Guidelines for Pre diabetes Diagnosis and Management by MikeJenny


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 “I have no financial
disclosures to report.”
Guidelines for Pre-diabetes
Diagnosis and Management

          Ali A. Rizvi, MD
     Department of Medicine
    University of South Carolina
        School of Medicine

Natural History of Type 2 Diabetes

Plasma                                        glucose
                     126 mg/dL                     Fasting glucose

                                                Insulin resistance

Relative -Cell     20     10
                                  0    10       20        30
Function                                          Insulin secretion

                          Years of Diabetes
      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”

 A1c Derived Average Glucose (ADAG) Study
         Diabetes Care, August 2008
   Translating the A1c assay into estimated average glucose
                                          A1C           eAG
                                           %           mg/dl
• Increased accuracy of HbA1c               6           126
  in reflecting the true average
                                           6.5          140
                                            7           154
• Results reported as A1c-                 7.5          169
  derived average glucose
                                            8           183
  “estimated average glucose”
                                           8.5          197
  – eAG
                                            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 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.*

 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.
        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

   Parameter                     Normal Diabetes Pre-diabetes Method

1 Fasting Plasma                 <100              ≥126                100–125                   No caloric intake
  Glucose (mg/dl)                                                                                for at least 8 h

2 2-h plasma                     <140              ≥200                140–199                   WHO method: 75
  glucose on                                                                                     g glucose load
  OGTT (mg/dl)
3 Random plasma                  <140              ≥200                           -              with classic
  glucose (mg/dl)                                                                                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.
                 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)
             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.

               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
       Men                       <40 mg/dL
       Women                     <50 mg/dL
Blood Pressure                   130/85 mmHg
Fasting Glucose                  110 mg/dL
 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
                      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 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
        Who should get tested for pre-
•   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-
                       discoloration usually
                       on the neck, axilla,
                       groin, dorsum of
                       • May point to PCOS
                       in females
                       • Insulin sensitivity
                       decreases by 30% at
                       puberty with
                       increase in insulin
   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 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
• 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   Metformin    Lifestyle: diet, exercise,
                                 850 mg bid   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 Program
                                                                  New Engl J Med Feb 2002
                 8                                                                             0

                                                                          Weight Change (kg)

                                                                                                                                               FPG (mg/dl)
                 6                                                                             -2                                                            110

                 4                                                                             -4
                 2                                                                             -6

                                                                                               -8                                                            100
                                                                                                                                                                   0   1              2               3   4
                     0       1              2               3         4                             0   1              2               3   4
                                                                                                                                                                           Years from Randomization
                                 Years from Randomization                                                   Years from Randomization

   HbA1c (%)



                         0         1                 2            3                            4
                                       Years from Randomization
               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       Lifestyle: diet, exercise,
                                         850 mg bid      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

• 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       Da Qing,       28%      GI
        Glucophage      Finnish, DPP
        Acarbose        STOP-NIDDM     25%      GI, poor
        Precose                                 compliance
        Rosiglitazone   DREAM          62%      Bone loss,
        Avandia                                 edema, CHF
        Orlistat        XENDOS         52-62%   GI, poor
        Xenical, Alli                           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 A1C
    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/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
    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   hyperglycemia
F   hypertension
F   diabetic dyslipidemia
F   microalbuminuria / use of ACE-inhibitors
F   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
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
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
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
C. All pharmacologic agents approved for the
   treatment of diabetes can also be used in pre-

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