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Diabetes and Cardiovascular Risk
not in the intensive arms of the blood pressure and lipid ACCORD trials, late in type 2 diabetes and whether using a particular therapeutic
this would answer the question raised above and provide very useful approach to glycemic control provides an advantage. The necessary
guidance for treating individual patients. Does it matter how we lower size, duration, and cost of such a trial, however, are formidable
blood glucose? The evidence for a beneficial effect of metformin on CVD obstacles that may prevent its execution. Therefore, clinical strategy
event rates is impressive and justifies its recommendation as first-line must proceed on the basis of what is known. In most patients, an HbA
1c
pharmacological treatment of type 2 diabetes.
49
The situation with the level ≤7.0% lowers the risks of retinopathy, nephropathy, and neuropathy
TZDs is less clear-cut, although this drug class has been shown to substantially, if not completely, but requires special effort to decrease
have numerous antiatherosclerotic, antiendothelial dysfunction, anti- episodes of severe hypoglycemia with their dangerous consequences.
thrombogenic, and pro-fibrinolytic actions.
3
On the other hand, TZDs
double the risks of congestive heart failure and fractures. There is now more reason to hope that CVD complications will also
diminish with this degree of glycemic control, if it is implemented at or
Of the two TZDs, the bulk of the evidence gives the advantage to soon after the time at which type 2 diabetes is diagnosed. Aiming for a
pioglitazone. In oral presentations at American Diabetes Association target much below 7.0% may be dangerous, particularly in elderly patients
meetings, neither ACCORD nor BARI 2D reported an association who already have CVD or strong CVD risk factors. Failure to respond
between rosiglitazone—used much more often in each study than promptly to intensification of glycemic control should call for caution in
pioglitazone—and adverse CVD outcomes. Even when reported fully, further efforts to drive HbA
1c
below 7.0%. Reducing insulin resistance
however, these will be secondary epidemiological analyses with lesser with metformin (in the liver) and TZDs adds to whatever effect lowering
weight in assessing safety. A consensus algorithm for treating type 2 blood glucose may have. Metformin should be the first-line drug
diabetes relegates TZDs to a second tier and no longer recommends treatment of type 2 diabetes, when not excluded by renal insufficiency
rosiglitazone.
49
The survival of the latter in the therapeutic or persistent gastrointestinal toxicity. Some but not all opinion favors
armamentarium, which is debatable,
50–52
may depend on offering pioglitazone over rosiglitazone, but this issue has not been resolved by
financial advantages that translate into greater cost-effectiveness. a head-to-head comparison of their efficacy and safety. There should be
no hesitancy in using insulin itself to lower blood glucose, bearing in
The results of the BARI 2D trial showed a trend toward reduced CVD mind its increased risk of hypoglycemia. Other approved approaches to
outcomes with a regimen that was based on insulin sensitization with lowering blood glucose by increasing incretin effects with GLP-1 analogs
metformin and/or TZDs. Most intriguing was the observation that CABG or DPP-4 inhibitors have not as yet been adequately tested for CVD
was superior to medical therapy alone, particularly in reducing the benefits or safety. n
incidence of MI in the insulin-sensitization glycemic arm but not in the
insulin-provision glycemic arm. These results indicate that patients
Saul M Genuth, MD, is a Professor of Medicine in the
about to undergo CABG whose HbA
1c
is >7.0% should have metformin
Division of Molecular and Clinical Endocrinology at the
and/or a TZD added to their glycemic management, rather than a School of Medicine at Case Western Reserve University.
beta-cell stimulant or an increased dose of insulin.
He is a member of the American Diabetes Association
(ADA) and a Fellow of the American College of
Physicians (ACP). Professor Genuth has served on the
Conclusion Editorial Board of Metabolism and has been a reviewer
There is still the need for more definitive randomized clinical trial
for numerous medical and scientific journals.
evidence to determine whether lowering blood glucose reduces CVD
1. Grundy SM, et al., Circulation, 1999;100:1134–46. 1998;352:837–53. 35. The BARI 2D Study Group; Frye RL, et al., N Engl J Med,
2. Wild S, et al., Diabetes Care, 2004;27:1047–53. 17. Holman RR, et al., N Engl J Med, 2008;359:1577–89. 2009;360:2503–15.
