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Primary Prevention of Type 2 Diabetes: Lifestyle Intervention Works and Saves Money, but What Should Be Done With Smokers?

Posted on: Wednesday, 2 March 2005, 03:00 CST

Reducing the risk factors that diseases have in common may prove to be an efficient prevention strategy (1, 2). For example, major risk factors, including obesity, physical inactivity, smoking, hypertension, hyperglycemia, and hyperlipidemia, predict the development of several chronic diseases, such as cardiovascular disease, cancer, diabetes, and dementia (3-5). Although one risk factor may confer a greater risk for a certain disease outcome than another risk factor, these risk factors are correlated and seem to operate in concert. A successful preventive intervention must, therefore, target several risk factors simultaneously (2, 6). This characteristic of preventive interventions means that they are necessarily complex and require considerable resources.

Although several public health interventions have succeeded without a precise understanding of the natural history of the disease and the risk factors' mechanisms of action, we now prefer randomized, controlled trials (RCTs) to demonstrate efficacy. Such trials are often performed in high-risk participants. A high-risk participant often may be defined in several ways, but the high cost of large RCTs may mandate a simple definition that will inexpensively identify participants with a high probability of experiencing a study end point. Previous type 2 diabetes prevention trials have used participants with impaired glucose tolerance (7- 11) since their glucose levels are worsening and 30% to 50% of them become diabetic in 10 years (12). Since people with impaired glucose tolerance are already hyperglycemic, we may ask whether high-risk people who have not yet experienced hyperglycemia would be better targets for primary prevention interventions. To date, no trial has been designed to prevent hyperglycemia from occurring, and we must learn from secondary analyses of previous studies.

In this issue, Davey Smith and colleagues (13) present new results from the Multiple Risk Factor Intervention Trial (MRFIT), one of the largest RCTs of a lifestyle intervention (14). The primary aim of the MRFIT was to measure the effect of the intervention on the incidence of coronary heart disease (14). Davey Smith and colleagues' study is a secondary analysis that measured the incidence of type 2 diabetes in the intervention and control groups (13). Most of the study participants were normoglycemic at baseline. The intervention included dietary advice to reduce the intake of saturated fats and body weight if the participant was obese or to increase physical activity and the intake of polyunsaturated fats. The main finding occurred in nonsmokers: The intervention program resulted in a statistically significant 18% reduction in the incidence of diabetes during a 6-year period compared with the usual care group. In smokers, however, the incidence increased by 26%.

Lifestyle trials are particularly difficult to design. While RCTs using pharmacologie interventions conveniently use placebo as the reference, RCTs of lifestyle interventions in high-risk participants cannot withhold health advice from those allocated to the control group. Therefore, to achieve equipoise, the study design must reduce the contrast between the intervention and the "usual care" groups. Usual care may have affected various subgroups differently since the health advice given to smokers differed from that given to nonsmokers. Obviously, smoking cessation was the primary intervention in smokers, while nonsmokers received more dietary advice. This is due to the fact that the inclusion criteria in the MRFIT differed between smokers and nonsmokers. The MRFIT design required participants to have higher blood pressure and serum cholesterol levels in order to be eligible. Therefore, the results could be biased, and the validity of the contrasting findings between smokers and nonsmokers could be threatened. Nevertheless, Davey Smith and colleagues' findings are interesting, although, as the authors point out, we should interpret them cautiously.

The effect of the MRFIT lifestyle intervention is smaller than that in more recent diabetes prevention trials, but the participants in the more recent trials were at high risk for diabetes and the MRFIT participants were closer to average risk for diabetes. For comparison, it would have been interesting to see results from a subgroup of MRFIT participants who were at high risk for type 2 diabetes. The MRFIT investigators could have identified high-risk participants by using one of the recently developed risk scores for diabetes (15, 16). Although smoking is a risk factor for type 2 diabetes (17), it is obvious and is now documented by these MRFIT data that smoking cessation alone is not sufficient to prevent diabetes.

The findings in smokers were interesting. First, some smokers in the intervention group developed diabetes after starting antihypertensive drug treatment, primarily diuretics and β- blockers, that can unmask an underlying susceptibility to diabetes. Whether this effect of these drugs is stronger in smokers than in nonsmokers is not known but should be studied. Second, a small increase in body weight may have contributed to the precipitation of diabetes in smokers, although it did not explain all of it. These participants were probably already far along in the natural history of their diabetes and would have developed it eventually. Third, some smokers were able to stop smoking. The good news is that by stopping smoking, they reduced their risk for microvascular and macrovascular complications of diabetes, as well as several other severe diseases. Fourth, it is important to consider ways to reduce the risk for diabetes in smokers who do not quit. Some smokers in the intervention group developed diabetes after starting antihypertensive drug treatment, primarily diuretics and β- blockers. The risk for diabetes is about 20% lower in patients receiving angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists have shown risk for type 2 diabetes (18) compared with patients receiving diuretics and β-blockers. Therefore, drugs that interfere with the renin-angiotensin system may be useful in treating hypertension in smokers, a hypothesis that should be tested experimentally. Fifth, managing obesity in smokers is important. Smokers have greater abdominal obesity than nonsmokers (19). The proportion of visceral fat might increase further after the weight gain associated with smoking cessation, a question that future research should address. In any case, physicians must remember about weight control in smokers who are trying to quit, especially if their patients are not lean.

