Prediabetes : why is it important

to identify & treat?

The Challenge and Countermeasures of
prediabetes management
 CONTENTS

A Challenge A
Management of
Pre-diabetes B Countermeasures
B
 The Challenge of prediabetes management

• High prevalence and

Disease level very harmful
• Lack of guidance
Management level

• Lack of cognition for

Doctor level prediabetes ， Missed the
opportunity for intervention
• Low awareness and poor
Patient level
compliance
 The prevalence of diabetes and prediabetes in the Asia-pacific
region is generally high ， account for more than 60% of the world
Comparison with the United States and the United Kingdom - prevalence of diabetes and IGT in Asia (%)
20
17.64
18

16 15.19
prevalence (%)

14 13.3
12.64 12.4 12.37
12 10.79 11.19

10 9.38 9.39
8.64 8.75 8.3
7.66 7.88
8 7.36
6.71 6.61 6.63
6.03 5.97 5.71
6 5.12 5.16
3.9
4

2 1
0

DM IGT

* ： 8.75%—North Korea
8.45%—South Korea

Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017

 Daqing Research ： Without intervention, 65.8% of
patients developed diabetes within 6 years
Percentage of progression to type 2

100
Control
Intervention
65.8%
90
80
70
diabetes (%)

60
50
40
6-year intervention hazard rate ratio: 0.49(95%CI 0.33-0.73)
30
20 20-year follow-up hazard rate ratio : 0.57(95%CI 0.41-0.81)
10

0 2 4 6 8 10 12 14 16 18 20
Years of follow-up
• A six-year clinical trial was conducted in daqing, China from 1986 to 1992 ,577 adults with impaired glucose tolerance were randomly
assigned to either the control group(n=138) or to one of three lifestyle intervention groups (diet, exercise, or diet plus exercise,n=438), After
6 years of lifestyle interventions, subjects were followed up until 2008 , We aimed to assess whether intensive lifestyle interventions have a
long-term effect on the risk of diabetes
Li G,et al.Lancet,2008,371:1783-1789.
 IGT progression to diabetes cardiovascular events
doubled ； The faster the progress, the higher the risk
IGT progression to diabetes Relationship between the duration of progression to
cardiovascular events doubled diabetes and the cumulative incidence of
cardiovascular events in IGT patients
27.9
Age - adjusted annual CVD event

30.0
incidence(/1000 person years)

A: patients who progressed to diabetes during the first 10 years of follow-up

IGT vs Progress to diabetes
20.0

First CVD events(%)

14.8
RR 1.90(1.55-2.32) B:Patients who developed diabetes were followed up for 10 to 20 years
C:Patients who did not progress to diabetes within 20 years were followed up
10.0
HR*(A/C):3.0(95%CI 1.9-4.8)
0.0 HR*(A/B):2.2(95%CI 1.3-3.7)

IG
T
tes *Adjusted for age, sex and intervention
e
iab
d
to
ss
g re
o
Pr
Years of follow-up

Li G,et al.Lancet,2008,371:1783-1789.
 The Challenge of prediabetes management

• High prevalence and very

Disease level harmful
• Lack of guidance
Management level

• Lack of cognition for

Doctor level prediabetes ， Missed the
opportunity for intervention
• Low awareness and poor
Patient level
compliance
 The Asia-Pacific consensus on pre-diabetes management points out:
Most Asian countries do not have formal guidance on diagnosis and
management of prediabetes
A Consensus of Key Opinion Leaders on the Management of Pre-diabetes in the Asia-Pacific
Region

It is urgent to formulate guidelines for pre-diabetes with

clinical guidance value
Most Asian countries do not have formal guidance on
diagnosis and management of prediabetes

Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017

 The Challenge of prediabetes management

• High prevalence and very harmful

Disease level

• Lack of guidance
Management level

• Lack of cognition for

Doctor level prediabetes ， Missed the
opportunity for intervention
• Low awareness and poor
Patient level
compliance
 Doctors do not have a clear understanding of pre-diabetes ，
has low compliance with the guideline for screening and intervention

positive attitude toward prediabetes （ as a clinical construct ）

Proportion of doctors who treat for pre- 1 Less Positive Attitude toward Prediabetes （ as a clinical construct ）
0.9
0.8
* 均 P<0.001
0.7 *
diabetes(%)

