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T h e n e w e ng l a n d j o u r na l o f m e dic i n e Navigating the Choices for Diabetes Prevention
The global epidemic of type 2 diabetes has prompt- less specific cardiovascular disease that is the ed a large number of clinical trials aimed at re- major cause of death in patients with type 2 dia- ducing its incidence.1 Not surprisingly, addressing betes. Safe, inexpensive, and acceptable inter- the underlying lifestyle behaviors — overeating ventions that lower glycemia, halt or delay the and inactivity — that result in obesity, the pri- progression to diabetes, and reduce cardiovas- mary cause of the epidemic, has had a major and cular disease are highly desirable.
consistent effect in reducing the cumulative inci- In this issue of the Journal, the investigators of dence of diabetes. In addition, lifestyle interven- the Nateglinide and Valsartan in Impaired Glu- tions have reduced the cardiovascular risk fac- cose Tolerance Outcomes Research (NAVIGATOR) tors that typically accompany the prediabetic study report the results of their international and diabetic states.2,3 Several drugs that are used trial that examined the effects of the approved to treat diabetes have also been studied as a means diabetes medication nateglinide, a relatively weak, of reducing the incidence of the development of rapid-acting, sulfonylurea-like drug, and the an- diabetes. Metformin, the alpha-glucosidase in- giotensin-receptor blocker valsartan on the de- hibitor acarbose, and the thiazolidinedione velopment of diabetes and cardiovascular disease rosiglitazone have been shown to reduce the in- in a high-risk population.4,5 Although the study cidence of diabetes to variable degrees.1 The Dia- had an efficient factorial design, the results with betes Prevention Program (ClinicalTrials.gov respect to nateglinide and valsartan are reported number, NCT00004992) and its long-term out- separately in the Journal, as if there were two par- come study (NCT00038727), which are the only allel trials, since the authors report no interactions studies that can address comparative effective- between the treatments. This presentation belies ness since they included random assignment to one of the stated goals of NAVIGATOR — specifi- lifestyle modification, a medication, and placebo, cally, to study the combined effects of the two showed that lifestyle intervention had a substan- study drugs.6 These effects are reported only brief- tially more powerful effect than did metformin ly in Supplementary Appendix 1 for each article.
when each was compared with placebo (a reduc- The rationale for studying nateglinide is that tion in incident diabetes with lifestyle intervention the meglitinide class of hypoglycemic medica- of 58% at 3 years and 34% after 10 years vs. a tions, of which nateglinide is a member, has been reduction with metformin of 31% at 3 years and shown to lower postprandial glycemia, a puta- tive treatment target, since rising postprandial Although a reduction in the incidence of dia- glucose is the most common route to the devel- betes is important, the major public health im- opment of diabetes.7 Moreover, postprandial hy- pact of prevention studies will be determined by perglycemia (or hyperglycemia after an oral glu- whether the prevention of diabetes — or a delay cose-tolerance test) has been shown to be more in the development of the disease — will trans- closely associated with the risk of cardiovascular late into a reduction in the diabetes-specific disease than are fasting glucose levels.8 There long-term complications affecting the eye, kid- has been widespread interest in determining ney, and nervous system and will ameliorate the whether a causal relationship exists between el- Downloaded from www.nejm.org on March 14, 2010 . For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e evated postprandial glycemia and cardiovascular substantial lowering of overall glycemic levels with disease, and it has been recommended that tri- nateglinide. The other factor that might have miti- als be performed to test this hypothesis.9 Final- gated any putative salutary effect of nateglinide ly, owing to its rapid-action profile, nateglinide on the development of diabetes or cardiovascu- has a relatively low risk of causing hypoglyce- lar disease was the provision of a lifestyle inter- mia. The rationale behind the choice of valsartan vention program for all participants. Consider- to inhibit the renin–angiotensin axis is less ing the powerful effects of lifestyle interventions clear, other than the fact that both nateglinide in other trials,1 this design feature may have re- and valsartan are manufactured by the pharma- duced the magnitude of the potential benefit ceutical sponsor, which also designed the study. from nateglinide. This explanation is not persua- Secondary analyses of clinical trials have sug- sive. The lifestyle intervention program was not gested that angiotensin-converting–enzyme (ACE) effectively implemented, as evidenced by the inhibitors and angiotensin-receptor blockers trivial weight loss over the course of the study (ARBs) are associated with a reduced incidence and the 8% annual incidence of diabetes in the of diabetes; however, the development of diabe- placebo group, which was close to the rates tes was not measured uniformly, and the only found in control groups from other studies.
