Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials
Boussageoun and colleagues [1] report the 9th meta-analysis [2-9] on
intensive glucose control in type 2 diabetes since the publication of 3
large, randomised controls trials (RCTs) in 2008-9 [10-12]. Their meta-
analysis included 10 RCTs. At best, the ratio of published RCTs to meta-
analyses (RCT:Met) [13] is 10/9 or 1.1. Three of the included RCTs [14-16]
had the same glycemic targets/strategies in both treatment arms so did not
compare intensive glycemic control with standard treatment, and another
included patients without diabetes [17]. Thus, at worst, the RCT:Met is
6/9 or 0.67.
Of the 10 RCTs included in the current meta-analysis, the 4 largest
RCTs [10-12, 18, 19] were included in all previous 8 meta-analysis, and
contributed approximately 80% of participants and events for the primary
endpoints in the current meta-analysis. Two small RCTs [20, 21] of
intensive treatment were included in 2 and 3 previous meta-analyses,
respectively. Of the 3 RCTs that did not compare intensive glycemic
control with standard treatment, 1 [14] was included in 5 previous meta-
analyses, and 2 [15, 16] were not included in any previous meta-analyses.
The remaining RCT [17] that included patients without diabetes was not
included in any previous meta-analysis. The two primary endpoints of the
current meta-analysis were included in all previous meta-analyses. Of the
secondary endpoints, the cardiovascular endpoints were included in between
5 and 8 of the previous meta-analyses, peripheral vascular endpoints in 2
meta-analyses, hypoglycaemia in 6 meta-analyses, and microvascular
endpoints in 1 meta-analysis. Therefore, it is difficult to see what
information the current meta-analysis adds to the 8 earlier meta-analyses,
nor how the results advance knowledge.
We have previously highlighted repeated meta-analyses of the same,
small number of RCTs in other fields [13, 22], and remain concerned at the
prominence given to such meta-analyses in medical journals. We suggest
that authors of meta-analysis should be required to demonstrate novelty,
important methodological improvements on previous meta-analyses, or
clinical equipoise before meta-analyses are published. At the very least,
no further trial-level meta-analyses of intensive glucose control in type
2 diabetes should be published unless further RCTs are carried out.
References:
1. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S,
Bergeonneau C, Kassai B, et al. Effect of intensive glucose lowering
treatment on all cause mortality, cardiovascular death, and microvascular
events in type 2 diabetes: meta-analysis of randomised controlled trials.
BMJ 2011;343:d4169.
2. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J.
Systematic review: glucose control and cardiovascular disease in type 2
diabetes. Ann Intern Med 2009;151:394-403.
3. Ma J, Yang W, Fang N, Zhu W, Wei M. The association between
intensive glycemic control and vascular complications in type 2 diabetes
mellitus: a meta-analysis. Nutr Metab Cardiovasc Dis 2009;19:596-603.
4. Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention
of cardiovascular disease through glycemic control in type 2 diabetes: a
meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis
2009;19:604-12.
5. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S,
Preiss D, et al. Effect of intensive control of glucose on cardiovascular
outcomes and death in patients with diabetes mellitus: a meta-analysis of
randomised controlled trials. Lancet 2009;373:1765-72.
6. Tkac I. Effect of intensive glycemic control on cardiovascular
outcomes and all-cause mortality in type 2 diabetes: Overview and
metaanalysis of five trials. Diabetes Res Clin Pract 2009;86 Suppl 1:S57-
62.
7. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP,
Duckworth WC, et al. Intensive glucose control and macrovascular outcomes
in type 2 diabetes. Diabetologia 2009;52:2288-98.
8. Zhang CY, Sun AJ, Zhang SN, Wu CN, Fu MQ, Xia G, et al. Effects
of intensive glucose control on incidence of cardiovascular events in
patients with type 2 diabetes: a meta-analysis. Ann Med 2010;42:305-15.
9. Wu H, Xu MJ, Zou DJ, Han QJ, Hu X. Intensive glycemic control and
macrovascular events in type 2 diabetes mellitus: a meta-analysis of
randomized controlled trials. Chin Med J (Engl) 2010;123:2908-13.
10. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT,
Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med 2008;358:2545-59.
11. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M,
et al. Intensive blood glucose control and vascular outcomes in patients
with type 2 diabetes. N Engl J Med 2008;358:2560-72.
12. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD,
et al. Glucose control and vascular complications in veterans with type 2
diabetes. N Engl J Med 2009;360:129-39.
13. Bolland MJ, Grey A, Reid IR. The randomised controlled trial to
meta-analysis ratio: original data versus systematic reviews in the
medical literature. N Z Med J 2007;120:U2804.
14. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-
Benedetti M, Moules IK, et al. Secondary prevention of macrovascular
events in patients with type 2 diabetes in the PROactive Study
(PROspective pioglitAzone Clinical Trial In macroVascular Events): a
randomised controlled trial. Lancet 2005;366:1279-89.
15. Dargie HJ, Hildebrandt PR, Riegger GA, McMurray JJ, McMorn SO,
Roberts JN, et al. A randomized, placebo-controlled trial assessing the
effects of rosiglitazone on echocardiographic function and cardiac status
in type 2 diabetic patients with New York Heart Association Functional
Class I or II Heart Failure. J Am Coll Cardiol 2007;49:1696-704.
16. Kooy A, de Jager J, Lehert P, Bets D, Wulffele MG, Donker AJ, et
al. Long-term effects of metformin on metabolism and microvascular and
macrovascular disease in patients with type 2 diabetes mellitus. Arch
Intern Med 2009;169:616-25.
17. Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the
effects of hypoglycemic agents on vascular complications in patients with
adult-onset diabetes. II. Mortality results. Diabetes 1970;19:Suppl:789-
830.
18. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive
blood-glucose control with metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
19. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 1998;352:837-53.
20. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S,
et al. Intensive insulin therapy prevents the progression of diabetic
microvascular complications in Japanese patients with non-insulin-
dependent diabetes mellitus: a randomized prospective 6-year study.
Diabetes Res Clin Pract 1995;28:103-17.
21. Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock
JP, et al. Cardiovascular events and correlates in the Veterans Affairs
Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic
Control and Complications in Type II Diabetes. Arch Intern Med
1997;157:181-8.
22. Bolland MJ, Grey A, Reid IR. Time for a moratorium on vitamin D
meta-analyses? BMJ 2009;339:b4394.
Rapid Response:
Too many meta-analyses?
Boussageoun and colleagues [1] report the 9th meta-analysis [2-9] on
intensive glucose control in type 2 diabetes since the publication of 3
large, randomised controls trials (RCTs) in 2008-9 [10-12]. Their meta-
analysis included 10 RCTs. At best, the ratio of published RCTs to meta-
analyses (RCT:Met) [13] is 10/9 or 1.1. Three of the included RCTs [14-16]
had the same glycemic targets/strategies in both treatment arms so did not
compare intensive glycemic control with standard treatment, and another
included patients without diabetes [17]. Thus, at worst, the RCT:Met is
6/9 or 0.67.
Of the 10 RCTs included in the current meta-analysis, the 4 largest
RCTs [10-12, 18, 19] were included in all previous 8 meta-analysis, and
contributed approximately 80% of participants and events for the primary
endpoints in the current meta-analysis. Two small RCTs [20, 21] of
intensive treatment were included in 2 and 3 previous meta-analyses,
respectively. Of the 3 RCTs that did not compare intensive glycemic
control with standard treatment, 1 [14] was included in 5 previous meta-
analyses, and 2 [15, 16] were not included in any previous meta-analyses.
The remaining RCT [17] that included patients without diabetes was not
included in any previous meta-analysis. The two primary endpoints of the
current meta-analysis were included in all previous meta-analyses. Of the
secondary endpoints, the cardiovascular endpoints were included in between
5 and 8 of the previous meta-analyses, peripheral vascular endpoints in 2
meta-analyses, hypoglycaemia in 6 meta-analyses, and microvascular
endpoints in 1 meta-analysis. Therefore, it is difficult to see what
information the current meta-analysis adds to the 8 earlier meta-analyses,
nor how the results advance knowledge.
We have previously highlighted repeated meta-analyses of the same,
small number of RCTs in other fields [13, 22], and remain concerned at the
prominence given to such meta-analyses in medical journals. We suggest
that authors of meta-analysis should be required to demonstrate novelty,
important methodological improvements on previous meta-analyses, or
clinical equipoise before meta-analyses are published. At the very least,
no further trial-level meta-analyses of intensive glucose control in type
2 diabetes should be published unless further RCTs are carried out.