58.4%
0.6
0.5 44.4% *
0.4 36.4%
0.3
20.9%
0.2
0.1
0
Follow national guidelines for screening Drug therapy

• An electronic survey of a national sample of academic family physicians (n 1248) was conducted in 2016. Evaluate
the relationship between attitudes toward prediabetes as a clinical construct and screening/treatment behaviors for
diabetes prevention
Mainous AG 3rd, et al. J Am Board Fam Med. 2016 Nov 12;29(6)663-671.
 Prescription rate for pre-diabetes was low
Proportion of patients with pre-diabetes who prescribed metformin
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1 7.8%
0.05 3.7%

0
All pre-diabetes patients Pre-diabetes patients with high risk factors for diabetes

• We examined data from 2010 to 2012 from United-Healthcare (UHC), the nation’s largest private insurer, using a
retrospective cohort analysis of metformin prescription among adults with prediabetes over a 3-year period.

Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017

Moin T, et al. Ann Intern Med. 2015 Apr 21;162(8):542-8.
 Miss the opportunity for pre-diabetes prevention
due to various reasons
The Main Obstacles of Intervention to Pre-diabetes
100
83.2
80 75.3 75.3
认同的医生比例 (%)

71.9

60

40

20

0
Series1
a patient’s a patient’s ability to time to sustaining
economic resources Modify his or educate patient patient motivation
her lifestyle
• An electronic survey of a national sample of academic family physicians (n 1248) was conducted in 2016. Evaluate
the relationship between attitudes toward prediabetes as a clinical construct and screening/treatment behaviors for
diabetes prevention
Mainous AG 3rd, et al. J Am Board Fam Med. 2016 Nov 12;29(6)663-671.
 The Challenge of prediabetes management

• High prevalence and very harmful

Disease level

• Lack of guidance
Management level

• Lack of cognition for

Doctor level prediabetes ， Missed the
opportunity for intervention
• Low awareness and poor
Patient level
compliance
 Low awareness rate for pre-diabetes

The prevalence of pre- The awareness rate of

diabetes was 30 % pre-diabetes patients was 7.3 %

• In 2009, data were analyzed from 1402 adults aged 20 years without diabetes who participated in the 2005–2006
National Health and Nutrition Examination Survey ， aimed to study lifestyle changes consistent with reducing
diabetes risk and factors associated with their adoption among adults with prediabetes.
Geiss LS, et al. Am J Prev Med. 2010 Apr;38(4)403-9.
 Poor compliance with lifestyle intervention for
pre-diabetes patients
without Intervention Ongoing in 2 years
100
Proportion of patients(%)

80
60
45.9
40 36.5 36.5
25.7 28.4
21.6
20
0
To control body weight To increase physical activity To reduce fat/calories in diet

• This study was conducted between Jan 2012 and May 2013, and involved 881 adults aged ≥ 20 years without
being diagnosed as diabetes previously in the Suzhou community of China ， In the examination, 148 were
newly diagnosed prediabetes. aimed to investigate the intervention status of lifestyle changes for pre-diabetes
prevention.
Qianling Zhuang,et al. Int J Clin Exp Med 2015;8(3):4480-4486.
 The countermeasures of Pre-diabetes Management

• Pay attention to
Disease level
disease screening

• Develop relevant
guidelines / consensus Management level
• Improve understanding of
pre-diabetes and
Doctor level
• Popularize disease standardize diagnosis and
knowledge and take treatment
appropriate intervention Patient level

measures
 Pay attention to pre-diabetes screening
and improve screening rate
A Consensus of Key Opinion Leaders on the Management of Pre-diabetes in the Asia-
Pacific Region

Early screening and treatment of IGT patients can delay

or prevent the development of T2DM

Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017

 2018 ADA ： People who need prediabetes screening

asymptomatic adults children and adolescents

• Testing should be considered in overweight or Criteria

obese (BMI≥25 kg/m2 or ≥23 kg/m2 in Asian
• Overweight (BMI>85th percentile for age
Americans) adults who have one or more of and sex, weight for height >85th percentile,
the following risk factors ： or weight >120% of ideal for height)
• First-degree relative with diabetes
• High-risk race/ethnicity
• History of CVD Plus one or more additional risk
• Hypertension(≥140/90 mmHg)
• HDL cholesterol level ＜ 35 mg/dL (0.90
factors ：
mmol/L) and/or a triglyceride level ＞ 250 • Maternal history of diabetes or GDM
mg/dL during the child’s gestation
• Women with polycystic ovary syndrome • Family history of type 2 diabetes in first-
• Physical inactivity or second-degree relative
Other clinical conditions associated with • Race/ethnicity(Native American, African
insulin resistance (e.g., severe obesity,
American, Latino, Asian American, Pacific
acanthosis nigricans)
• For all other patients, testing should begin at age
Islander)
45 years • Signs of insulin resistance or conditions
associated with insulin resistance

Diabetes Care 2018;41(Suppl. 1):S13–S27.

