Prediabetes: Metformin vs.

Lifestyle Intervention  

Tannaz Moin, MD, MBA, MSHS Assistant  Professor,  David  Geffen  School  of  Medicine  at  UCLA  

Division  of  Endocrinology,  Diabetes  and  Metabolism  HSR&D  Center  for  the  Study  of  Healthcare  InnovaEon,  ImplementaEon  &  Policy  

VA  Greater  Los  Angeles  Healthcare  System        

 I  have  no  conflicts  of  interest  to  disclose  

Outline  

•  Prediabetes  – DefiniEon,  controversies  and  emerging  data  

•  MeIormin  and  lifestyle  intervenEon  for  type  2  diabetes  prevenEon  

•  TranslaEon  in  real-­‐world  pracEce  

Prediabetes  

Intermediate  metabolic  state    with  abnormally  elevated    

blood  sugars      

Diagnos)c  thresholds?  Medicaliza)on  of  risk?  To  treat  or  not  to  treat?  

Prevent  vs.  delay?      

Exis8ng  Controversies  •  Tests  and  diagnosEc  thresholds:  

   

     

Prevalence    Risk  for  progression  to  type  2  diabetes    

Risk  of  micro-­‐  and  macrovascular  complica8ons  

Type  2  Diabetes  

Prediabetes  

Normal  

Diabetes  Care  2016  Jul;  39(7):  1186-­‐1201  

FPG    (mg/dL)  

126  

110  100  

Type  2  Diabetes  

Type  2  Diabetes  

2  hour  OGTT    (mg/dL)  

HbA1c  (%)  

Prediabetes   Prediabetes  

Normal   Normal  

200  

140  

6.5  

5.7  6.0  

Emerging  Data  •  Microvascular:  associaEon  cited  in  numerous  studies  •  Macrovascular:  meta-­‐analysis  of  53  prospecEve  studies  

–  é  risk  CV  events  (35  studies)  and  CHD  disease  (24  studies)  with  IFG,  IGT  and  HbA1c  5.7-­‐6.4%    

–  é  risk  all  cause  mortality  (25  studies)  and  stroke  (18  studies)  with  IFG  and  IGT  but  not  HbA1c  5.7-­‐6.4%  

•  Healthcare  uElizaEon:  1.3x  rates  of  hospitalizaEon  •  Prevalence  rising  worldwide  

–  Racial  and  ethnic  dispariEes  

 Lancet.  2012;379.  BMJ  2016;355:i5953    Diabetes  Care  2016  Mar;  dc151335  Policy  Brief  UCLA  Cent  Health  Policy  Res.  2016  Mar;(PB2016-­‐1):1-­‐8  

1  in  3  US  adults  have  prediabetes      

15-­‐30%  Percentage  who  will  transiEon  to  type  2  diabetes  in  5  years        

Growing  Public  Health  Concern  

MeWormin  vs.  Lifestyle  Interven8on  

The  Diabetes  Preven8on  Program  (DPP)  Study  

•  Double  blind  randomized  trial    •  3,234  parEcipants  from  27  centers  in  the  US  

– Mean  age  50.6  years  and  BMI  34.0  kg/m2  – 67.7%  women,  45.3%  minoriEes  – FPG  95-­‐125  mg/dL  and  OGTT  75g,  2hr  140-­‐199  mg/dL  

DPP  

Placebo   MeIormin  850mg  BID  

Intensive  Lifestyle  

16  one-­‐on-­‐one  sessions  Goals  =  7%  weight  loss,                  >150  min/wk  moderate  acEvity  

DPP  Results  

Intensive  lifestyle                                              was  most  effecEve      •  By  subgroup,  

meIormin  more  effecEve  if:  –  FPG  >110  mg/dL  –  Age  <60  years  –  BMI  >35  kg/m2  

REDUCING THE INCIDENCE OF TYPE 2 DIABETES WITH LIFESTYLE INTERVENTION OR METFORMIN

N Engl J Med, Vol. 346, No. 6

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February 7, 2002

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397

er increase in leisure physical activity than did par-ticipants assigned to receive metformin or placebo.The average weight loss was 0.1, 2.1, and 5.6 kg in theplacebo, metformin, and lifestyle-intervention groups,respectively (P<0.001).

