Improving diabetes prevention with benefit based tailored treatment: risk based reanalysis of Diabetes Prevention ProgramBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h454 (Published 19 February 2015) Cite this as: BMJ 2015;350:h454
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The present article (1) has provided leads to the effectiveness of lifestyle modifications in reducing the incidence of diabetes from a pre-diabetes state in the general population. The common concept of initiating metformin for the treatment of pre-diabetic state, as the only effective measure seems to be limited with the findings of this study. Though metformin treatment reduced the incidence by 21.5% in absolute terms, the benefit was maximal in the quarter with the highest risk of developing diabetes. The effect of lifestyle modification, on the other hand showed six fold reduction in absolute risk (28.3%) in the highest risk quarter, which is higher than metformin group.
A meta-analysis study (2) done on three randomized clinical trials showed that metformin decreases the rate of conversion from prediabetes to diabetes. The effective dose was 850 mg twice daily and lower dosage 250 mg twice or 3 times daily was not very effective. The studies were done in people of varied ethnicity. The number needed to treat was between 7 and 14 for treatment over a 3-year period. The study showed variations in the in overall rates of progression to diabetes in these 3 groups. The study from China(3) had an overall rate of conversion to diabetes of 10%; while that from India (4) showed a conversion rate of 48%. In the study (5) with mixed ethnicity (55% white, 20% African American, and only 5% Asian), a rate of conversion to diabetes was 24%.
The advantage of lifestyle modification is also stressed by Tulso P (6) which showed that there is 20% decline in the development of diabetes from pre-diabetic state by lifestyle intervention and that too for as long as 10 years. It also showed that 6.9 persons are needed to participate in the lifestyle intervention programme to prevent 1 case of diabetes during a 3-year period.
Considering the above facts, it would be customary and prudent for the health care professionals to advice strictly to follow life style modifications in the form of regular exercises, reduce sedentary workstyle, stress, dietary control and weight reduction measures for controlling pre-diabetes state progressing to diabetes. This aspect should be implemented in the health care system where diabetes prevention and control is a part of the national programme. Metformin can be used in the high risk category and that too, with lifestyle modification.
1.Sussman JB, Kent DM, Nelson JP, Hayward RA. Improving diabetes prevention with benefit based tailored treatment: risk based reanalysis of Diabetes Prevention Program.BMJ 2015;350:h454.
2.Lilly M, Godwin M. Treating prediabetes with metformin. Systematic review and meta-analysis. Can Fam Physician. 2009;55:363–9.
3. Li CL, Pan CY, Lu JM, Zhu Y, Wang JH, Deng XX, et al. Effect of metformin on patients with impaired glucose tolerance. Diabet Med. 1999;16(6):477–81.
4. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. Indian Diabetes Prevention Programme (IDPP) The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1) Diabetologia. 2006;48(2):289–97.
5. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.
6. Tuso P. Prediabetes and lifestyle modification: time to prevent a preventable disease. Perm J. 2014 Summer;18(3):88-93.
Competing interests: No competing interests
We read this research paper with interest, a thought provoking article. The benefit of metformin, however, was seen almost entirely in patients in the top quarter of risk of diabetes. No benefit was seen in the lowest risk quarter . A well known fact is “prevention is better than cure”; epidemiological studies reveal that being physical active improves longevity , also there is report from metaepidemiological study that therapeutic life style changes may be potentially as effective as many drug interventions in the secondary prevention of coronary heart disease, stroke, heart failure, and prediabetes .
Metformin was introduced in Europe in the 1970s and approved in the United States in 1995and it has an excellent therapeutic index for diabetes . It is a biguanide developed from galegine, found in Galega officinalis (French lilac) . Clinical trials showed that metformin has advantages over other agents used in the management of type II diabetes , and has documented effectiveness in diabetes prevention for subjects at a high risk . In the United Kingdom Prospective Diabetes Study, metformin was associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, and it also proved to be effective in decreasing diabetes-related death, myocardial infarction, and stroke . Currently because of proven benifits, metformin is one of the most frequently prescribed drugs in patients with type 2 diabetes all over the world.
