia, criteria 1– 3 should be confirmed by repeat testing.

How is pre-diabetes diagnosed? Categories of increased risk for diabetes Impaired Fasting Glucose [IFG]: Fasting Plasma Gluocse 100– 125 mg/dl Impaired Glucose Tolerance [IGT]: 2 -hour Plasma Glucose on the 75 -g Oral Glucose Tolerance Test 140– 199 mg/dl A 1 C 5. 7 – 6. 4% For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.

ADA Diagnostic Criteria: Normal, Diabetes, and Pre-diabetes Clinical Practice Recommendations 2010 Parameter Normal Diabetes Pre-diabetes Method 1 Fasting Plasma Glucose (mg/dl) <100 ≥ 126 100– 125 No caloric intake for at least 8 h 2 2 -h plasma glucose on OGTT (mg/dl) <140 ≥ 200 140– 199 WHO method: 75 g glucose load 3 Random plasma glucose (mg/dl) <140 ≥ 200 4 A 1 C % <5. 7 ≥ 6. 5 - 5. 7 – 6. 4 with classic symptoms of hyperglycemia or crisis NGSP certified method standardized to the DCCT assay In the absence of unequivocal hyperglycemia, criteria 1, 2, and 4 should be confirmed by repeat testing.

The Epidemic of Diabetes and Pre-diabetes “What lies beneath…” • Diabetes: 26 million (11. 3%) and increasing. • By 2015, 37 million (15%) Americans will have diabetes • Pre-diabetes: 57 million: About 1/4 (22. 6%) of overweight adults aged 45– 74 (CDC data) http: //www. cdc. gov/diabetes/pubs/pdf/ndfs_2007. pdf http: //www. cdc. gov/diabetes/pubs/factsheets/prediabetes. htm

Pre-Diabetes in the Young and the Old • The diabetogenic process begins early – low birth weight and poor nutrition • Diabetes epidemic due to: -lack of exercise and overweight in young persons, and -aging of the population • Correlation with central obesity, insulin resistance, glucose intolerance, high blood pressure , and dyslipidemia – metabolic syndrome

The Metabolic Syndrome: NCEP ATP III Criteria (May 2001 Guidelines) NCEP ATP III. JAMA. 2001; 285: 2486 -2497. 3 of the Following Risk Factor Defining Level Abdominal Obesity (waist circumference) Men >40 inches (102 cm) Women Triglycerides HDL Cholesterol Men Women Blood Pressure Fasting Glucose >35 inches (88 cm) 150 mg/d. L <40 mg/d. L <50 mg/d. L 130/ 85 mm. Hg 110 mg/d. L

What are the health risks associated with pre-diabetes? • Progression to diabetes: on average, 11% of people with pre-diabetes develop type 2 diabetes each year (DPP) • Other studies: majority with pre-diabetes develop type 2 diabetes in 10 years • Presence of microvascular complications at onset of diabetes • 50% higher risk of CVD: CAD and stroke

CDC Data http: //www. cdc. gov/diabetes/pubs/factsheets/prediabetes. htm accessed June 2010 Among adults with pre-diabetes in 2000, the prevalence of cardiovascular (heart) disease risk factors was high: 94. 9% had dyslipidemia (high blood cholesterol); 56. 5% had hypertension (high blood pressure); 13. 9% had microalbuminuria 16. 6% were current smokers

Population-based and Epidemiologic Data Relationship between A 1 c and CVD/allcause mortality is continuous and significant, even in persons without known diabetes EPIC-NORFOLK Study Each 1% increase in A 1 c above 5% was associated with a 21% increase in CV events. Ann Intern Med, Sept 2004 Harvard School of Public Health Study on Global CVD mortality: 21% of IHD and stroke deaths attributable to glucose above 90 mg/dl worldwide. Danaei et al, Lancet, Nov 2006 HUNT study 20 year f/u of newly diagnosed diabetes. 20% increase in IHD mortality per 1% increment in A 1 c. Eur Heart J, Feb 2009

Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults Selvin et al, NEJM, March 4, 2010 11, 092 adults from the ARIC Study, 1990 -92 Outcome Hazard Ratios for Glycated Hemoglobin ranges <5 5 – <5. 5 – <6 6 – <6. 5 ≥ 6. 5 Diagnosed Diabetes 0. 52 1. 00 1. 86 4. 48 16. 47 CHD 0. 96 1. 00 1. 23 1. 78 1. 95 HR for stroke were similar Association between A 1 c and death from any cause was J-shaped • Compared to fasting glucose, A 1 c was similarly associated with a risk of diabetes and more strongly associated with risks of CVD and death • Evidence supported the use of A 1 c as a diagnostic test for diabetes

Who should get tested for prediabetes? • • Age 45 or older Overweight Family history of diabetes Other risk factors for diabetes or pre-diabetes: sedentary lifestyle, hypertension, low HDL cholesterol, high triglycerides, history of gestational diabetes or giving birth to a baby weighing more than 9 pounds, or belonging to an ethnic or minority group at high risk for diabetes

Acanthosis Nigricans: a Sign of Insulin Resistance • Velvety, lightbrown-to-black discoloration usually on the neck, axilla, groin, dorsum of hands • May point to PCOS in females • Insulin sensitivity decreases by 30% at puberty with compensatory increase in insulin secretion

How often should be testing done? • Every 3 years if glucose tolerance is normal • Every 1 -2 years if pre-diabetes is diagnosed

What is the Treatment for Pre-diabetes? • Pre-diabetes is a serious medical condition! • It CAN be treated • TRIALS: Da Qing 1997, Finnish study 2001, DPP 2002: persons with pre-diabetes can prevent the development of T 2 DM by sustained lifestyle changes • 5 -10% reduction in body weight coupled with 30 minutes a day of moderate physical activity • Reversal of pre-diabetes and return of blood glucose levels to the normal range is possible

“I have bad genes”

DPP: Intensive Lifestyle Changes Reduce the Risk of Developing Type 2 Diabetes • 27 centers nationwide (1998 -2002) • Pre-diabetes, av. age 51, BMI 34, 68% women, 45% minority participants • Other groups at high risk: >60, women with h/o GDM, firstdegree relative with diabetes • > 7% loss of body weight and maintenance of weight loss • Dietary fat goal -- <25% of calories from fat • Calorie intake goal -- 1200 -1800 kcal/day • > 150 minutes per week of physical activity Parameter Placebo Metformin 850 mg bid Lifestyle: diet, exercise, behavior modification Weight Loss none 5 lbs 1 st yr: 15 lbs, end 10 lbs 7. 8% 4. 8% Diabetes at 2. 8 yrs 11%

Diabetes Prevention Program New Engl J Med Feb 2002

A Decade Later…. DPPOS The Lancet, Oct 2009 • At end of DPP: participants were offered a 16 -session program of intensive lifestyle changes (88% agreed) Parameter Placebo Metformin 850 mg bid Lifestyle: diet, exercise, behavior modification Weight Loss <2 lbs 5 lbs 7. 8% 4. 8% Diabetes at 2. 8 yrs 11% Diabetes at 10 yrs 5 -6% Percent reduction - 18 34 Delay in diabetes - 2 yrs 4 yrs • Lifestyle group: 34% reduction in diabetes risk maintained • More favorable CV risk factors: BP and TG’s, despite fewer drugs • Benefits more pronounced in elderly: 50% reduction in age >60

Pharmacologic Treatments for Pre-diabetes • Since many individuals with pre-diabetes are generally healthy, benefits of preventive therapy must outweigh any associated side-effects or risks • Expense • None are FDA-approved Agent Study RRR Side-effects Metformin Glucophage Da Qing, Finnish, DPP 28% GI Acarbose Precose STOP-NIDDM 25% GI, poor compliance Rosiglitazone Avandia DREAM 62% Bone loss, edema, CHF Orlistat Xenical, Alli XENDOS 52 -62% GI, poor compliance

