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2. Guidelines for Pre-diabetes Diagnosis and Management
Ali A. Rizvi, MD
Department of Medicine
University of South Carolina
School of Medicine

3. Relative -Cell Function
TYPE 2 DIABETES A PROGRESSIVE DISEASE Natural History of Type 2 Diabetes
Postmeal glucose
Plasma
Glucose
126 mg/dL
Fasting glucose
Insulin resistance
Slide 6-6
TYPE 2 DIABETES…A PROGRESSIVE DISEASE
Natural History of Type 2 Diabetes
The natural history of type 2 diabetes shows the progressive emergence of the disorder. Well before diagnosis, patients may have had significant hyperglycemia for years, perhaps more than a decade. Patients with type 2 diabetes have altered islet b-cell function and impaired insulin action in varying degrees. Plasma glucose may rise above normal in early adulthood, and as age- related declines in b-cell function occur—together with less physical activity and increases in adipose tissue mass—plasma glucose continues to rise. By the time diabetes is diagnosed, plasma glucose may range from 180 to 220 mg/dL. It has been estimated that only about one third of the population has acceptable glycemic control by current standards. Based on the progressive nature of diabetes, complications that may take years to develop are often already present at the time of diagnosis.
Riddle MC. Tactics for type II diabetes. Endocrinol Metab Clin North Am. 1997;26: ; Skyler JS. Insulin therapy in type 2 diabetes mellitus. In: DeFronzo RA, ed. Current Therapies of Diabetes Mellitus. St Louis, Mo: Mosby-Year Book Inc; 1998:
Relative -Cell Function 10
20 20 30
10
Insulin secretion
Years of Diabetes 3

4. 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

5. A1c Derived Average Glucose (ADAG) Study Diabetes Care, August 2008 Translating the A1c assay into estimated average glucose
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
Increased accuracy of HbA1c in reflecting the true average glycemia
Results reported as A1c-derived average glucose “estimated average glucose” – eAG
To facilitate patient-doctor communication regarding glucose levels, the A1c values are now being reported as eAG,
After standardization of A1c in the ADAG trial using CGMs for 6 months, and determining an accurate correlation with average glucose levels..
All labs now report…

6. Advantages of A1c over FPG or OGTT:
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 % indicates high risk for developing diabetes: “pre-diabetes”
Partly as a result of this standardization across labs and communities internationally (Col, SC, Paris, Fr) and other advantages (list)…
The Intl Expert Comm….
Rec a cut-off of 6.5 %
Not official rec yet, but perhaps in the next Annual ADA practice guidelines due in Jan 2010… 6

7. ADA Diagnostic Criteria for Diabetes Clinical 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.*
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.*
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.

8. How is pre-diabetes diagnosed
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 – 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.

9. 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) -
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
In the absence of unequivocal hyperglycemia, criteria 1, 2, and 4 should be confirmed by repeat testing.

10. 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)

11. 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

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

13. 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

14. CDC Data http://www. cdc. gov/diabetes/pubs/factsheets/prediabetes
CDC Data 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

15. 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
Plenty of Observational Data to support….

16. Hazard Ratios for Glycated Hemoglobin ranges
Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults Selvin et al, NEJM, March 4, ,092 adults from the ARIC Study,
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
1.23
1.78
1.95
HR for stroke were similar
Association 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
Plenty of Observational Data to support….

17. 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

18. 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

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

20. 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

22. “I have bad genes”
Will this knowledge help to change patients’ behavior? Or make them more fatalistic as in this case.. “I have a …”
A negative result may induce false complacency and an individual may give up on healthy lifestyle modifications…

23. DPP: Intensive Lifestyle Changes Reduce the Risk of Developing Type 2 Diabetes
27 centers nationwide ( )
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 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
1st yr: 15 lbs, end 10 lbs
Diabetes at 2.8 yrs
11%
7.8%
4.8%

24. Diabetes Prevention Program New Engl J Med Feb 2002

25. 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)
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
Metformin
850 mg bid
Lifestyle: diet, exercise, behavior modification
Weight Loss
<2 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

26. 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%

27. 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

28. 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 A1C >6%

29. 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

30. Plasma glucose: pre-meal 90-130 mg/dl postprandial < 180 mg/ml
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 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/dl
Patients >40 years: statin therapy to achieve LDL reduction of 30-40%
In overt CVD <70 using high-dose statins
HDL > 40 mg/dl
Triglycerides < 150 mg/dl
The ADA has adopted this multifaceted risk reduction in its recommendations which come out each year in January.
The guidelines do not stop with glucose goals… 30

31. 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:
hyperglycemia
hypertension
diabetic dyslipidemia
microalbuminuria / use of ACE-inhibitors
aspirin
A 53% reduction in all cardiovascular endpoints and microvascular complications compared with conventional therapy
To emphasize, in the last few slides we discussed glucose control only.
Hyperglycemia may be the a hallmark manifestation of diabetes, and it is true that some complications of diabetes may be mediated through high glucose, but diabetes is more than just high sugar…
When we move away from this rather glucocentric view and embrace a broader approach which involves a multifactorial intervention of the risk factors that cluster in diabetes… as was studied in the two Steno 2 trials

32. Preventive Strategies and Evidence-based Interventions that make sense
Changes at the individual level
Community- and population-based

33. Conflicting Messages!

34. 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?
Pre-diabetes is the same as "borderline diabetes" or a "touch of sugar" and should only be treated aggressively when it progresses to diabetes
Pre-diabetes is a serious condition that increases the risk of future diabetes and cardiovascular disease
A diagnosis of pre-diabetes mandates that blood pressure and cholesterol be well-controlled

35. Tell him he has type 2 diabetes and start lifestyle changes
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?
Tell him he has type 2 diabetes and start lifestyle changes
Tell him he has pre-diabetes and start lifestyle changes
Tell him he needs a glucose tolerance test

36. Metformin is approved for the drug treatment of pre-diabetes
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
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
Metformin is approved for the drug treatment of pre-diabetes
All pharmacologic agents approved for the treatment of diabetes can also be used in pre-diabetes