PREVENTION OF TYPE 2 DIABETES
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DR JAVAID IQBAL FCPS ASSISTANT PROFESSOR MEDICINE FMH CM AND
DCONSULTANT DIABETOLOGISTDIABETIC INSTITUTE PAKISTAN
Discussion with Family Physicians At UHS on
Diabetes
case1A 49 YEAR OLD FEMALE HAS BEEN REFERRED
TO YOU BY DENTIST FOR ADVICE WITH FOLLOWING LAB REPORTS
FASTING BSR 119HBA1C 6.3% HER MOTHER IS DIABETIC PHYSICAL
EXAMINATION REMARKABLE FOR WEIGHT 160 LB HEIGHT 5-3
BP 135/89 AND NECK EXAM. SHOWED BELOW
Neck exam
Questions ?Is she diabetic or normal?
What will be her long ter management ?What additional pathology she has?
AN APPROACH TO SUCH SCENARIOS
Can you guess normal values of fasting Random and HA1c?
NORMAL VALUES OF BLOOD SUGAR
Fasting plasma glucose (FPG) <100 mg/dL (5.6 mmol/L).
Two-hour glucose during OGTT <140 mg/dL (7.8 mmol/L).
Normal HbA1c Less than 5.7%
WHAT ARE VALUES OF BSR BSF AND HBA1c IN DIABETICS?
ADA Criteria for the Diagnosis of Diabetes
A1C ≥6.5%OR
Fasting plasma glucose (FPG)≥126 mg/dl (7.0 mmol/l)
OR
Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT
OR
A random plasma glucose ≥200 mg/dl (11.1 mmol/l) in the presence of
symptoms
What is state of this patient?
She is ----------------
Fasting
Diabetes >126 mg/dL
Normal 70-99 mg/dL
Impaired fasting glucose
100-125 mg/dL
Diabetes >200 mg/dL
Normal <140 mg/dL
Impaired glucosetolerance
140-199 mg/dL
OGTT
ADA Standards of Care. Diabetes Care, Suppl.1, 2010; ADA , EASD, IDF International
Expert Committee Report on HbA1c for Diagnosis of Diabetes.
Pre-diabetes(54 million)
Diabetes >6.5%
Normal <5.7.0%
High risk for diabetes 5.7-6.4%
HbA1c
New
Who will be labelled as PREDIABETIC?
Prediabetes: IFG, IGT, Increased A1C
Fasting plasma glucose between 100 and 125 mg/dL (5.6 to 6.9 mmol/L).
Impaired glucose tolerance (IGT) Two-hour plasma glucose value during a 75 g oral glucose tolerance test between 140 and 199 mg/dL (7.8 to 11.0 mmol/L).
A1C Persons with 5.7 to 6.4 percent
Will you manage this patient Actively?
Can we make her normoglycemic?
Can we delay onset of TYPE 2 Diabetes?
WHY IS IT IMPORTANT TO MANAGE PREDIABETICS ?
AACE Prediabetes Consensus Statement: Summary Untreated individuals with prediabetes are at
increased risk for diabetes as well as for micro- and macrovascular complications
Treatment goals are to prevent deterioration in glucose levels and modify other risk factors such as obesity, hypertension, and dyslipidemia The same blood pressure and lipid goals are suggested
for prediabetes and diabetes Intensive lifestyle management is the
cornerstone of all prevention efforts; pharmacotherapy targeted at glucose may be considered in high-risk patients
Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):1-53. Garber AJ, et al. Endocr Pract. 2008;14:933-946.
What clinical risks ensue if prediabetes is not treated
In the large DECODE Study, risks for all-cause mortality increased linearly as the 2-hour blood glucose level increased from 95 to 200 mg/dL.
In the Diabetes Prevention Program, approximately 8% of patients with impaired glucose tolerance had diabetic retinopathy as did nearly 13% of those whose condition progressed to diabetes.
The STOP NIDDM trial showed an increase in hypertension (> 140/90 mm Hg) in the placebo-treated patients with impaired glucose tolerance during a 3-year period, with an increase in clinical cardiovascular disease (CVD) events by approximately 5% during 4 years.
The Honolulu Heart Study showed that postchallenge hyperglycemia was associated with an increase in sudden death during a 23-year follow-up.