Incidence of Diabetes

The cumulative incidence of diabetes was lower inthe metformin and lifestyle-intervention groups thanin the placebo group throughout the follow-up pe-riod (Fig. 2). The crude incidence was 11.0, 7.8, and4.8 cases per 100 person-years for the placebo, met-formin, and lifestyle-intervention groups, respective-ly (Table 2). The incidence of diabetes was 58 per-cent lower (95 percent confidence interval, 48 to 66percent) in the lifestyle-intervention group and 31percent lower (95 percent confidence interval, 17 to43 percent) in the metformin group than in the pla-cebo group. The incidence of diabetes was 39 per-cent lower (95 percent confidence interval, 24 to 51percent) in the lifestyle-intervention group than inthe metformin group. The results of all three pair-wise group comparisons were statistically significantby the group-sequential log-rank test. None of theseresults were materially affected by adjustment forbase-line characteristics. The estimated cumulativeincidence of diabetes at three years was 28.9 percent,21.7 percent, and 14.4 percent in the placebo, met-formin, and lifestyle-intervention groups, respective-ly. On the basis of these rates, the estimated numberof persons who would need to be treated for threeyears to prevent one case of diabetes during this pe-riod is 6.9 (95 percent confidence interval, 5.4 to9.5) for the lifestyle intervention and 13.9 (95 per-cent confidence interval, 8.7 to 33.9) for metformin.

Treatment Effects among Subgroups

Incidence rates and risk reductions within sub-groups of participants and the results of tests of thehomogeneity of risk reduction among subgroups areshown in Table 2; 95 percent confidence intervals forthe subgroup data indicate the precision of the risk-reduction estimate for each stratum. The study hadinadequate power to assess the significance of effectswithin the subgroups, nor were such tests planned.Significant heterogeneity indicates that treatment ef-fects differed according to the values of the covariates.Treatment effects did not differ significantly accord-ing either to sex or to race or ethnic group (Table 2).The lifestyle intervention was highly effective in allsubgroups. Its effect was significantly greater amongpersons with lower base-line glucose concentrationstwo hours after a glucose load than among thosewith higher base-line glucose values. The effect of met-formin was less with a lower body-mass index or a low-er fasting glucose concentration than with higher

values for those variables. Neither interaction wasexplained by the other variable or by age. The ad-vantage of the lifestyle intervention over metforminwas greater in older persons and those with a lowerbody-mass index than in younger persons and thosewith a higher body-mass index.

Glycemic Changes

In the first year, there was a similar reduction inthe mean fasting plasma glucose values in the met-formin and lifestyle-intervention groups, whereas thevalues rose in the placebo group (Fig. 3). The valuesrose in parallel in all three groups in subsequentyears. There was a similar temporal pattern in thevalues for glycosylated hemoglobin, except that thevalues in the metformin group were in betweenthose in the lifestyle-intervention and placebo groups.Figure 4 shows the percentage of participants whohad normal glucose concentrations (fasting values,post-load values, and both) at each annual examina-tion. Metformin and the lifestyle intervention weresimilarly effective in restoring normal fasting glucosevalues, but the lifestyle intervention was more effec-tive in restoring normal post-load glucose values.

Adverse Events

The rate of gastrointestinal symptoms was highestin the metformin group, and the rate of musculo-skeletal symptoms was highest in the lifestyle-inter-vention group (Table 3). Hospitalization and mor-tality rates were unrelated to treatment. No deathswere attributed to the study intervention.

Figure 2.

Cumulative Incidence of Diabetes According to StudyGroup.The diagnosis of diabetes was based on the criteria of theAmerican Diabetes Association.

11

The incidence of diabetes dif-fered significantly among the three groups (P<0.001 for eachcomparison).