 Asia Pacific guidelines/consensus:
people who need prediabetes screening
1 2 3
2017 A Consensus of Key Opinion 2017 RSSDI clinical practice 2014 Singapore MOH Clinical Practice
Leaders on the Management of Pre- recommendations for the management of Guidelines3
diabetes in the Asia-Pacific Region1 type 2 diabetes mellitus2
• Overweight/obesity (body mass index ≥25.0
• Patients aged ≥35 years and/or • Individuals presenting to kg/m2)
high risk individuals, High risk healthcare settings for • First degree relative with diabetes mellitus
individuals include overweight or unrelated illness • High risk race/ethnicity
• Family members of diabetes • Women who have delivered a baby 4 kg or more;
obese patients(country-specific),
or previously diagnosed with gestational diabetes
family history of diabetes, high patients mellitus
blood pressure, dyslipidemia, • Antenatal care • Hypertension ≥140/90 mmHg) or on therapy
history of large babies or • aged ＞ 30 years for hypertension
gestational diabetes • HDL cholesterol level <1.0 mmol/l (male), <1.3
mmol/l (female) and/or triglyceride level ≥2.2
mmol/l
• Women with polycystic ovarian syndrome
• IGT, or IFG on previous testing
• History of cardiovascular disease

1. Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017. 2. Int J Diabetes Dev Ctries. 2018 Mar;38(Suppl 1):1-115. 3. www.moh.gov.sg
 Guidelines/consensus
recommendations for pre-diabetes screening
2017
2018
Asia
ADA
To test for prediabetes,fasting plasma Pacific
glucose, 2-h plasma glucose during
75-g oral glucose tolerance test, and • for patients aged ≥35 years and/or high risk
HbA1c are equally appropriate individuals, followed by laboratory tests (i.e.,
FPG, HbA1c and/or 75-gram OGTT)

2013
ESC/EASD
• In the general population and people with assumed abnormalities
 start with aDM risk score andto investigate individualswith a high
value with an OGTT or a combination of HbA1c and FPG
• In CVD patients,no diabetesrisk score is needed but an OGTT is indicated if
HbA1c and/or FPG are inconclusive

1. Diabetes Care 2018;41(Suppl. 1):S13–S27. 2.Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017 3. Eur Heart J. 2013 Oct;34(39):3035-87.
 The countermeasures of Pre-diabetes Management

• Pay attention to
Disease level
disease screening

• Develop relevant
guidelines / consensus Management level
• Improve understanding of
pre-diabetes and
Doctor level
• Popularize disease standardize diagnosis and
knowledge and take treatment
appropriate intervention Patient level

measures
 Develop guidelines for pre-diabetes with clinical
guidance value
• As early as 2008, Europe and the United States developed a special pre-diabetes
management Guidelines ， while the Asia - Pacific region lacks a pre-diabetes management
guide

2013
2007
-Guidelines for the treatment of
-ADA pre-diabetes consensus pre-diabetes

2008
2018-ADA Guidelines
-Guidelines for the treatment of pre-
A pre-diabetes screening program
diabetes was clearly put forward

1.Xiao Xinhua. Journal of Practical Diabetes, 2008,4(4):3-4. 2.Guo yifang. Clinical metaphor,2010,25: 1937-1938. 3. Eur Heart J. 2013 Oct;34(39):3035-87. 4. ADA.Diabetes Care
2018;41(Suppl. 1):S13–S27.
 The countermeasures of Pre-diabetes Management

• Pay attention to
Disease level
disease screening

• Develop relevant
guidelines / consensus Management level
• Improve understanding of
pre-diabetes and
Doctor level
• Popularize disease standardize diagnosis and
knowledge and take treatment
appropriate intervention Patient level

measures
 To strengthen doctors' understanding of
pre-diabetes period
 Emphasize the significance of pre-diabetes management

lifestyle therapy ——Daqing research1

Lifestyle intervention during the IGT reduced the

risk of diabetes for up to 30 years
Study on Prevention of
Diabetes Mellitus in Japan2