Road Map to Prevent Type 2 Diabetes
EarlyIdentification
Therapeutic Lifestyle
Management Pharmacologic
PersistentMonitoring ofGlucose and
Risk ReductionMeasures
Intervention
Age 30 or above for populations at high risk:
FPG or 2-h OGTT is therecommended screening procedure
•Medical nutritiontherapy (MNT)
•Physical fitnessProgram
•Weight loss
• 5%-7% reduction in bodyweight (if overweight)
• 30 minutes exercise, 5 times per week at the equivalence of brisk walking
Non-FDA approved*• TZD**• Metformin• Orlistat• AGI
* Shown to be effective in delaying theonset of type 2 diabetes in clinical studies
** A recent report (NEJM; 6/14/07) suggestsa possible link of rosiglitazone tocardiovascular events that requires furtherevaluation
• Hypertension• Dyslipidemia• Physical fitness• Weight control
• Family history of diabetes• Cardiovascular disease• Overweight• Sedentary lifestyle• Latino/Hispanic, African
American, Asian American,Native American, or Pacific Islander
• Previously identified IGTor IFG
• Hypertension• Elevated triglycerides,
low HDL, or both• History of gestational
diabetes• Delivery of a baby weighing
>9 lbs• Severe psychiatric illness
WHO SHOULD BE SCREENED AFTER AGE OF 30Family history of diabetesCardiovascular diseaseOverweightSedentary lifestyleLatino/Hispanic, AfricanAmerican, Asian American,Native American, or Pacific Islander
Previously identified IGTor IFG
HypertensionElevated triglycerides,low HDL, or both
History of gestationaldiabetes
Delivery of a baby weighing>9 lbs
Severe psychiatric ill
2-Track Approach to Reduce Risk Associated With Prediabetes
• Therapeutic lifestyle management
• Pharmacotherapy in high-risk patients
(1) Lower glucose to
prevent microvascular complications
and progression to diabetes
• Therapeutic lifestyle management
• Blood pressure goals: <130/80 mm Hg
• LDL goal: <100 mg/dL
(2) Address cardiovascular
disease risk factors
.
There is a long period of glucose intolerance that precedes the development of diabetes
Screening tests can identify persons at high risk
There are safe, potentially effective interventions that can address modifiable risk factors:
I. ObesityII. Body fat distribution III. Physical inactivityIV. High blood glucose
Feasibility of Preventing T2DM
Interventions to Reduce Risks Associated With PrediabetesTherapeutic lifestyle management is the
cornerstone of all prevention effortsNo pharmacologic agents are currently
approved for the management of prediabetes
Pharmacotherapy targeted at glucose may be considered in high-risk patients after individual risk-benefit analysis
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Lifestyle Intervention in Prediabetes
Persons with prediabetes should reduce weight by 5% to 10%, with
long-term maintenance at this level
A diet that includes caloric restriction, increased fiber intake, and (in some cases) carbohydrate
intake limitations is advised.
• A program of regular moderate-intensity physical activity for 30-60 minutes daily, at least 5 days a week, is recommended
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Self-Reported Risk Reduction Activities in Patients With Prediabetes (National Health and Nutrition Examination Survey Data)
0%20%40%60%80% 68% 60% 55%
42%
Percent of Patients
CDC. MMWR Morb Mortal Wkly Rep. 2008;57:1203-1205.
Interventions Proven to Delay or Prevent T2DM Development
Intervention
Rate of Conversion to
Normal Glucose Tolerance
Lifestyle (3 trials) 52%-58%Metformin (2 trials) 26%-31%Acarbose (1 trial) 25%Pioglitazone (1 trial) 48%
.
Prevention of T2DM: Lifestyle Modification Trials
Study N BMIkg/m2
Time(years)
RRR% ARR % NNT
Diabetes
Prevention
Study
523 31.0 3 58 12 22
, Diabete
s Prevent
ion Progra
m
2161 34.0 3 58 15 21
The Chinese Prevention Study
Series10
2
4
6
8
10
12
14
11.6
4.1
Inci
den
ce o
f D
iab
etes
(%
/yr)
RRR=65%
Control Metformin
The Effect of Metformin on the Progressionof IGT to Diabetes Mellitus (N=321)
IGT, impaired glucose tolerance; RRR, relative risk reduction.Yang W, et al. Chin J Endocrinol Metab. 2001;17:131-136.
T2DM Prevention in Women With a History of GDM: Effect of Metformin and Lifestyle Interventions
Findings from the DPP:Progression to diabetes is more common in women
with a history of GDM vs those without, despite equivalent degrees of IGT at baseline
Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM
DPP, Diabetes Prevention Program; GDM, gestational diabetes mellitus;IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.