This issue has another article related to diabetes prevention. Recent trials, including the Diabetes Prevention Program (DPP), have shown that type 2 diabetes may be prevented by weight control, balanced diet, and sufficient physical activity (10). In this issue, Herman and colleagues (20) have now performed a detailed analysis of the DPP data to estimate the lifetime cost-effectiveness of the DPP interventions. Their findings suggest that, compared with usual care, the lifestyle intervention would delay the development of type 2 diabetes by 11 years and reduce the absolute incidence of diabetes by 22% in high-risk participants. The corresponding estimates for metformin treatment were 3 years and 9%, respectively. Lifestyle intervention was clearly cost-effective relative to usual care. Using metformin to prevent progression from impaired glucose tolerance to diabetes was less cost-effective, especially in older participants. Herman and colleagues' analysis is the first to show that diabetes prevention is cost-effective. We need cost- effectiveness data from other diabetes prevention studies to compare the results with these from the DPP.

A limitation in this cost-effectiveness analysis is that the authors did not consider adherence to the intervention. The Finnish Diabetes Prevention Study (DPS) (9) demonstrated that diabetes did not develop in any high-risk participant who managed to achieve moderate lifestyle goals (reduction of weight and dietary total and saturated fats and increase in dietary unsaturated fats and fiber and physical activity). An intention-to-treat analysis of the lifestyle intervention would reflect the effect of nonadherence. The intention-to-treat analysis of the DPS showed the same 58% relative risk reduction that occurred in the DPP (10), which shows the importance of adherence to the overall trial results. Therefore, improving the adherence to the lifestyle intervention would increase its cost-effectiveness substantially. While we know that not everyone can change his or her habits, the DPS results showed that 21% of the study participants in the intervention group achieved 4 or 5 of the 5 lifestyle goals and only 6% did not reach any goal (9). An important problem for the clinician is to identify patients who are unable to improve their lifestyle. Perhaps these patients would benefit from switching to a pharmacologie approach. A sequenced combination of lifestyle and pharmacologie strategies might further improve the cost-effectiveness of diabetes prevention when it is translated to clinical practice. T\his hypothesis is worth testing experimentally in high-risk participants.

Randomized trials have now unequivocally proven that preventing type 2 diabetes is possible. New RCTs may be needed to answer some specific questions, but the time is right to implement community- wide diabetes prevention programs. Finland has launched a nationwide program (21), and many other communities are making plans. The long- term follow-up of the DPP and the DPS are ongoing, and the findings may provide further insights. As demonstrated by the 2 papers in this issue, secondary analyses of data collected during the major RCTs can lead to new insights. The need for caution in interpreting results from secondary and subgroup analyses is not a valid reason not to do these analyses of valuable data. Finally, we must remember that a large proportion of the human population, including all ethnic groups, carries genes that permit type 2 diabetes to develop if a person's environment and lifestyle is conducive. During the history of public health, many large public health problems and epidemics have been overcome by acting on much less evidence than we have today for preventing type 2 diabetes. Therefore, we should act as if vigorous measures could control the emerging epidemic of diabetes, even though we may not eradicate this disease in those with a strong genetic background. In the 1970s, Dr. Jeremiah Stamler, one of the founders of the MRFIT, stated that mass diseases require mass prevention. The results from Herman and colleagues now suggest that the return on investment in diabetes prevention is similar to that for other preventive health interventions (20). Preventing diabetes would require major investment of resources, but the cost of this investment should probably be less than that needed to treat the disease and its complications.

References

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20. Herman WH, Hoerger TJ, Brandie M, Hicks K, Sorensen S, Zhang P, et al. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med. 2005;142:323-32.

21. Finnish Diabetes Association. Development Programme for the Prevention and Care of Diabetes in Finland 2000-2010. Tampere, Finland: Finnish Diabetes Association; 2001.

2005 American College of Physicians

Jaakko Tuomilehto, MD, PhD, MPolSc

University of Helsinki

National Public Health Institute

Helsinki, Finland

South Ostrobothnia Central Hospital

Seinajoki, Finland

Grant Support: By the Academy of Finland (46558).

Potential Financial Conflicts of Interest: Honoraria: Merck & Co., Inc.; Stock ownership or option (other than mutual funds): Orion Pharma; Grants received: AstraZeneca, Novartis.

Requests for Single Reprints: Jaakko Tuomilehto, MD, PhD, MPolSc, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland; e-mail, jaakko.tuomilehto@ktl.fi.

Ann Intern Med. 2005;142:381-383.

Copyright American College of Physicians Mar 1, 2005

Source: Annals of Internal Medicine

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