Lifestyle intervention reduced the risk of diabetes

by 67.4% and significantly reduced weight

SMS Study on Prevention of Diabetes in India3

The Continuous Beneficial Effects of

Lifestyle Intervention

1.Gong Q, et al. Diabetes 2018 Jul; 67 (Supplement 1): 130-OR.Kosaka K,et al. 2. Diabetes Res Clin Pract. 2005 Feb;67(2):152-62.
3. Nanditha A,et al.Diabetes Res Clin Pract. 2018 Aug;142:213-221.
 Doctors should follow the existing guidelines and
intervene as soon as possible

The effect of lifestyle intervention is not good

and pharmacotherapy needs to be started
pharmacotherapy
Several studies have confirmed that the intervention of metformin and other
drugs can reduce the risk of new-onset diabetes in pre-diabetes patients  1-5

The basic treatment from pre-diabetes to the

whole process of diabetes
lifestyle therapy
Domestic and international studies show that lifestyle
interventions can significantly reduce the risk of diabetes6-10

1. Diabetes Prevention Program (DPP) Research Group, et al. Diabetes Care. 2002 Dec;25(12):2165-71.2.Ramachandran A, et al. Diabetologia. 2006
Feb;49(2):289-97.; 3.Holman R, et al. Diabetes, 2003, 20:S15.;4. Chiasson JL, et al. Lancet. 2002 Jun 15;359(9323):2072-7. 5. DREAM Trial Investigators, et
al. Lancet2006 Sep 23;368(9541)1096-105. 6.Li G,et al.Lancet,2008,371:1783-1789. 7.Tuomilehto J, et al. N Engl J Med. 2001 May 3;344(18)1343-50.
8.Knowler WC, et al.N Engl J Med. 2002 Feb 7;346(6)393-403.9.Kosaka K, et al. Diabetes Res Clin Pract. 2005 Feb;67(2):152-62.
 The countermeasures of Pre-diabetes Management

• Pay attention to
Disease level
disease screening

• Develop relevant
guidelines / consensus Management level

• Improve understanding of
pre-diabetes and
Doctor level
• Popularize disease standardize diagnosis and
knowledge and take treatment
appropriate intervention Patient level

measures
 Improve patients' understanding of pre-diabetes

Patient knowledge Doctor knowledge

 What is pre-diabetes?  What is the significance of

 What is the significance of pre- pre-diabetes
diabetes management ？ management ？
 Intervention Measures for
Pre-diabetes
The cooperation between doctors and patients can
realize the management goal of diabetes mellitus
Drug intervention in prediabetes ：
Timing and Choice
 Base on evidence ， national guidelines affirm the effectiveness of drug
intervention, expand drug intervention population,encourage early drug use
2018 ADA
1
： •Pre-diabetes patients recommend drug intervention to prevent diabetes

2017 CDS Guideline2

• The drug intervention was positively identified and recommended for the first time.
Indicate possible time nodes for drug intervention

2017 《 A Consensus of Key Opinion Leaders on the Management of Pre-diabetes in the Asia-Pacific Region 》
3
• Pharmacologic intervention is recommended if there is inadequate response to lifestyle
intervention after 3 to 6 months.
2017 RSSDI clinical practice recommendations for the management of type 2 diabetes mellitus 4
• People with prediabetes failing to achieve any benefit on lifestyle modifications after 6 months
may be initiated on oral antidiabetic agents (OADs)

2014-2015 RACGP General practice management of type 2 diabetes 5

• Interventions to achieve target HbA1c should begin with lifestyle modifcation followed by pharmacological
options selected on the basis of individual clinical circumstances, side effects and contraindications

1. Diabetes Care 2018;41(Suppl. 1):S13–S27. 2. 中华医学会糖尿病学分会 . 中华糖尿病杂志 ,2018,10(1):4-67. 3. Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine
 AACE/ACE guidelines recommend:
drugs such as metformin interfere with prediabetes

Alan J. Garber,et al, Endocr Pract. 2018;24(No. 1)

 Multiple studies have shown that drug interventions
can reduce the risk of new diabetes in patients with
prediabetes
Metformin Metformin Acarbose Acarbose TZD