Ratner RE, et al. J Clin Endocrinol Metab. 2008;93:4774-4779.
Effect of Acarbose on Reversion of IGT to NGT
200
210
220
230
240
250
P<0.0001
Placebo Acarbose
Nu
mb
er
of
Pa
tien
ts
n=241(35.3%)
n=212(30.9%)
IGT, impaired glucose tolerance; NGT, normal glucose tolerance.Chiasson JL, et al. Lancet. 2002;359:2072-2077.
The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM)
Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Patients With and Without Prediabetes
Patients N=152, weight 108.6 +/- 23.0 kg, BMI 39.6 +/- 7.0 kg/m2 (IGT
or IFG 25%)
Design 24-week randomized controlled trial: exenatide or placebo
plus lifestyle intervention
Results: Exenatide-treated patients lost 5.1 kg from baseline vs 1.6 kg with
placebo (P<0.001) Both groups reduced their daily caloric intake IGT or IFG normalized at end point in 77% and 56% of exenatide and
placebo subjects, respectively
BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.Rosenstock J, et al. Diabetes Care. 2010;33:1173-1175.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Special Concerns for Thiazolidinedione Use in Patients With Prediabetes
Because of concerns about long-term safety, use of thiazolidinediones should be reserved for higher risk populations and those failing other, lower-risk strategies
Medical Weight-Loss StrategiesOrlistat may prevent progression from
prediabetes to diabetesLorcaserin, a selective serotonin 2C
agonist, is indicated for use in obese patients with at least 1 weight-related comorbid condition (eg, hypertension, dyslipidemia, CVD, glucose intolerance, sleep apnea)
QYSMIA Low-dose, immediate-release phentermine and controlled-release topiramate is recommended for obese or overweight patients with weight-related comorbidities such as hypertension, T2DM, dyslipidemia, or central adiposity
CVD, cardiovascular disease; obese, BMI ≥30 kg/m2; overweight, BMI ≥27 kg/m2; T2DM, type 2 diabetes mellitus.
Garber AJ, et al. Endocr Pract. 2008;14:933-946.
Pharmacologic Weight-Loss Strategies
Drug name
Placebo-subtracted
mean % body weight loss
from baseline
Patients (N) in clinical program/
patients (n) with diabetes
% of patients losing ≥5% of body weight
Clinical trial withdrawal
rates
Orlistat
2.4% (following 4
years of treatment
with orlistat 120
mg TID)
7504/321
35.5%-54.8%
(following 1 year of
treatment with
orlistat 120 mg TID)
8.8%
Lorcaserin 3.3% at 52 weeks 6888/510 47.1% 36%-50%
Phentermine/ topiramate)
3.5%-6.4% 3678/808 45%-70% 31%-40%LOCF, last observation carried forward.
Orlistat [package insert]. South San Francisco CA; Genentech USA; 2010. Belviq [package insert]. Woodcliff Lake, NJ; Eisai Inc.; 2012.
Qsymia [package insert]. Mountain View, CA; VIVUS , Inc; 2012.
BLOOD PRESSURE MANAGEMENT
DPP Year 1: Mean Change in Blood Pressure
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
-3.4
-0.91 -0.9
Lifestyle Metformin Placebo
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
-3.6
-1.3
-0.89
Lifestyle Metformin Placebo
Ch
ang
e in
BP
(mm
Hg
)
Baseline BP 124 124 124 79 78 78
Systolic Diastolic
BP, blood pressure; DPP, Diabetes Prevention Program.Ratner R, et al. Diabetes Care. 2005;28:888.
Placebo Metformin Lifestyle0
5
10
15
20
25
30
35
40
Baseline
12 months
24 months
36 months
Pr e
vale
nce
of H
yper
ten
sio
n(%
of p
atie
nts
)
*
Effects of Metformin, Lifestyle Modifications, and Placebo on Hypertension Over 36 Months in DPP
P<0.001
P=0.08 P<0.001
DPP, Diabetes Prevention Program; HTN, hypertension.Ratner R, et al. Diabetes Care. 2005;28:888-894.
Hypertension defined as BP 140/90 mmHg
Cu
mu
lat i
ve I n
cid
ence
(%
)
0 4321 5
Years After Randomization
8
6
4
2
0
12
10
18
16
14
Acarbose
Placebo
RRR = 34% P=0.0059
BP, blood pressure; IGT, impaired glucose tolerance; STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus Trial
Chiasson JL, et al. JAMA. 2003;290:486-494.