Regarding future aspects:
Metformin has received increased attention due to the identification of anticancer effects; the risks of cancer among metformin users were significantly lower than those among non-metformin users. Also the use of metformin in diabetic patients was associated with significantly lower risks of cancer mortality and incidence . Metformin could become a more attractive chemoprevention agent in future than its present role in management of type 2 diabetes mellitus.
1. Sussman JB, Kent DM, Nelson JP, Hayward RA. Improving diabetes prevention with benefit based tailored treatment: risk based reanalysis of Diabetes Prevention Program. BMJ 2015;350:h454.
2. Lee I-M, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 2012;380:219-229.
3. Naci H, Ioannidis JPA. Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. BMJ 2013;347:f5577
4. Bailey CJ, et al. Metformin. N Engl J Med 1996;334:574–9.
5. Cusi K, Defronzo RA. Metformin: a review of its metabolic effects. Diabetes Reviews. 1998;6:89–131.
6. Bolen S, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007;147:386–99.
7. Knowler WC, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.
8. UKPDS Group, Turner RC, et al. Effects of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–865.
9. Noto H, Goto A, Tsujimoto T, Noda M. Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-analysis. PLoS ONE. 2012; 7(3): e33411. doi:10.1371/journal.pone.0033411
Competing interests: No competing interests
Sussman JB, et al’s paper investigated whether some participants in the Diabetes
Prevention Program were more or less likely to benefit from metformin or a structured lifestyle modification program by using a diabetes risk model. 3060 people without diabetes but with evidence of impaired glucose metabolism were analyzed. Although the lifestyle intervention provided a sixfold greater absolute risk reduction in the highest risk quarter than
in the lowest risk quarter, patients in the lowest risk quarter still received substantial benefit..
The benefit of metformin, however, was seen almost entirely in patients in the top quarter of risk of diabetes. No benefit was seen in the lowest risk quarter.1
Diabetes is the worst risk factor for most diseases including cardiovascular disease. It is well known that diabetes increases the risk of cardiovascular disease 3 times higher than other risk factors. Accordingly, to prevent diabetes is important. Unfortunately, the incidence of diabetes is increasing in a world.2 In this regard, the objective of the current study should be acknowledged. However, as Perera R and Stevens RJ discussed in their editorial, the dangers of subgroup analyses should be kept in mind, especially when not pre-specified in the original study protocol. The more such analyses are conducted, the greater the likelihood of a spurious finding.3 However, the conclusion of the current study seems to be appropriate and important that only people at the highest risk of diabetes should be given metformin for its prevention. Other patients would do better to concentrate on lifestyle changes, providing a personalized approach.1
On the other hand, Naci H, et al investigated to determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes. They included 16 (four exercise and 12 drug) meta-analyses and included 305 randomised controlled trials with 339 274 participants. They observed that no statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise v anticoagulants 0.09 and exercise v antiplatelets 0.10). Diuretics were more effective than exercise in heart failure (exercise vs diuretics 4.11). They concluded that although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.4 Indeed, the current study reported that the lifestyle intervention provided a similar hazard ratio and absolute risk reduction in the highest risk quarter compared with metformin.1 These studies point the importance of therapeutic life style changes compared with drugs intervention. All physicians should think about this message in time of many drugs being prescribed while elderly population is increasing fast and life expectancy is longer.
Funding: None, Disclosures: None
1. Sussman JB, Kent DM, Nelson JP, Hayward RA. Improving diabetes prevention with
benefit based tailored treatment: risk based reanalysis of Diabetes Prevention Program.
2. Lim S, Shin H, Song J, Kwak SH, Kang SM, Won Yoon J, et al. Increasing prevalence of metabolic syndrome in Korea - The Korean National Health and Nutrition Examination Survey for 1998-2007. Diabetes Care 2011;34:1323-8.
3. Perera R and Stevens RJ. Personalising results from large trials. BMJ 2015;350:h553.
4. Naci H, Ioannidis JPA. Comparative effectiveness of exercise and drug
interventions on mortality outcomes: metaepidemiological study. BMJ 2013;347:f5577
Competing interests: No competing interests