DPP1 IDDP2 EDIT3 STOP-NIDDM4 DREAM5

31%* 26%* 34%* 25%* 60%*

*P<0.05 compared with the control group

1. Diabetes Prevention Program (DPP) Research Group, et al. Diabetes Care. 2002 Dec;25(12):2165-71.2.Ramachandran A, et al. Diabetologia. 2006 Feb;49(2):289-97.; 3.Holman R, et
al. Diabetes, 2003, 20:S15.;4. Chiasson JL, et al. Lancet. 2002 Jun 15;359(9323):2072-7. 5. DREAM Trial Investigators, et al. Lancet2006 Sep 23;368(9541)1096-105
 Normalization of glucose homeostasis of pre-diabetes
reduce macrovascular & microvascular complications
The risk of complications has increased Intensive glycemic therapy——the longer the duration,
before the diagnosis of diabetes the lower the benefit

DPP study1 UKPDS3 ADVANCE4 ACCORD5 VADT6

DaQing study2

Average disease duration 0 8 10 11.5

• Intensive hypoglycemic and
(years) conventional treatment have
no significant difference in
cardiovascular complications

• Intensive glucose increased

mortality compared with
DPP study conventional therapy
——microvascular complications benefits • Intensive hypoglycemic and conventional
DaQing study treatment have no significant difference
——follow-up 30 years, macrovascular in cardiovascular complications

complications benefits • After 30 years of follow-up, the risk of

cardiovascular complications was significantly
reduced compared with the conventional group.

1.DPP.Lancet Diabetes Endocrinol. 2015 Nov; 3(11): 866–875. 2. Gong Q, et al. Diabetes 2018 Jul; 67 (Supplement 1): 130-OR 3.UKPDS Group. Lancet 1998;352:837–853.
4ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–2572. 5.ACCORD Study Group. N Engl J Med 2008;358:2545–2559. 6.Meyers C, et al. Am J Cardiol 2006;98:63–65.
 Drug intervention timing:start drug intervention after 3-
6 months lifestyle intervention
RSSDI clinical practice recommendations for the
management of type 2 diabetes mellitus 20171

• People with prediabetes failing to achieve any benefit on lifestyle modifications

after 6 months may be initiated on oral antidiabetic agents (OADs)

China Guidelines for Type 2 Diabetes （ 2017 ） 2

• Drug intervention may be considered if the lifestyle intervention is

not effective for 6 months and other risk factors are combined.

A Consensus of Key Opinion Leaders on the Management of

Pre-diabetes in the Asia-Pacific Region3
• Pharmacologic intervention is recommended if there is
inadequate response to lifestyle intervention after 3 to 6 months.

1. Int J Diabetes Dev Ctries. 2018 Mar;38(Suppl 1):1-115. 2. 中华医学会糖尿病学分会 . 中华糖尿病杂志 ,2018,10(1):4-67. 3. Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017.
Metformin is an ideal drug choice for patients with prediabetes

pharmacodynamics
significant
Glucoregulation lasting
weight loss

Improve insulin Good safety

resistance and tolerance 的

Delay diabetes
cost effective
progression

Metformin is tailor-made for Asian populations

 DPP study:
Metformin reduced the risk of diabetes
Efficacy
RESULTS ：
• The incidence of diabetes in the intensive intervention
Mechanism
group, the metformin group, and the placebo group was
4.8, 7.8, and 11.0/100 person/year
Glucoregulation • Compared with placebo, metformin reduced the incidence
of new diabetes 31% of patients who achieved the goal,
Durability the risk of diabetes decreased by more than 90%
• At an average follow-up of 2.8 years, the weight lost 5kg,
and the risk of diabetes decreased by 55%.
Adiposity

Safety and • Standard Lifestyle Intervention: Adjust diet, weight loss and
tolerability appropriate exercise
• Intensive Life Intervention Goals: Weight loss reaches 7% of total
NCost weight, exercise at least 150 minutes per week, reduces fat intake
(25% of total calories)

• A total of 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a
lifestyle-modification program with the goals of at least a 7 percent 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 was 34.0; 68 percent were women, and 45 percent were members of minority groups

Knowler WC, et al. N Engl J Med. 2002 Feb 7;346(6):393-403

 DPPOS 15 years follow-up:
Metformin reduced the incidence of
Efficacy diabetes by 18% Placebo