3. Genuth S, Interventional Cardiology, New York: McGraw Hill, 18. Duckworth W, et al., N Engl J Med, 2009;360:129–39. 36. Lincoff AM, et al., JAMA, 2007;298:1180–88.
2007;697–721. 19. The ACCORD Study Group, Am J Cardiol, 2007;99S:21i–33i. 37. Nissen SE, et al., N Engl J Med, 2007;356:2457–71.
4. Hurst RT, et al., Ann Intern Med, 2003;139:824–34. 20. The Action to Control Cardiovascular Risk in Diabetes Study 38. Psaty BM, et al., N Engl J Med, 2007;356:2522–4.
5. Lotufo PA, et al., Arch Intern Med, 2001;161:242–7. Group, N Engl J Med, 2008;385:2545–9. 39. Singh S, et al., JAMA, 2007;298:1189–95.
6. Hu FB, et al., Arch Intern Med, 2001;161:1717–23. 21. Patel A, et al., N Engl J Med, 2008;352:2560–72. 40. Mannucci E, et al., et al., Int J Cardiol, 2009 (Epub ahead
7. Smith NL, et al., Arch Intern Med, 2002;162:209–16. 22. Ray KK, et al., Lancet, 2009;373:1765–72. of print).
8. DECODE Study Group, the European Diabetes Epidemiology 23. UK Prospective Diabetes Study (UKPDS) Group, Lancet, 41. Lago RM, et al., Lancet, 2007;370:1129–36.
Group. Arch Intern Med, 2001; 161:397–404. 1998;352:854–65. 42. Goff DC, et al., Am J Cardiol, 2007;99S:4i–20i.
9. Stratton IM, et al., BMJ, 2000;321:405–12. 24. Koov A, et al., Arch Intern Med, 2009;169:616–25. 43. Baigent C, et al., Lancet, 2005;366:1267–78.
10. Khaw KT, et al., Ann Intern Med, 2004;141:413–20. 25. Ambery P, et al., Primary Care Diabetes, 2009;3:57–9. 44. Shepherd J, et al., Diabetes Care, 2006;29:1220–26.
11. Moss SE, et al., Arch Intern Med, 1994;154:2473–9. 26. Winkelmayer WC, et al., Arch Intern Med, 2008;168:2368–75. 45. Turnbull F, et al., Arch Intern Med, 2005;165:1410–19.
12. Juutilainen A, et al., Diabetes Care, 2008;31:714–19. 27. Hennekens CH, et al., Am J Med, 2009;122:315–16. 46. UK Prospective Diabetes Study Group, BMJ, 1998;317:703–13.
13. The Diabetes Control and Complications Trial Research 28. Selvin E, et al., Arch Intern Med, 2008;168:2070–80. 47. ALLHAT Officers and Coordinators for the ALLHAT
Group, N Engl J Med, 1993;329:977–86. 29. Pantalon KM, et al., Acta Diabetol, 2009;46:145–54. Collaborative Research Group, JAMA, 2002;288:2981–97.
14. The Writing Team for the Diabetes Control and Complication 30. Viljoen A, et al., Vasc Health Risk Manag, 2009;5:389–95. 48. Patel A, et al., Lancet, 2007;370:829–40.
Trial/Epidemiology of Diabetes Interventions and 31. Dormandy JA, et al.; Lancet, 2005;366:1279–89. 49. Nathan DM, et al., Diabetes Care, 2009;32:193–203.
Complications Research Group, JAMA, 2002;287:2563–9. 32. Erdmann E, et al., J Am Coll Cardiol, 2007;49:1772–80. 50. Diamond GA, et al., Ann Intern Med, 2007;147:578–81.
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94 US ENDOCRINOLOGY
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