clinical trial that directly examined whether ACE The finding that valsartan failed to have an inhibition would prevent diabetes failed to show effect on either of the cardiovascular-disease out- that diabetes was prevented or that there were comes but had a positive effect on the incidence any beneficial effects on insulin resistance or of diabetes is surprising. Previous studies of ACE inhibitors and ARBs have suggested that these The results of the NAVIGATOR study are large- drugs have a beneficial effect on cardiovascular ly negative. Neither drug (nor the combination, disease in patients with diabetes, and the low- keeping in mind that one quarter of the study co- er blood pressure achieved would be expected hort took both drugs) reduced the two coprimary to result in a reduction in cardiovascular disease. cardiovascular-disease outcomes. The only posi- In the NAVIGATOR study, the high rates of loss tive result was a weak, albeit statistically signifi- to follow-up (13%), use of off-study ACE inhibi- cant, reduction in the incidence of diabetes with tors or ARBs among participants assigned to pla- valsartan.5 The relative reduction of 14% and cebo (24%), and nonadherence to valsartan (34% the absolute reduction of 3.7 percentage points by study end) could explain the absence of an in incident diabetes with valsartan, as compared effect on cardiovascular disease.
with placebo, over a mean follow-up of 5 years make valsartan the weakest of the drugs studied not support the contention that reducing post- prandial hyperglycemia has a specific role in Unfortunately, the NAVIGATOR study has not preventing diabetes or reducing cardiovascular definitively answered whether lowering postpran- disease. Other than increasing the rate of hypo- dial glycemia reduces the incidence of cardiovas- glycemia by a factor of two, nateglinide had lit- cular disease or diabetes, since the mean glucose tle effect. Although the authors suggest that the levels 2 hours after a glucose challenge in the prevention of diabetes with valsartan might make annual oral glucose-tolerance tests were higher in it a preferred drug as compared with antihyper- the nateglinide group than in the placebo group. tensive drugs that potentially worsen glycemia, The authors describe this paradoxical finding as valsartan was relatively weak in preventing dia- a rebound effect, since nateglinide was not ad- betes, and it did not lower the rates of cardio- ministered on the mornings that the oral glucose- vascular disease. The prevention of diabetes re- tolerance tests were performed, suggesting that on mains a critical public health priority, but for now the 364 other days of the year, when the admin- we should steer away from these two drugs and istration of nateglinide was not delayed, postpran- use effective lifestyle interventions and, in select- dial glucose levels were lower in the nateglinide ed persons, metformin to combat the epidemic.
group. However, there are no direct data to sup- Disclosure forms provided by the author are available with the port this contention, and no data on glycated he- full text of this article at NEJM.org.
moglobin are presented, other than in the sub- From the Diabetes Center, Massachusetts General Hospital, group that progressed to diabetes, to support a Harvard Medical School, Boston.
Downloaded from www.nejm.org on March 14, 2010 . For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved. This article (10.1056/NEJMe1002322) was published on March 6. Califf RM, Boolell M, Haffner SM, et al. Prevention of diabe-
14, 2010, at NEJM.org.
tes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide And Valsartan 1. Crandall JP, Knowler WC, Kahn SF, et al. The prevention of in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR)
type 2 diabetes. Nat Clin Pract Endocrinol Metab 2008;4:382- Trial. Am Heart J 2008;156:623-32.
7. Meigs JB, Muller DC, Nathan DM, Blake DR, Andres R. The
2. Goldberg RB, Temprosa M, Haffner S, et al. Effect of pro-
natural history of progression from normal glucose tolerance to gression from impaired glucose tolerance to diabetes on cardio- type 2 diabetes in the Baltimore Longitudinal Study of Aging. vascular risk factors and its amelioration by lifestyle and met- Diabetes 2003;52:1475-84.
formin: the Diabetes Prevention Program randomized trial by 8. Meigs JB, Nathan DM, D’Agostino RB, Wilson PW. Fasting
the Diabetes Prevention Program Research Group. Diabetes and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care 2002;25:1845-50.
3. Diabetes Prevention Program Research Group. 10-Year fol-
9. Nathan DM, Davidson MB, DeFronzo RA, et al. Impaired
low-up of diabetes incidence and weight loss in the Diabetes fasting glucose and impaired glucose tolerance: implications for Prevention Program Outcomes Study. Lancet 2009;374:1677-86. care. Diabetes Care 2007;30:753-9.
10. The DREAM Trial Investigators. Effect of ramipril on the
4. The NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes. N Engl J Med 2006;355:1551-62.
incidence of diabetes and cardiovascular events. N Engl J Med 11. Hanley AJ, Zinman B, Sheridan P, Yusuf S, Gerstein HC. Ef-
fect of rosiglitazone and ramipril on β-cell function in people 5. Idem. Effect of valsartan on the incidence of diabetes and with impaired glucose tolerance or impaired fasting glucose.
cardiovascular events. N Engl J Med 2010. DOI: 10.1056/ Diabetes Care 2010;33:608-13.
Copyright 2010 Massachusetts Medical Society. Downloaded from www.nejm.org on March 14, 2010 . For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

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