Cumulative incidence of diabetes (%)

Metformin
Mechanism
Followed-up for 15 years, Cumulative
Glucoregulation incidence of diabetes ：
Placebo 62% 、 Metformin 56%

compared with placebo,

Durability
Followed-up for 10 years,
Metformin ：↓ 18%*
compared with placebo

Adiposity
Metformin ：
↓ 18%
Safety and
tolerability
*P ＜
NCost 0.05

Years Since DPP Randomization

• The DPP (1996–2001) was a randomized trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to
be at very high risk to develop diabetes. All participants were offered lifestyle training at DPP-end. 2776 (88%) of the surviving DPP cohort were
followed in the DPP Outcome Study (DPPOS 2002–2013) and analyzed by intention-to-treat based on original DPP assignment. During DPPOS, the
lifestyle group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin.
 Metformin as an AMPK-dependent energy balance regulator
with multiple benefits: regulating glucose and fat metabolism

Efficacy Food intake

NPY and AgPR
AMPK POMC
Mechanism
Leptin and insulin sensltivity

Glucoregulation

AMPK Insulin-stimulated glucose uptake

Durability Fat oxidation
Metformi
Adiposity
n
Safety and Leptin
tolerability AMPK
Weight

NCost

AMPK
Hepatic glucose production
Fat synthesis
Cholesterol synthesis
Malin SK,et al.Curr Opin Endocrinol Diabetes Obes. 2014 Oct;21(5):323-9.
AgRP, agouti-related protein;
AMPK, adenosine monophosphate
kinase;
CHO, carbohydrate;
GLP-1, glucose-like polypeptide-1;
NPY, neuropeptide-Y;
POMC, pro-opiomelanocortin
 Metformin significantly increased insulin sensitivity in
men and women with prediabetes
Efficacy
P < 0.05
Rd/I （ mg/kg FFA /min/pmol/ml ）
12
Mechanism
10
Glucoregulation
8
Durability 6
4
Adiposity
2
Safety and
tolerability 0
Before
治疗前 treatment After
治疗后 treatment
NCost
• For 12 weeks, men and women with prediabetes were assigned to the following groups: placebo (P), 2,000 mg/day metformin (M),
exercise training with placebo (EP), or exercise training with metformin (EM) (n = 8 per group). Before and after the intervention,
insulin sensitivity was measured by euglycemic hyperinsulinemic (80 mU/m2/min) clamp enriched with [6,6-2H]glucose. We
evaluated the effects of exercise training plus metformin on insulin sensitivity in men and women with prediabetes, compared with
each treatment alone.

Malin SK, et al. Diabetes Care. 2012 Jan;35(1)_131-6.

 Metformin significantly reduced blood glucose levels
• In the first year, there was a similar reduction in the mean fasting plasma glucose values in the
Efficacy metformin and lifestyle-intervention groups, whereas the values rose in the placebo group

Mechanism Panel A Panel B

Fasting Plasma Glucose

Glucoregulation
(mg/dL)

HbA1c(%)
Durability

Adiposity

Safety and
tolerability

NCost
Year Year

• A total of 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a
lifestyle-modification program with the goals of at least a 7 percent 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 was 34.0; 68 percent were women, and 45 percent were members of minority groups

Knowler WC, et al. N Engl J Med. 2002 Feb 7;346(6):393-403

 Metformin has a significant hypoglycemic effect
and it is recommended by the guidelines for prediabetes
Efficacy Guidelines drug Recommendations Adverse reactions
• Metformin therapy for prevention
Mechanism of type 2 diabetes should be considered in
those with prediabetes, especially for those
2018 ADA1 • Metformin
with BMI 35 kg/m2,those aged ,60 years, and
Glucoregulation
women with prior gestational diabetes
mellitus

Durability • Safe, well-tolerated ， may confer

• Metformin
a cardiovascular risk beneft
• Safe, well-tolerated ， may confer
Adiposity • acarbose
a cardiovascular risk beneft
2018 AACE/ACE2 • GLP-1 RA • safe ， effective
Safety and
tolerability • subcutaneous fat weight gain,
• TZD(Use with despite visceral adiposity
• Reduce the risk of diabetes
caution) reduction water retention and
NCost
potentially heart failure