0

40

0

10

20

30

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Year

Lifestyle

Metformin

Placebo

Cum

ulat

ive

Inci

denc

eof

Dia

bete

s (%

)

The New England Journal of Medicine Downloaded from nejm.org on August 22, 2013. For personal use only. No other uses without permission.

Copyright © 2002 Massachusetts Medical Society. All rights reserved.

The New England

Journal

of

Medicine

Copyr ight © 2002 by the Massachusett s Medical Society

VOLUME 346

F

EBRUARY

7, 2002

NUMBER 6

N Engl J Med, Vol. 346, No. 6

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February 7, 2002

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www.nejm.org

·

393

REDUCTION IN THE INCIDENCE OF TYPE 2 DIABETES WITH LIFESTYLE INTERVENTION OR METFORMIN

D

IABETES

P

REVENTION

P

ROGRAM

R

ESEARCH

G

ROUP

*

A

BSTRACT

Background

Type 2 diabetes affects approximate-ly 8 percent of adults in the United States. Some riskfactors — elevated plasma glucose concentrations inthe fasting state and after an oral glucose load, over-weight, and a sedentary lifestyle — are potentiallyreversible. We hypothesized that modifying thesefactors with a lifestyle-intervention program or theadministration of metformin would prevent or delaythe development of diabetes.

Methods

We randomly assigned 3234 nondiabeticpersons with elevated fasting and post-load plasmaglucose concentrations to placebo, metformin (850mg twice daily), or a lifestyle-modification programwith the goals of at least a 7 percent weight loss andat least 150 minutes of physical activity per week.The mean age of the participants was 51 years, andthe mean body-mass index (the weight in kilogramsdivided by the square of the height in meters) was34.0; 68 percent were women, and 45 percent weremembers of minority groups.

Results

The average follow-up was 2.8 years. Theincidence of diabetes was 11.0, 7.8, and 4.8 cases per100 person-years in the placebo, metformin, and life-style groups, respectively. The lifestyle interventionreduced the incidence by 58 percent (95 percent con-fidence interval, 48 to 66 percent) and metformin by31 percent (95 percent confidence interval, 17 to 43percent), as compared with placebo; the lifestyle in-tervention was significantly more effective than met-formin. To prevent one case of diabetes during aperiod of three years, 6.9 persons would have to par-ticipate in the lifestyle-intervention program, and 13.9would have to receive metformin.

Conclusions

Lifestyle changes and treatment withmetformin both reduced the incidence of diabetes inpersons at high risk. The lifestyle intervention wasmore effective than metformin. (N Engl J Med 2002;346:393-403.)

Copyright © 2002 Massachusetts Medical Society.

The writing group (William C. Knowler, M.D., Dr.P.H., Elizabeth Bar-rett-Connor, M.D., Sarah E. Fowler, Ph.D., Richard F. Hamman, M.D.,Dr.P.H., John M. Lachin, Sc.D., Elizabeth A. Walker, D.N.Sc., and DavidM. Nathan, M.D.) takes responsibility for the content of this article.

Address reprint requests to the Diabetes Prevention Program Coordinat-ing Center, Biostatistics Center, George Washington University, 6110 Ex-ecutive Blvd., Suite 750, Rockville, MD 20852.

*The members of the Diabetes Prevention Program Research Group arelisted in the Appendix.

YPE 2 diabetes mellitus, formerly callednon-insulin-dependent diabetes mellitus, isa serious, costly disease affecting approxi-mately 8 percent of adults in the United

States.

1

Treatment prevents some of its devastatingcomplications

2,3

but does not usually restore normo-glycemia or eliminate all the adverse consequences.The diagnosis is often delayed until complications arepresent.

4

Since current methods of treating diabetesremain inadequate, prevention is preferable. The hy-pothesis that type 2 diabetes is preventable

5,6

is sup-ported by observational studies and two clinical tri-als of diet, exercise, or both in persons at high riskfor the disease

7,8

but not by studies of drugs used totreat diabetes.

