1. Reducing the Risk of T2DM: What Works?
Alice YY Cheng

2. Presenter Disclosure Faculty: Alice Cheng
CFPC CoI Templates: Slide 1
Presenter Disclosure
Faculty: Alice Cheng
Relationships with commercial interests:
Grants/Research Support: None
Speakers Honoraria: Abbott, AZ, BI, BD, BMS, Eli Lilly, Lifescan, Merck, Novo Nordisk, Sanofi, Servier, Valeant
Consulting Fees: Merck, Novo Nordisk, Sanofi, Takeda, Janssen
Other: none
This slide must be visually presented to the audience AND verbalized by the speaker.

3. Disclosure of Commercial Support
This program has received financial support from the following companies in the form of an educational grant:
AZ/BMS, Eli Lilly, BI, Novo Nordisk, Sanofi, Merck, Janssen, Takeda, Amgen, Paladin, Servier, Valeant, Abbott
Potential for conflict(s) of interest:
Alice Cheng has received honorarium from “CVH Endocrine Day”
The companies listed above benefit from the sale of product(s) that will be discussed in this program: all diabetes, hypertension and androgen related products
This slide must be visually presented to the audience AND verbalized by the speaker.

4. Mitigating Potential Bias
CFPC CoI Templates: Slide 3
Mitigating Potential Bias
All content based on peer-reviewed publications or the 2013 Canadian Diabetes Association clinical practice guidelines
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5. Learning Objectives
At the completion of this program, participants will be able to:
Define prediabetes
Discuss the strategies that have worked to reduce the risk of diabetes
Apply the strategies to their own clinical practice

6. guidelines.diabetes.ca

8. Fasting = no caloric intake for at least 8 hours
Diagnosis of Diabetes
2013
FPG ≥7.0 mmol/L
Fasting = no caloric intake for at least 8 hours or
A1C ≥6.5% (in adults)
Using a standardized, validated assay, in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes
2hPG in a 75-g OGTT ≥11.1 mmol/L
Random PG ≥11.1 mmol/L
Random= any time of the day, without regard to the interval since the last meal
Script:
Diabetes can be diagnosed by many different cut-offs. The biggest change from the previous set of guidelines is that HbA1c > 6.5% is part of diagnostic cut-off if a standardized validated assay is used with absence of other factors that affect A1c and not suspecting Dm. So FBG >7, A1c >6.5%, or 2h PG > 11.1 or random PG >11.1 can be used to used to diagnose diabetes.
Diagnosis of diabetes is based on thresholds of glycemia that are associated with microvascular disease
2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose

9. Glycemia and Retinopathy Thresholds
FPG 15
2hPG
Pima Indians
HbA1c
Retinopathy (%) 10 5
Threshold levels for the development of retinopathy are similar in all 3 populations: FPG ≥7.0 mmol/L
2hPG ≥11.1 mmol/L
A1C ≥6.5%
FPG (mg/dl)
70-
89-
93-
97-
100-
105-
109-
116-
136-
226-
2hPG (mg/dl)
38-
94-
106-
116-
126-
138-
156-
185-
244-
364-
HbA1c (%)
3.4-
4.8-
5.0-
5.2-
5.3-
5.5-
5.7-
6.0-
6.7-
9.5- 50
FPG
2hPG 40
HbA1c
Egyptians
Retinopathy (%) 30 20 10
FPG (mg/dl)
57-
79-
84-
89-
93-
99-
108-
130-
178-
258-
2hPG (mg/dl)
39-
80-
90-
99-
110-
125-
155-
218-
304-
386-
HbA1c (%)
2.2-
4.7-
4.9-
5.1-
5.4-
5.6-
6.0-
6.9-
8.5-
10.3-
FPG
As you can see through the graphs in different population such as the PIMA Indians, Egyptians and NHANES data, the threshold for retinopathy development is similar in all 3 population studies. 15
2hPG
HbA1c
NHANES III
Retinopathy (%) 10 5
FPG (mg/dl)
42-
87-
90-
93-
96-
98-
101-
104-
109-
120-
2hPG (mg/dl)
34-
75-
86-
94-
102-
112-
120-
133-
154-
195-
HbA1c (%)
3.3-
4.9-
5.1-
5.2-
5.4-
5.5-
5.6-
5.7-
5.9-
6.2-
The International Expert Committee. Diabetes Care 2009; 32:

10. Diagnosis of Prediabetes*
2013
Test
Result
Prediabetes Category
Fasting Plasma Glucose
(mmol/L)
Impaired fasting glucose (IFG)
2-hr Plasma Glucose in a 75-g Oral Glucose Tolerance Test (mmol/L)
7.8 – 11.0
Impaired glucose tolerance (IGT)
Glycated
Hemoglobin
(A1C) (%)
Prediabetes
* Prediabetes = IFG, IGT or A1C %  high risk of developing T2DM