STOP NIDDM: Incidence of New Cases of Hypertension in IGT Patients
DPP Study: Mean Change in Total and LDL Cholesterol
DPP, Diabetes Prevention Program; LDL-C, low-density lipoprotein.DPP Research Group. Diabetes Care. 2005;28:2472–2479.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
-2.5
-2
-1.5
-1
-0.5
0
-2.3
-0.9
-1.2
Lifestyle Metformin Placebo
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
-0.700000000
000001
-0.3
-1.3
Lifestyle Metformin Placebo
Ch
ang
e in
Lip
ids
(%)
Baseline (mg/dL) 202 127
Total Cholesterol LDL-C
DPP Study: Mean Change in Triglycerides and HDL Cholesterol
DPP, Diabetes Prevention Program.DPP Research Group. Diabetes Care. 2005;28:2472–2479.
Ratner R, et al. Diabetes Care. 2005;28:888-894.
-30
-25
-20
-15
-10
-5
0
-25.4
-7.4
-11.9
Lifestyle Metformin Placebo
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
1
0.3
-0.1
Lifestyle Metformin Placebo
Ch
ang
e in
Lip
ids
(mg
/dL
)
Baseline (mg/dL) 172 40
Triglycerides HDL-C
SUMMARY
Diabetes Prevention ProgramScreened 158,177
OGTT, then randomize
Metformin1073
Lifestyle1079
3819 randomized
Placebo1082
Thiazolidinedione585
3% Wt loss5% Wt loss ~10 month followup
31% Risk Reduction
58 %Risk Reduction
Diabetes Rate11 % per year
23 %Risk Reduction
Diabetes Prevention Program Research Diabetes Prevention Program Research GpGp, , NEJM NEJM 346(6): 393346(6): 393--403, 2002.403, 2002.
SUMMARY SLIDESStudy Highlights Individuals with prediabetes have glucose levels lower
than those with diabetes but higher than normal (fasting glucose level, 100 - 125 mg/dL; 2-hour levels, 140 - 199 mg/dL).
Prediabetes may be associated with, or may increase the risk for, cardiovascular disease and microvascular complications, and it may lead to the development of overt type 2 diabetes.
All patients with prediabetes should have intensive lifestyle management, which is safe and effective in improving glycemia and in decreasing cardiovascular risk.
Treatment goals for blood pressure and lipid control should match those for diabetes.
INTERVENTIONIndividuals with prediabetes should lose 5% to 10% of body weight and maintain it long term.
Regular, moderate-intensity physical activity is recommended for 30 to 60 minutes daily at least 5 days weekly.
Diet should be low in total fat, saturated fat, and trans-fatty acids and should include adequate dietary fiber.
SUMMARY For blood pressure control, lower sodium intake and
avoidance of excess alcohol are recommended. No drugs are currently FDA approved for prediabetes,
so decisions to start pharmacotherapy must be based on a risk-benefit analysis.
For persons with prediabetes at particularly high risk, pharmacologic glycemic treatment may be considered in addition to lifestyle changes.
Metformin and acarbose are safe and effective in helping prevent diabetes.
Although thiazolidinediones decrease the risk for progression from prediabetes to diabetes, safety concerns include congestive heart failure or fractures
Hypertension in prediabeticsAngiotensin-converting enzyme
inhibitors or angiotensin receptor blockers are recommended as first-line agents and calcium channel blockers as second-line treatment of hypertension.
Thiazides and/or β-blockers should be used with caution because of adverse effects on glycemia.
All persons with prediabetes who are not at increased risk for gastrointestinal tract, intracranial, or other bleeding should take aspirin.
TARGETS LDL AND BP . Statins are recommended if needed to
achieve treatment goals for low-density lipoprotein cholesterol levels (100 mg/dL), nonhigh-density lipoprotein cholesterol levels (130 mg/dL), and apolipoprotein B (90 mg/dL).
Patients with prediabetes should have the same target blood pressure as do persons with diabetes (systolic < 130 mg Hg; diastolic 80 mm Hg)
Monitoring Highest-risk patients should be
monitored more often.The costs of prediabetes management
may be offset by cost savings from reduced patient-years of the disease, complications, and hospitalizations.
Monitoring for patients with prediabetes should include an annual glucose tolerance test and twice-yearly testing for microalbuminuria and fasting plasma glucose, hemoglobin A1C, and lipid levels.
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