Transcript Guidelines for Pre-diabetes Diagnosis and Management

Disclosure Statement
“I have no financial
disclosures to report.”
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/dL
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
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 A1cderived average glucose
“estimated average glucose”
– eAG
A1C
%
6
6.5
7
7.5
8
8.5
9
9.5
10
eAG
mg/dl
126
140
154
169
183
197
212
226
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 overdiagnosis. 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.*
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
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 A1C
%
<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/dL
<40 mg/dL
<50 mg/dL
130/85 mmHg
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
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/allcause 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 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 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, 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
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
6
4
2
-2
-4
-6
0
1
2
3
0
4
Years from Randomization
6.0
5.9
5.8
0
1
2
Years from Randomization
1
2
Years from Randomization
6.1
3
4
110
105
100
-8
0
HbA1c (%)
115
0
FPG (mg/dl)
Weight Change (kg)
MET-hours/week
8
3
4
0
1
2
Years from Randomization
3
4
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
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
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 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
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 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
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
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 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 prediabetes