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Guidelines for Pre-diabetes Diagnosis and Management

Ali A. Rizvi, MDDepartment of Medicine

University of South Carolina School of Medicine

http://www.bluenile.com/

20 100 10 20 30

TYPE 2 DIABETES . . . A PROGRESSIVE DISEASE

Natural History of Type 2 Diabetes

Years of Diabetes

Relative -Cell Function

PlasmaGlucose

Insulin resistance

Insulin secretion

126 mg/dL Fasting glucose

Postmeal glucose

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

A1c Derived Average Glucose (ADAG) Study Diabetes Care, August 2008

Translating the A1c assay into estimated average glucose

• Increased accuracy of HbA1c in reflecting the true average glycemia

• Results reported as A1c-derived average glucose “estimated average glucose” – eAG

A1C eAG

% mg/dl

6 126

6.5 140

7 154

7.5 169

8 183

8.5 197

9 212

9.5 226

10 240

Role of A1c Testing to Diagnose Diabetes: Joint Recommendations from IDF, EASD, and ADA

June 2009

Advantages of A1c 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 over-

diagnosis. An A1c 5.7-6.4% indicates high risk for developing diabetes: “pre-diabetes”

ADA Diagnostic Criteria for DiabetesClinical Practice Recommendations 2010

1. A1C ≥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

A1C 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

In the absence of unequivocal hyperglycemia, criteria 1, 2, and 4 should be confirmed by repeat testing.

Parameter Normal Diabetes Pre-diabetes Method1 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 - with classic symptoms of hyperglycemia or crisis

4 A1C %

<5.7 ≥6.5 5.7 – 6.4 NGSP certified method standardized to the DCCT assay

The Epidemic of Diabetes and Pre-diabetes

• 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)

““What lies beneath…”What lies beneath…”

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: The Metabolic Syndrome: NCEP ATP III Criteria NCEP ATP III Criteria

(May 2001 Guidelines)(May 2001 Guidelines)

3 of the FollowingRisk Factor Defining LevelAbdominal Obesity (waist circumference)

Men >40 inches (102 cm)Women >35 inches (88 cm)

Triglycerides 150 mg/dLHDL Cholesterol

Men <40 mg/dLWomen <50 mg/dL

Blood Pressure 130/85 mmHgFasting Glucose 110 mg/dL

NCEP ATP III. JAMA. 2001;285:2486-2497.

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 A1c and CVD/all-cause mortality is continuous and significant,

even in persons without known diabetes

EPIC-NORFOLK Study Each 1% increase in A1c 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 A1c. 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 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 similarAssociation between A1c and death from any cause was J-shaped

• Compared to fasting glucose, A1c was similarly associated with a risk of diabetes and more strongly associated with risks of CVD and death• Evidence supported the use of A1c as a diagnostic test for diabetes

Who should get tested for pre-diabetes?

• 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, light- brown-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 T2DM 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, first-degree 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 Metformin850 mg bid

Lifestyle: diet, exercise, behavior modification

Weight Loss none 5 lbs 1st yr: 15 lbs, end 10 lbs

Diabetes at 2.8 yrs 11% 7.8% 4.8%

Diabetes Prevention ProgramNew Engl J Med Feb 2002

5.8

5.9

6.0

6.1

0 1 2 3 4

Years from Randomization

HbA

1c (%

)

100

105

110

115

0 1 2 3 4

Years from Randomization

FPG

(mg/

dl)

0

2

4

6

8

0 1 2 3 4

Years from Randomization

MET

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rs/w

eek

-8

-6

-4

-2

0

0 1 2 3 4

Years from Randomization

Wei

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e (k

g)

A Decade Later….DPPOSThe Lancet, Oct 2009

• At end of DPP: participants were offered a 16-session program of intensive lifestyle changes (88% agreed)

• 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

Parameter Placebo Metformin850 mg bid

Lifestyle: diet, exercise, behavior modification

Weight Loss <2 lbs 5 lbs 5 lbs

Diabetes at 2.8 yrs 11% 7.8% 4.8%

Diabetes at 10 yrs 5-6%

Percent reduction - 18 34

Delay in diabetes - 2 yrs 4 yrs

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

MetforminGlucophage

Da Qing, Finnish, DPP

28% GI

AcarbosePrecose

STOP-NIDDM 25% GI, poor compliance

RosiglitazoneAvandia

DREAM 62% Bone loss, edema, CHF

OrlistatXenical, Alli

XENDOS 52-62% GI, poor compliance

NAVIGATOR StudyNEJM 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-diabetesDiabetes 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 A1C >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 A1c < 7.0% *

In Pregnancy < 6.5%

Plasma glucose: pre-meal 90-130 mg/dl postprandial < 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 mmHg In nephropathy < 125/75 mmHg

LDL < 100 mg/dlPatients >40 years: statin therapy to achieve LDL reduction of 30-40%

In overt CVD <70 using high-dose statins HDL > 40 mg/dlTriglycerides < 150 mg/dl

Multifactorial therapy to reduce Multifactorial therapy to reduce Macrovascular risk: 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:

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 Evidence-based 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 pre-diabetic 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 HbA1c 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 pre-diabetes