In consideration of the enormous public health impact of diabetes and the evidence of benefit from pharmacological treatment for the prevention of diabetes, the ADA issued a consensus statement recommending preventive treatment in individuals at high risk of developing diabetes, defined as those with more severe pre-diabetes (both IFG and IGT as well as an additional risk factor) (8
). To determine the proportion of individuals who would be targeted by such a recommendation, we examined a relatively healthy population without previously diagnosed diabetes (SIGT) and representative samples of the U.S. population (NHANES III and NHANES 2005–2006) and found that one-quarter to one-third had pre-diabetes. Among those with IFG, nearly one-third of subjects met the criteria for consideration of metformin treatment to prevent diabetes in accordance with the recent ADA consensus statement, more than one-half of all of the subjects with IGT qualified, and almost all of those with both IFG and IGT qualified. Overall, 8–9% met the recommended criteria. Assuming that our data are generalizable to the U.S. population, ~24 million Americans might benefit from pharmacological treatment in addition to lifestyle modification.
The epidemic of diabetes and the insidious onset of its complications have prompted a call for early identification and preventive treatment of the disease. Diabetes is currently the leading cause of blindness, end-stage renal disease requiring dialysis, and nontraumatic amputations in the U.S. and increases the risk for cardiovascular disease and stroke by two- to fourfold, compared with those without diabetes (1
). It is the seventh leading cause of death (1
) and in 2007 cost $174 billion in both direct and indirect health care expenditures (2
). In addition, the prevalence of diabetes has been on the rise in the adolescent population (13
), indicating that the epidemic is likely to continue into the next generation.
Pre-diabetes, the stage preceding the development of diabetes, increases the risk for the development of diabetes, such that 25–39% of patients with IFG or IGT go on to develop diabetes over a period of 5–10 years (14
). Moreover, pre-diabetes alone has been associated with an increased risk for the development of cardiovascular disease (16
) and microvascular complications typically seen with diabetes (18
). Given these risks, prospective studies have been conducted to identify preventive treatment. In addition to lifestyle modification, pharmacological treatment with acarbose (5
), rosiglitazone (6
), orlistat (19
), or metformin (4
) has shown efficacy in preventing or delaying the onset of diabetes in individuals with pre-diabetes. The relative risk reduction for diabetes in the pre-diabetic population was 25% over 3.3 years in patients treated with acarbose (5
), 52–62% over 2–4 years with orlistat (19
), 62% over 3 years with rosiglitazone (6
), and 26–31% over 2.5–2.8 years with metformin (4
). However, because many individuals with pre-diabetes are generally healthy, the benefit of preventive treatment must outweigh any associated side effects or additional risks, particularly because none of these medications have U.S. Food and Drug Administration approval for the indication of diabetes prevention. Gastrointestinal side effects are commonly associated with acarbose (5
) and orlistat (19
), leading to poor patient compliance, whereas an increased risk of bone loss (20
), worsening or new-onset edema (21
), and heart failure (22
) are associated with rosiglitazone. Therefore, metformin, which has been used for many years and is both generally well tolerated and relatively safe, has become the leading candidate for preventive treatment.
In addition to the recommendations of the ADA, the American College of Endocrinology (ACE) has recently issued their consensus statement on the management of pre-diabetes (23
). Similar to the ADA recommendations, the ACE statement recognizes the need for preventive treatment, beginning with lifestyle modification, but also emphasizes the importance of treating relevant comorbid conditions, such as hypertension, hypercholesterolemia, and obesity, and provides a looser set of criteria regarding the initiation of pharmacological treatment. Acarbose and metformin are their recommended treatments for individuals who are at high risk of developing diabetes, which include, but are not limited to, those with IFG, IGT, and/or the metabolic syndrome, worsening glycemia, cardiovascular disease, nonalcoholic fatty liver disease, a history of gestational diabetes, or polycystic ovary syndrome. Taking into account the target populations as defined by the ADA and the ACE, >8% of Americans could benefit from pharmacological treatment to prevent or delay development of diabetes.
Use of pharmacological agents for the many Americans who may benefit from preventive treatment would incur substantial costs: at current generic rates for metformin, possibly $4/month × 12 months × 24 million Americans = $1.15 billion per year. However, several studies suggest that diabetes prevention or delay with metformin is likely to be cost-effective and/or cost-saving (24
); further evaluation using a variety of cost analysis methods may be required to reach a definitive conclusion regarding the cost of preventive treatment.
To our knowledge, our findings are the first evaluation of the proportion of relatively healthy individuals who might benefit from metformin treatment for the prevention or delay of development of diabetes. However, our study has limitations. Because all SIGT subjects were recruited on a volunteer basis, there may have been a selection bias toward higher family history of diabetes and/or other risk factors for diabetes. Therefore, the SIGT population may represent a group of individuals at higher risk. However, because many SIGT subjects were recruited from university and health care settings, they may also follow healthier lifestyles, which could offset such a bias. Moreover, the proportion with diabetes or pre-diabetes in SIGT was no higher than that in NHANES III and was comparable to that in the more recent NHANES 2005–2006, both of which represent randomized, stratified samples of the American population.
The morbidity, mortality, and cost of the epidemic of diabetes have prompted a call for primary prevention of diabetes in high-risk individuals by the use of metformin in addition to lifestyle changes. To the extent that our findings are representative of the U.S. population, close to 1 in 12 American adults may meet the recommended guidelines for consideration of metformin treatment for diabetes prevention or delay. Notably, eligibility for metformin use appeared to be almost completely determined by impaired glucose metabolism alone, because 99% of the SIGT population and 96% of the NHANES populations with both IFG and IGT had at least one risk factor. Therefore, once the presence of both IFG and IGT has been established, the presence of additional risk factors could almost be assumed, and initiation of metformin should be considered. Moreover, because nearly one-third of all subjects with IFG met the criteria for metformin treatment, providers should perform OGTTs in all patients with IFG to test for the presence of IGT (or unrecognized diabetes) and thereby determine whether they merit consideration of metformin treatment.