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O R I G I N A L
Many Americans Have Pre-Diabetes and
Should Be Considered for Metformin
ARY K. RHEE, MD
K.M. VENKAT NARAYAN, MD
diabetes and then more rapidly to diabetes.
IRSTEN HERRICK, MSC
PAUL KOLM, PHD
AVID C. ZIEMER, MD
ENNIFER G. TWOMBLY, MD, PHD
studies, ϳ25–40% of individuals with pre- IOLA VACCARINO, MD, PHD
AWRENCE S. PHILLIPS, MD
diabetes go on to develop diabetes over 3– 8 ILLIAM S. WEINTRAUB, MD
years (4 – 6), and there is evidence of com-plications in 50% of patients at the time ofdiagnosis of diabetes (7).
OBJECTIVE — To determine the proportion of the American population who would merit
metformin treatment, according to recent American Diabetes Association (ADA) consensus panel recommendations to prevent or delay the development of diabetes.
lifestyle change and/or medication (4 – 6),the American Diabetes Association (ADA) RESEARCH DESIGN AND METHODS — Risk factors were evaluated in 1,581 Screen-
ing for Impaired Glucose Tolerance (SIGT), 2,014 Third National Health and Nutrition Exam-ination Survey (NHANES III), and 1,111 National Health and Nutrition Examination Survey 2005–2006 (NHANES 2005–2006) subjects, who were non-Hispanic white and black, without known diabetes. Criteria for consideration of metformin included the presence of both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), with Ն1 additional diabetes risk factor: age Ͻ60 years, BMI Ն35 kg/m2, family history of diabetes, elevated triglycerides, reduced HDL cholesterol, hypertension, or A1C Ͼ6.0%.
years, BMI Ն35 kg/m2, family history ofdiabetes in first-degree relative, elevated RESULTS — Isolated IFG, isolated IGT, and IFG and IGT were found in 18.0, 7.2, and 8.2%
of SIGT; 22.3, 6.4, and 9.4% of NHANES III; and 21.8, 5.0, and 9.0% of NHANES 2005–2006 subjects, respectively. In SIGT, NHANES III, and NHANES 2005–2006, criteria for metformin consideration were met in 99, 96, and 96% of those with IFG and IGT; 31, 29, and 28% of allthose with IFG; and 53, 57, and 62% of all those with IGT (8.1, 9.1, and 8.7% of all subjects), CONCLUSIONS — More than 96% of individuals with both IFG and IGT are likely to meet
ADA consensus criteria for consideration of metformin. Because Ͼ28% of all those with IFG met the criteria, providers should perform oral glucose tolerance tests to find concomitant IGT in all patients with IFG. To the extent that our findings are representative of the U.S. population, ϳ1 in 12 adults has a combination of pre-diabetes and risk factors that may justify consideration of metformin treatment for diabetes prevention.
teers without known diabetes who werescreened for diabetes/pre-diabetes by the Diabetes Care 33:49–54, 2010
75-g oral glucose tolerance test (OGTT).
Diabetesisapublichealthepidemic havepre-diabetes:impairedfastingglu- RESEARCHDESIGNAND
cose (IFG) and/or impaired glucose toler- METHODS — I n c r o s s - s e c t i o n a l
rently, an estimated 38 million Americans w h i c h t i m e g l u c o s e m e t a b o l i s m ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Emory University to change in lifestyle. Criteria for con- School of Medicine, Atlanta, Georgia; the 2Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, Georgia; the 3Department of Medicine, Division of Cardiology, Emory Program in Cardiovascular Outcomes Research and Epidemiology, At-lanta, Georgia; the 4Christiana Care Health System, Newark, Delaware; the 5Hubert Department of Global additional diabetes risk factor: age Ͻ60 Health, Rollins School of Public Health, Emory University, Atlanta, Georgia; the 6Department of Medi- cine, Emory University School of Medicine, Atlanta, Georgia; and the 7Atlanta VA Medical Center, Corresponding author: Mary K. Rhee, [email protected].