11. A1C Level and Future Risk of Diabetes: Systematic Review
A1C Category (%)
5-year incidence of diabetes
<5 to 9%
9 to 25%
25 to 50%
Script: Zhang et al did a systematic review on A1c level and future risk of diabetes and you as the A1C increased from 6.0 to 6.5%, this covereted to a 5-year incidence of diabetes across 25% -50%.
Zhang X et al. Diabetes Care. 2010;33:

12. Risk of diabetes in the next 5 years…
IFG + A1C ( %) = 100%
Heianza Y et al. Diabetic Med 2012;29:e

13. Lifestyle

14. Da Qing – 20 yrs follow up of IGT population
HR 0.49
( )
HR 0.57
( )
Annual incidence of DM:
7% intervention vs 11% control
Li G, et al. Lancet :

15. Diabetes Prevention Program (DPP)
Years
Benefit of diet and exercise on diabetes prevention in at-risk patients
N = 3234 with IFG and IGT, without diabetes 10 20 30 40
1.0
2.0
3.0
4.0
Placebo
Lifestyle
Cumulative
incidence of diabetes
(%)
58%
< 0.001
*vs placebo
IFG = impaired fasting glucose, IGT = impaired glucose tolerance
In DPP, 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations were randomly assigned to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body mass index (BMI) was 34; average follow-up was 2.8 years.
Compared to placebo, the lifestyle intervention reduced the incidence of diabetes by 58% (95% CI, 48 to 66%) and metformin reduced the incidence by 31% (95% CI, 17 to 43%); the lifestyle intervention was significantly more effective than metformin.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:
Diabetes Prevention Program (DPP) Research Group. N Engl J Med 2002;346:

16. DPP – 10 years follow up Placebo Lifestyle 34%
DPP investigators. Lancet 2009;374:

17. Systematic review of lifestyle for IGT showing incidence of diabetes
Yoon U et al. Metab Clin Exp 2013;62:

18. Yoon U et al. Metab Clin Exp 2013;62:303-314

19. Pharmacologic

20. Diabetes Prevention Program (DPP)
Years
Benefit of diet and exercise or Metformin on diabetes prevention in at-risk patients
N = 3234 with IFG and IGT, without diabetes 10 20 30 40
1.0
2.0
3.0
4.0
Placebo
Metformin
Lifestyle
Cumulative
incidence of diabetes
(%)
31%
58% P*
< 0.001
*vs placebo
IFG = impaired fasting glucose, IGT = impaired glucose tolerance
In DPP, 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations were randomly assigned to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7% weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body mass index (BMI) was 34; average follow-up was 2.8 years.
Compared to placebo, the lifestyle intervention reduced the incidence of diabetes by 58% (95% CI, 48 to 66%) and metformin reduced the incidence by 31% (95% CI, 17 to 43%); the lifestyle intervention was significantly more effective than metformin.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:
Diabetes Prevention Program (DPP) Research Group. N Engl J Med 2002;346:

21. STOP-NIDDM Study Effects of Acarbose on the risk of T2DM
N = 1429 people with IGT, BMI 25-40, yrs, 3.3 years follow up
Days after randomization
Cumulative probability
P =
Acarbose
Placebo
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1.00
0.95
0.90
0.50
0.45
0.40
0.65
0.60
0.55
0.80
0.75
0.70
0.85
Acarbose
25%
STOP-NIDDM examined the effect of acarbose in preventing or delaying conversion of IGT to type 2 diabetes. Patients with IGT were randomly assigned to 100 mg of acarbose (n = 714) or placebo (n = 715) three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat.
Patients assigned to acarbose were 25% less likely to develop diabetes than those on placebo (P = )
Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359:
Lancet Jun 15;359(9323):
Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group.
Source
Research Centre, Centre Hospitalier de l'Université de Montréal, Hôtel-Dieu, Department of Medicine, University of Montreal, Quebec, Canada.
Abstract
BACKGROUND:
The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes.
METHODS:
In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat.
FINDINGS:
We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI ]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea.
INTERPRETATION:
Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.
Chiasson JL, et al. Lancet 2002;359:

22. Intervention Studies for Diabetes Prevention: Risk Reduction and Number Needed To Treat
Study
Intervention
RRR (%)
NNT for 3y
DPP1
(n = 3234 IFG+IGT)
Lifestyle intervention
Metformin 58 31
STOP-NIDDM2
(n = 1429 IGT)
Acarbose 25 11
DREAM 3
(n = 5269 IFG / IGT)
Rosiglitazone 62 7
ACT NOW4
(n = 602 IGT or both)
Pioglitazone
8.5
CANOE5
(n = 207 IGT)
Rosiglitazone + metformin 66
3.8
XENDOS 6
(n = 694 IGT)
Orlistat + lifestyle 45 10
A number of diabetes prevention studies have shown a reduction in the risk of diabetes with lifestyle and pharmaceutical interventions. The Da Qing IGT and Diabetes Study,1 the Finnish Diabetes Prevention Study (DPS)2, and the Diabetes Prevention Program (DPP) study3 all showed substantial reductions – up to 58% – in the risk of developing diabetes with lifestyle intervention in individuals with impaired glucose tolerance (IGT). Studies have also shown a reduction in the risk of diabetes with pharmaceutical interventions including the oral anti-diabetic agents rosiglitazone,4 metformin,3 troglitazone5 and acarbose.6
The relative risk reduction (RRR) and number needed to treat (NNT) for rosiglitazone in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial4 is similar to lifestyle intervention in the DPP trial2 and the Finnish DPS,3 and to troglitazone in the Troglitazone in Prevention of Diabetes (TRIPOD) study5 and DPP,2 and better than metformin in DPP2 and acarbose in the Study to Prevent Non-insulin Dependent Diabetes Mellitus (STOP-NIDDM).6
Note: It should be noted that the TRIPOD study was conducted exclusively on Hispanic women with recent gestational diabetes mellitus, who were therefore at high risk of developing type 2 diabetes.5 Furthermore, it should be noted that patients randomized to the intensive lifestyle-modification group of DPP were required to engage in at least 150 minutes of moderate physical activity per week and participate in a 16-lesson curriculum covering diet, exercise and behaviour modification.2 Such intensive lifestyle-modification strategies may not be achieved in the real-life patient setting.
For comparison purposes, the table in this slide provides the NNT for 3 years for each intervention. The original, published NNT values are as follows:
Da Qing:1 diet = 4 for 6 years, physical activity = 4 for 6 years, diet and exercise = 5 for 6 years
Finnish DPS:2 diet and exercise = 8 for 4 years
DPP:3 lifestyle intervention = 7 for 3 years, metformin = 14 for 3 years, troglitazone = 15 for 0.9 years
TRIPOD:5 troglitazone = 6 for 2.5 years
STOP-NIDDM:6 acarbose = 10 for 3.3 years
DREAM:4 rosiglitazone = 7 for 3 years, ramipril = not significant
Another trial, XENical in the prevention of Diabetes in Obese Subjects (XENDOS), compared the effects of orlistat to placebo (with diet and exercise in both groups) over 4 years in 3305 patients. Orlistat significantly reduced the rate of diabetes over 4 years (RRR 37.3%, P < 0.001).7
*The information contained herein does not necessarily reflect the content of the approved Canadian Product Monograph. The indication for rosiglitazone use in prediabetes has not been authorized for marketing within Canada.
1. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:
2. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:
3. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:
4. The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006;368:
5. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002; 51:
6. Chiasson JL, Josse RG, Gomis R, et al; STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359:
7. Torgerson JS, Moldrin MN, Hauptman J, et al. XENical in the prevention of diabetes in obese subjects (XENDOS) study. Diabetes Care 2004;27:
1. Knowler WC, et al. N Engl J Med 2002;346: Chiasson JL, et al. Lancet 2002;359:2072-7; 3.The DREAM Trial Investigators. Lancet 2006;368: Defronzo RA, et al. N Engl J Med 2011;364: Zinman B et al. Lancet Jul 10;376(9735): doi: /S (10) Epub 2010 Jun Torgorsen JS et al. Diabetes Care 2004;27:

23. Recommendation 1 and 2
2013
A structured program of lifestyle modification that includes moderate weight loss and regular physical activity should be implemented to reduce risk of T2DM in individuals with IGT [Grade A, Level 1A] or IFG [Grade B, Level 2] or A1C % [Grade D, consensus].
In individuals with IGT, pharmacologic therapy with Metformin [Grade A, Level 1A] or Acarbose [Grade A, level 1A] may be used to reduce the risk of T2DM.

24. THEREFORE … LIFESTYLE, LIFESTYLE, LIFESTYLE PHARMACOLOGIC
Low calorie, low fat
Moderate activity ≥ 150 minutes per week
Increase fibre intake
Goal of 5-10% weight loss
PHARMACOLOGIC
Metformin 850 mg BID
Acarbose 100 mg TID