2017 《 A Consensus of Key Opinion • Metformin should be initiated at a starting

Leaders on the dose
• Metformin
Management of Pre-diabetes in the of 500 mg/day titrated up to a maximum of
Asia-Pacific Region 》 3 2,000 mg/day as required

1.Diabetes Care 2018;41(Suppl. 1):S51–S54. 2. Alan J. Garber,et al, Endocr Pract. 2018;24(No. 1).3. Roberto Mirasol,et al. Journal of the ASEAN Federation of Endocrine Societies.2017
 DPPOS study, metformin is effective for up to 15 years
Efficacy
Placebo

Cumulative incidence of diabetes (%)

Metformin
Mechanism
Followed-up for 15 years, Cumulative
Glucoregulation incidence of diabetes ：
Placebo 62% 、 Metformin 56%

compared with placebo,

Durability
Metformin ：↓ 18%*

Adiposity

Safety and
tolerability
*P ＜
NCost 0.05

Years Since DPP Randomization

• The DPP (1996–2001) was a randomized trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to
be at very high risk to develop diabetes. All participants were offered lifestyle training at DPP-end. 2776 (88%) of the surviving DPP cohort were
followed in the DPP Outcome Study (DPPOS 2002–2013) and analyzed by intention-to-treat based on original DPP assignment. During DPPOS, the
lifestyle group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin.

DPP.Lancet Diabetes Endocrinol. 2015 Nov; 3(11): 866–875.

 Meta-analysis showed that the most common oral hypoglycemic
agent with the largest weight loss was metformin
• Compared with sulfonylureas, thiazolidinediones, DPP-4 inhibitors, glinides, and α-glycosidase
Efficacy inhibitors, metformin has the largest weight loss
Tolbutamide +2.8 kg
Mechanism
Pioglitazone +2.6 kg

Glimepiride +2.1 kg
Glucoregulation

Gliclazide +1.8 kg

Durability +2.6 kg
Glyburide

Glipizide +2.2 kg
Adiposity
Sitagliptin +0.55 kg

Safety and +0.3 kg

tolerability Nateglinide
Metformin -1.1 kg
NCost -0.4 kg
Acarbose
-0.7 kg
Miglitol

-1.5 -1.0 -0.5 0 0.5 1.0 1.5 2.0 2.5 3.0

weight loss weight gain

Domecq JP,et al.J Clin Endocrinol Metab. 2015 Feb;100(2):363-70.
 DPP randomized after 10 years of follow-up ， subjects in the
metformin group maintained moderate weight loss
DPP Study DPP randomized after 10 years of follow-up
Efficacy
Placebo
安慰剂 Metformin
二甲双胍 Lifestyle Metformin Placebo
Mechanism 0

体重自 DPP 基线变化 (kg)

-0.1
Mean body weight (kg)

Glucoregulation -0.5

Durability
-1

-1.5
Adiposity
-2
Safety and
tolerability -2.1
-2.5 0 1 2 3 4 5 6 7 8 9 10
NCost P<0.001
Years
• All active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5·7 years (IQR 5·5–5·8). 910
participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle
intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group
(850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support.
The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat.

Diabetes Prevention Program Research Group. Lancet. 2009 Dec 19;374(9707):1677-86.

 Metformin has been widely used for 60 years,
with good safety and tolerability
Efficacy

Metformin has widely experienced and could prevent diabetes

Mechanism

Glucoregulation
Metformin significantly reduced the severity and presence of
coronary calcification(in men)
Durability
y !
d el
Adiposity w i Metformin does not affect the balance of lactic acid metabolism
t and minimizes the risk of lactic acidosis
os
Safety and m
tolerability
t he Gastrointestinal symptoms attributed to study medication
reports declined throughout the DPP
NCost

Starting metformin has a lower risk of renal dysfunction and

death compared to the starting sulfonylurea
 DPPOS outcomes: Metformin significantly reduced the severity and
presence of coronary calcification(in men)

CAC severity CAC Presence

80
66.9 86% 84% 85%
70
58.3
60 82%
(Agatston units)
CAC severity

50

CAC Presence (%)

39.5
† 78%
40 75%
30 74% †
20 ‡
10 70%
0 Se-
Series1 ries1
Placebo lifestyle intervention Metformin Placebo lifestyle intervention Metformin
†p<0.05 vs
placebo
‡p<0.05 vs
CAC:coronary calcification, its severity is expressed in Agatston units, lifestyle
the normal value is 0, the higher the score, the more serious the CAC

Goldberg RB,et al.Circulation. 2017 Jul 4;136(1):52-64.