Received 3 March 2009 and accepted 21 September 2009. Published ahead of print at http://care.
diabetesjournals.org on 6 October 2009. DOI: 10.2337/dc09-0341.
2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
participate in the Screening for Impaired org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Metformin indicated in many pre-diabetic patients
by the Emory Institutional Review Board.
The invitation to participate was extended after ingestion of the glucose load. For our well as to members of the community.
Criteria for eligibility were age Ն18 years, and had a survey weight value Ͼ0 (n ϭ prior diagnosis of diabetes, not pregnant or breast-feeding, not taking glucocorti- Ն126 mg/dl or 2-h postchallenge glucose and A1C were categorized using the cut- Ն200 mg/dl. Isolated IFG was further offs recommended by the ADA: age Ͻ60 first visits (selected largely on the basis of (8). Other risk factors for diabetes that need to balance participant sex and race), begun before 11:00 A.M. after an overnight line, 1 h, and 2 h. Blood samples were also Hospital and Grady Memorial Hospital.
part in the Third National Health and Nu- within 30 min. All samples were stored at Ϫ80°C until assayed. Chemical analyses number of subjects in NHANES III and were performed in the central clinical lab- the diabetes status of one or more first- left blank (NHANES III, n ϭ 1,163; Statistics of the Centers for Disease Con- NHANES 2005–2006, n ϭ 116), relatives trol and Prevention that include both in- nationally representative sample to assess the health and nutritional status of adults for the analysis of the SIGT study group.
In addition, subjects with missing values 11:00 A.M. after an overnight fast of at least load, and had a survey weight value Ͼ0.
Among this subset (n ϭ 2,833), we in- by self-report and included family history of diabetes in a first-degree relative, race, history of hypertension, history of diabe- study population) (n ϭ 2,057).
seen in the morning session were asked to sured using digital scales with subjects in overnight for at least 9 h, reported no use jects had been seated quietly for 5 min.
of oral medications or insulin for diabetes, philia, and did not receive cancer chemo- therapy in the previous 3 weeks. All blood DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Rhee and Associates
Table 1—Characteristics of study subjects
of elevated triglycerides and A1C levels(Table 2). Even with the differences in theprevalence of risk factors, almost all sub- 2005–2006) and those with IGT (isolated IFG (isolated or with IGT), one-quarter to NHANES III, and 28% in NHANES2005–2006) met the recommended crite- to account for the complex survey design, had diabetes, similar to the proportions in ternational, Research Triangle Park, NC).
RESULTS — Among 1,581 volunteers
NHANES 2005–2006) did so (Fig. 1).
populations met the criteria for consider- NHANES III population (n ϭ 2,014), the CONCLUSIONS — In consideration
(n ϭ 1,111), the average age was 46 years diabetes, as specified by the ADA consen- presence of each risk factor was generally high risk of developing diabetes, defined Table 2—Prevalence of risk factors for diabetes in study subjects
Data are %. Glucose tolerance categories: IFG (ϮIGT), IFG with or without IGT; IGT (ϮIFG), IGT with or without IFG; IFG ϩ IGT, both IFG and IGT. *ReducedHDL cholesterol defined as Յ40 mg/dl in men and Յ50 mg/dl in women. †Hypertension defined by any of the following: history of hypertension, systolic bloodpressure Ն130 mmHg, or diastolic blood pressure Ն85 mmHg. ‡Metformin indicated per the ADA consensus statement (8) criteria of the presence of both IFG andIGT and one of the following diabetes risk factors: age Ͻ60 years, BMI Ն35 kg/m2, family history of diabetes, elevated triglycerides, reduced HDL cholesterol, andA1C Ͼ6.0%. Risk factors for diabetes that were not specifically defined by the ADA were categorized according to the AHA/NHLBI diagnostic criteria for metabolicsyndrome (12): presence of hypertension by history, systolic blood pressure Ͼ130 mmHg or diastolic blood pressure Ͼ85 mmHg, triglyceride level Ն150 mg/dl,and HDL cholesterol Ͻ40 mg/dl in men and Ͻ50 mg/dl in women.
DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Metformin indicated in many pre-diabetic patients
Figure 1—Prevalence of metformin indication, stratified by glucose tolerance category. Metformin is indicated per the ADA consensus statementcriteria of the presence of both IFG and IGT and one of the following diabetes risk factors: age Ͻ60 years, BMI Ն35 kg/m2, family history of diabetes,elevated triglycerides, reduced HDL cholesterol, and A1C Ͼ6.0% (8). Risk factors for diabetes that were not specifically defined by the ADA werecategorized according to the AHA/NHLBI diagnostic criteria for metabolic syndrome (12): presence of hypertension by history, systolic bloodpressure Ͼ130 mmHg or diastolic blood pressure Ͼ85 mmHg, triglyceride level Ն150 mg/dl, and HDL cholesterol Ͻ40 mg/dl in men and Ͻ50 mg/dlin women. Glucose tolerance categories are as follows: IFG 100 –109, FPG levels 100 –109 mg/dl and 2-h postchallenge plasma glucose Ͻ140 mg/dl;IFG 110 –125, FPG 110 –125 mg/dl and 2-h postchallenge plasma glucose Ͻ140 mg/dl; all IFG, isolated IFG (FPG 100 –125 mg/dl and 2-hpostchallenge plasma glucose Ͻ140 mg/dl); IGT, isolated IGT; and IFG 100 –125 ϩ IGT, all IFG and IGT. (both IFG and IGT as well as an additional and preventive treatment of the disease.
risk factor) (8). To determine the propor- Diabetes is currently the leading cause of identify preventive treatment. In addition tion of individuals who would be targeted blindness, end-stage renal disease requir- to lifestyle modification, pharmacological treatment with acarbose (5), rosiglitazone tions in the U.S. and increases the risk for cardiovascular disease and stroke by two- the onset of diabetes in individuals with pre-diabetes. The relative risk reduction billion in both direct and indirect health IFG, nearly one-third of subjects met the treated with acarbose (5), 52– 62% over prevalence of diabetes has been on the rise 2– 4 years with orlistat (19), 62% over 3 years with rosiglitazone (6), and 26 –31% cating that the epidemic is likely to con- over 2.5–2.8 years with metformin (4).
statement, more than one-half of all of the subjects with IGT qualified, and almost all of those with both IFG and IGT qualified.
benefit of preventive treatment must out- Overall, 8 –9% met the recommended cri- risk for the development of diabetes, such weigh any associated side effects or addi- teria. Assuming that our data are general- that 25–39% of patients with IFG or IGT tional risks, particularly because none of go on to develop diabetes over a period of dication of diabetes prevention. Gastroin- cardiovascular disease (16,17) and micro- associated with acarbose (5) and orlistat (19), leading to poor patient compliance, with diabetes (18). Given these risks, pro- DIABETES CARE, VOLUME 33, NUMBER 1, JANUARY 2010 Rhee and Associates
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Acknowledgments — This work was sup-
ported in part by grants DK-070715 and RR- effective and/or cost-saving (24); further glucose tolerance: implications for care.
evaluation using a variety of cost analysis 066204 (to L.S.P., W.S.W., P.K., and V.V.), VA HSR&D SHP 08-144 and IIR 07-138 (to finitive conclusion regarding the cost of the first evaluation of the proportion of No potential conflicts of interest relevant to 10. Centers for Disease Control and Preven- Parts of this study were presented in ab- prevention or delay of development of di- stract form at the 68th Scientific Sessions of Statistics (NCHS). National Health and the American Diabetes Association, San Fran- Nutrition Examination Survey Data. Third cisco, California, 6 –10 June 2008.
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