5

The validity of generalizing the results of previousprevention studies is uncertain.

9

Interventions thatwork in some societies may not work in others, be-cause social, economic, and cultural forces influencediet and exercise. This is a special concern in theUnited States, where there is great regional and ethnicdiversity in lifestyle patterns and where diabetes is es-pecially frequent in certain racial and ethnic groups,including American Indians, Hispanics, African Amer-icans, Asians, and Pacific Islanders.

10

The Diabetes Prevention Program Research Groupconducted a large, randomized clinical trial involv-ing adults in the United States who were at high riskfor the development of type 2 diabetes. The studywas designed to answer the following primary ques-tions: Does a lifestyle intervention or treatment with

T

The New England Journal of Medicine Downloaded from nejm.org on August 22, 2013. For personal use only. No other uses without permission.

Copyright © 2002 Massachusetts Medical Society. All rights reserved.

DPP  Outcomes  Study  (DPPOS)  Follow-­‐Up  Results  

Diabetes Prevention Program. Lancet. 2009;374:1677-1686. Lancet Diabetes Endocrinol 2015;3: 866–75.

2.8  Years  A\er  Randomiza8on  

10  Years  A\er  Randomiza8on  

15  Years  A\er  Randomiza8on  

Lifestyle   58%     34%     27%    

MeWormin   31%     18%     18%    

2.8  Years  

L  =  58%    

M  =  31%    

10  Years  

L  =  34%    

M  =  18%    

15  Years  

L  =  27%    

M  =  18%    

DPP  DPPOS  

Cumula8

ve  incide

nce  of  diabe

tes  (%)  

Time  since  DPP  randomiza8on  (years)  

Addi8onal  DPP  Findings  •  Intensive  lifestyle  lost  the  most  weight,  but  partly  regained;  meIormin  maintained  modest  weight  loss  

•  Heterogeneity  of  effect  by  age  and  subgroup  •  Reversion  to  normal  glycemia  was  associated  with  lower  rates  of  progression  to  type  2  diabetes  

•  Lifestyle  and  meIormin  had  similar  effect  in  prevenEng  HbA1c-­‐defined  diabetes  

•  Quality  of  life  é  with  lifestyle  but  not  meIormin  •  Lifestyle  cost-­‐effecEve,  meIormin  marginally  cost-­‐saving  vs.  placebo  

Lancet.  2012  Jun  16;  379(9833):2243-­‐51.  Diabetes  Care  2015  Jan;  38(1):  51-­‐58.    Ann  Intern  Med.  2005:142:323-­‐332.  Diabetes  Care.  2012;35:723-­‐730.

MeIormin  +  Lifestyle  IntervenEon  

Stepwise  Approach:  Diabetes  Community  Lifestyle  Improvement  Program  (D-­‐CLIP)  

•  Randomized,  controlled,  translaEonal  trial    •  578  Asian  Indian  adults  

– Mean  age  44.4  years  and  BMI  27.9  kg/m2  –  IGT,  IFG  or  IGT+IFG  

D-­‐CLIP  

Control  DPP  Lifestyle  +    MeIormin    500mg  BID  

At  4  months,  those  with  IFG+IGT  and  IFG  and  HbA1c>5.7%  were  prescribed  meIormin  

Diabetes  Care  2016  Aug;  dc161241.  

Stepwise  Approach:  Diabetes  Community  Lifestyle  Improvement  Program  (D-­‐CLIP)  

•  Mean  weight  loss  =  4%  at  6  months  •  Over  3  years  of  follow-­‐up,  32%  relaEve  risk  reducEon  (RRR)  with  lifestyle  +  meIormin  – Diabetes  incidence  34.9%  control  vs.  25.7%  lifestyle  +  meIormin,  p=0.014  

– Heterogeneity  of  effect  across  prediabetes  subtypes:    IGT+IFG>IGT>IFG  

•  Number  needed  to  treat  (NNT)  to  prevent  one  case  of  diabetes  =  9.8  

Diabetes  Care  2016  Aug;  dc161241.  