References:
1. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S,
Bergeonneau C, Kassai B, et al. Effect of intensive glucose lowering
treatment on all cause mortality, cardiovascular death, and microvascular
events in type 2 diabetes: meta-analysis of randomised controlled trials.
BMJ 2011;343:d4169.
2. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J.
Systematic review: glucose control and cardiovascular disease in type 2
diabetes. Ann Intern Med 2009;151:394-403.
3. Ma J, Yang W, Fang N, Zhu W, Wei M. The association between
intensive glycemic control and vascular complications in type 2 diabetes
mellitus: a meta-analysis. Nutr Metab Cardiovasc Dis 2009;19:596-603.
4. Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention
of cardiovascular disease through glycemic control in type 2 diabetes: a
meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis
2009;19:604-12.
5. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S,
Preiss D, et al. Effect of intensive control of glucose on cardiovascular
outcomes and death in patients with diabetes mellitus: a meta-analysis of
randomised controlled trials. Lancet 2009;373:1765-72.
6. Tkac I. Effect of intensive glycemic control on cardiovascular
outcomes and all-cause mortality in type 2 diabetes: Overview and
metaanalysis of five trials. Diabetes Res Clin Pract 2009;86 Suppl 1:S57-
62.
7. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP,
Duckworth WC, et al. Intensive glucose control and macrovascular outcomes
in type 2 diabetes. Diabetologia 2009;52:2288-98.
8. Zhang CY, Sun AJ, Zhang SN, Wu CN, Fu MQ, Xia G, et al. Effects
of intensive glucose control on incidence of cardiovascular events in
patients with type 2 diabetes: a meta-analysis. Ann Med 2010;42:305-15.
9. Wu H, Xu MJ, Zou DJ, Han QJ, Hu X. Intensive glycemic control and
macrovascular events in type 2 diabetes mellitus: a meta-analysis of
randomized controlled trials. Chin Med J (Engl) 2010;123:2908-13.
10. Gerstein HC, Miller ME, Byington RP, Goff DC, Jr., Bigger JT,
Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med 2008;358:2545-59.
11. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M,
et al. Intensive blood glucose control and vascular outcomes in patients
with type 2 diabetes. N Engl J Med 2008;358:2560-72.
12. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD,
et al. Glucose control and vascular complications in veterans with type 2
diabetes. N Engl J Med 2009;360:129-39.
13. Bolland MJ, Grey A, Reid IR. The randomised controlled trial to
meta-analysis ratio: original data versus systematic reviews in the
medical literature. N Z Med J 2007;120:U2804.
14. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-
Benedetti M, Moules IK, et al. Secondary prevention of macrovascular
events in patients with type 2 diabetes in the PROactive Study
(PROspective pioglitAzone Clinical Trial In macroVascular Events): a
randomised controlled trial. Lancet 2005;366:1279-89.
15. Dargie HJ, Hildebrandt PR, Riegger GA, McMurray JJ, McMorn SO,
Roberts JN, et al. A randomized, placebo-controlled trial assessing the
effects of rosiglitazone on echocardiographic function and cardiac status
in type 2 diabetic patients with New York Heart Association Functional
Class I or II Heart Failure. J Am Coll Cardiol 2007;49:1696-704.
16. Kooy A, de Jager J, Lehert P, Bets D, Wulffele MG, Donker AJ, et
al. Long-term effects of metformin on metabolism and microvascular and
macrovascular disease in patients with type 2 diabetes mellitus. Arch
Intern Med 2009;169:616-25.
17. Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the
effects of hypoglycemic agents on vascular complications in patients with
adult-onset diabetes. II. Mortality results. Diabetes 1970;19:Suppl:789-
830.
18. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive
blood-glucose control with metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.
19. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with conventional
treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 1998;352:837-53.
20. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S,
et al. Intensive insulin therapy prevents the progression of diabetic
microvascular complications in Japanese patients with non-insulin-
dependent diabetes mellitus: a randomized prospective 6-year study.
Diabetes Res Clin Pract 1995;28:103-17.
21. Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock
JP, et al. Cardiovascular events and correlates in the Veterans Affairs
Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic
Control and Complications in Type II Diabetes. Arch Intern Med
1997;157:181-8.
22. Bolland MJ, Grey A, Reid IR. Time for a moratorium on vitamin D
meta-analyses? BMJ 2009;339:b4394.
Competing interests: No competing interests