NAVIGATOR Study NEJM online, March 14, 2010 Effect of Nateglinide and Valsartan on the Incidence of Diabetes and CV Events 9306 persons with IGT with CVD or CV risk factors followed for 5 years • Nateglinide: A postprandial glucose-lowering approach; incidence of diabetes 36% vs. 34%; composite CV outcome 14. 2% vs. 15. 2%; increased the risk of hypoglycemia • Valsartan: incidence of diabetes 33. 1% vs. 36. 8% (RR 14%); 38 fewer cases per 1000 pts treated for 5 years; no reduction in rate of CV events

ADA Consensus Statement: Preventive treatment in high-risk individuals with pre-diabetes Diabetes Care 2007 In addition to lifestyle modification, the following individuals should be considered for treatment with metformin: -those who have both IFG and IGT, and -at least one additional risk factor (age <60, BMI ≥ 35, FH of diabetes in first degree relative, elevated TGs, reduced HDL, or A 1 C >6%

What proportion of the US population merits consideration for metformin treatment? Rhee et al. Diabetes Care Jan 2010 • • • 1581 relatively healthy subjects from NHANES 25 -33% had pre-diabetes 1/3 of IFG, ½ of IGT, and all of IFG/IGT qualified 96 -99% had at least one other risk factor Overall, 8 -9% of all people qualified for metformin Perform OGTT in persons with IFG to test for IGT (or unrecognized diabetes) and possible metformin

2010 ADA Recommendations for Adults with Diabetes: Importance of Multi-factorial Therapy Diabetes Care, January 2010 Hemoglobin A 1 c < 7. 0% * In Pregnancy Plasma glucose: pre-meal postprandial < 6. 5% 90 -130 mg/dl < 180 mg/ml *Goals should be individualized. Less intensive glycemic targets may be indicated if there is frequent or severe hypoglycemia (older pts with long-standing disease? ) Blood Pressure < 130/80 mm. Hg In nephropathy < 125/75 mm. Hg LDL < 100 mg/dl Patients >40 years: statin therapy to achieve LDL reduction of 30 -40% In overt CVD HDL Triglycerides <70 using high-dose statins > 40 mg/dl < 150 mg/dl

Multifactorial therapy to reduce Macrovascular risk: Steno-2 Trial Debunking the “gluco-centric” view New Engl J Med, 2003, 2008 Multifactorial intervention aimed at multiple risk factors, behavior modification and pharmacologic therapy in type 2 diabetes: F F F hyperglycemia hypertension diabetic dyslipidemia microalbuminuria / use of ACE-inhibitors aspirin A 53% reduction in all cardiovascular endpoints and microvascular complications compared with conventional therapy

Preventive Strategies and Evidencebased Interventions that make sense • Changes at the individual level • Community- and population-based

Conflicting Messages!

A 57 -year-old accountant has a stressful lifestyle, has gained 12 lbs in the past year, and does not exercise regularly. She has a fasting glucose of 109 mg/dl. She is anxious about her prediabetic condition and wants to avoid having diabetes and its complications. Which of the following is NOT accurate advice for her? A. Pre-diabetes is the same as "borderline diabetes" or a "touch of sugar" and should only be treated aggressively when it progresses to diabetes B. Pre-diabetes is a serious condition that increases the risk of future diabetes and cardiovascular disease C. A diagnosis of pre-diabetes mandates that blood pressure and cholesterol be well-controlled

A 63 -year-old patient has a fasting blood glucose of 112 mg/dl. He has a BMI of 32, a Hb. A 1 c of 6. 1%, and a strong family history of type 2 diabetes. What is the most prudent next step? A. Tell him he has type 2 diabetes and start lifestyle changes B. Tell him he has pre-diabetes and start lifestyle changes C. Tell him he needs a glucose tolerance test

You diagnose a 49 -year old woman with pre-diabetes on the basis of screening with fasting glucose. In addition to emphasizing sustained lifestyle changes, you advise the patient that A. Although metformin has been shown to be effective in preventing progression of pre-diabetes, no medications are currently approved for treatment of the pre-diabetic state B. Metformin is approved for the drug treatment of pre-diabetes C. All pharmacologic agents approved for the treatment of diabetes can also be used in prediabetes