Other  Trials  Examining  MeWormin  +  Lifestyle  Interven8on  

Study, Year,

Country

Design Criteria N=total (n=Met)

Follow-up

(Years)

Arms Relative Risk

Reduction

IDPP, 2006 India

RCT IGT Age 33-55

531 (n=136)

2.5 1=control 2= L 3= M 250-500mg BID 4= L+ M 250-500mg BID

L = 28.2% M = 26.4% L + M = 28.2%

Andreadis et al, 2009 Greece

RCT BMI>27 Age>18

366 (n=95)

1 1= L (control) 2= L + M

L+M = 7% all (18.5% with predm)

Iqbal et al, 2012 Pakistan

RCT IGT 317 (n=95)

1.5 1= Control 2= L 3= L+ M 500mg BID

L = 71% L + M = 76.5%

SystemaEc  Review  of  MeIormin  Use  for  Type  2  Diabetes  PrevenEon.  Under  Review    

Summary  Lifestyle   MeWormin   Lifestyle  +  

MeWormin  Efficacy   Higher  relaEve  risk  

reducEon  overall      

More  effecEve  in  higher  risk  subgroups    Similar  to  placebo  in  those  >60  years  

More  effecEve    in  higher  risk  subgroups    (IFG+IGT)  

Safety     No  side  effects   Good  safety  profile    (GI,  B12)  

Same  

Cost   Cost-­‐effecEve   Marginally    cost-­‐saving   ?  Feasibility   Resource  intensive   Rx  readily  available   ?  Other  Considera8ons  

Benefits  beyond  diabetes  prevenEon  

No  FDA  indicaEon     Same    

NNT  over  3  yrs.   7   14   10  

Are  We  Transla8ng    Evidence  into  Prac8ce?  

Ann  Intern  Med.  2015;162(8):542-­‐548.  CDC  Prediabetes  Could  it  Be  You?  2016  

•  Lifestyle    –  Numerous  real  world  translaEonal  studies  –  Uptake  and  reach  remain  a  criEcal  challenge  

•  MeIormin  –  Efforts  to  translate  this  arm  of  the  DPP  have  been  limited  –  Extremely  low  rates  of  use  à  3.7%  of  insured  working  age  adults  with  prediabetes  were  prescribed  meIormin  2010-­‐12  

Prevent  Diabetes  STAT  

•  Public  health  campaign  launched  by  CDC  and  AMA    •  Healthcare  Provider  Toolkit    

– Methods  to  screen  and  refer  high-­‐risk  paEents  to  CDC-­‐recognized  community  based  or  virtual  DPP  in  their  communiEes    

www.PreventDiabetesSTAT.org  

Changing  Real  World  Prac8ce  

•  Refer  paEents  with  prediabetes  to  CDC  recognized  DPP  lifestyle  intervenEons  (preferred)    

•  Consider  meIormin  for  diabetes  prevenEon  in  high  risk  paEents:  age  <60  years,  BMI>35  kg/m2  ,  and  women  with  prior  gestaEonal  diabetes  

•  Monitor  for  development  of  diabetes  annually    •  Screen  and  treat  modifiable  risk  factors  for  CVD    

ADA Standards of Care 2016

Changing  Real  World  Prac8ce  

•  Increase  prediabetes  awareness  –  Prediabetes-­‐aware  adults  are  more  likely  to  engage  in  lifestyle  change  intervenEons    

•  Help  paEents  make  informed  choices  that  are  aligned  with  their  preferences  and  values  – OpportuniEes  to  promote  paEent-­‐centered  dialogue  about  prediabetes  in  primary  care    

–  PaEents  may  consider  both  intensive  lifestyle  and  meIormin  as  acceptable  treatment  opEons  

– UCLA  MyMeds  pharmacist  consults  available  in  EPIC    

Diabetes  Educ.  2016  Dec;42(6):667-­‐677  

Research  Funding  Acknowledgement:      

Thank  You!