 No evidence of drug induced hepatotoxicity or drug-
induced elevations in serum ALT was observed
The percentage of patients with an ALT The percentage of patients with an ALT
value ≥ 3 times the upper limit of normal value >2 times the upper limit of normal

0% 0% 0% 1%
pioglitazone + metformin placebo + metformin pioglitazone + metformin placebo + metformin

alanine aminotransferase (ALT) value ≥3 times the upper limit of normal, a commonly used marker of potential liver damage.

• This was a 16-week, double-blind study with the option of enrollment in a separate open-ended, open-label study. It included patients with poorly controlled
diabetes mellitus (glycated hemoglobin [HbA1C] ≥8.0%, fasting C-peptide ~1.0 ng/mL) who had been receiving a stable regimen of metformin for ≥30 days. Patients
with diabetic retinopathy, nephropathy, or neuropathy; impaired liver or kidney function; or unstable cardiovascular or cerebrovascular conditions were excluded.
Patients were randomized to receive once-daily pioglitazone 30 mg + metformin or placebo + metformin. Patients in the openlabel extension received pioglitazone
30 mg (with optional titration to 45 mg) + metformin.

Einhorn D, et al. Clin Ther. 2000 Dec;22(12):1395-409.

 From the societal perspective*,
metformin intervention to reduce total economic cost
• The cost of lifestyle modification from the societal perspective would have to be reduced in order
Efficacy to match the cost-effectiveness of metformin intervention.

Type 2 diabetes Pre-diabetes/

Mechanism
40,000 NGR
35163
35,000 32921 33232
Glucoregulation
economic cost ($)

30,000 28108
25867 26177
Durability 25,000
20,000
Adiposity 15,000
Safety and 10,000
tolerability
5,000
NCost 0 2 型糖尿病 糖尿病前期 /NGR
安慰剂
Placebo 生活方式干预
Lifestyle modification 二甲双胍
Metformin intervention
* Societal perspective = total direct medical cost+direct nonmedical cost+indirect cost.

• Cost effectiveness was analysed from 2010–2012 using a decision-based model to estimate the rates of getting diabetes, healthcare costs and
health-related quality of life. Cost per quality-adjusted life year (QALY) was estimated using costs relevant to the time horizon of the study from
Singapore. All costs are expressed in 2012 US dollars.

Png ME, et al. PLoS One. 2014 Sep 9;9(9):e107225.

 Recommendation for metformin dose

The Stepwise Approach to Diabetes Prevention: Results

From the D-CLIP Randomized Controlled Trial

The recommended dose of Asian

population evidence1 ：
• Metformin 500mg twice daily

The recommended dose of DPP study2 ：

• Metformin 850mg twice daily

Reduction in the Incidence of Type 2 Diabetes With

Lifestyle Intervention or Metformin

1. Weber MB, et al. Diabetes Care. 2016 Oct;39(10)_1760-7. 2. Knowler WC, et al. N Engl J Med. 2002 Feb 7;346(6)_393-403.
 Conclusion
 From evidence to clinical ： The benefits of drug intervention in diabetes prevention have been confirmed. Base on
Evidence ， national guidelines(ADA,CDS et al) affirm the effectiveness of drug intervention, expand drug intervention
population,encourage early drug use
 Pre-diabetes drug intervention can delay diabetes progression and reduce the risk of complications, which translates into
potential pharmacoeconomic benefits
 Drug intervention timing:start drug intervention after 3-6 months lifestyle intervention
 Prediabetes drug intervention model:
 efficacy, mechanism, Glyco-metabolism regulation, durability, body weight impact, Safety, Tolerance and Cost-
effectiveness
 From mechanism to evidence-based evidence, metformin has sufficient evidence and high cost-effectiveness, making it
an ideal drug choice for patients with pre-diabetes
 Delay diabetes progression
 Activate AMPK pathway to improve insulin resistance
 Significant hypoglycemic, a hypoglycemic drug recommended in the pre-diabetes guidelines
 Well tolerated: DPPOS study, metformin is effective for up to 15 years
 Significant weight loss
 Metformin has been widely used for 60 years, with good safety and tolerability
 Metformin costs low and the cost efficiency is high
 Recommendation for metformin dose
THANKS
谢谢聆听