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 doi: http://dx.doi.org/10.1136/bmj.d4169 (Published 26 July 2011)
Cite this as: BMJ 2011;343:d4169

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I would like to point out that, as observed from the Forest plot of All Myocardial Infarctions, there was a trend towards reduction with intensive glycemia control, with a risk ratio of 0.9 (0.81 to 1.01), and P value of 0.02. The same was not observed for stroke.(1)

Similarly, in the meta-analysis of Mannucci et al(2) and Ray et al(3), a reduction was observed for myocardial infarction, but not for stroke.

A possibility that is often hypothesized, but yet with very little clinical evidence, is the pleiotropic beneficial effect(s) of drugs like metformin and pioglitazone. A lot of pre-clinical research has been going into this topic, particularly following the UKPDS 34 analysis.(4) There have been pre-clinical evidences of the possible cardiovascular effect(s) of these drugs, beyond glycemia control, but still a robust clinical evidence regarding the dose-response relationship for such effect(s), the in vivo mechanisms of action and the relationship of such effect(s) to glycemia, is lacking.

It is also known that the Gp2b3a inhibitors were unsucessful for the management of stroke, when used in dosage schedule recommended for coronary vascular disease. It is quite possible that the vascular dynamics of the coronary bed are quite different than that of the cerebral vessels, and these differences could demand differential management strategies for these disorders.

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. 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.

3. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. 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 May 23;373(9677):1765-72.

4. 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.

Competing interests: Dr Jignesh Ved is working as a Medical Advisor with Pfizer, India. However, the response submitted herewith includes his personal views and does not relate to his relationship with his organisation.

Jignesh K Ved, Medical Advisor

Pfizer

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The Arrow Plot is very useful.

As a left-brainer, I first became convinced by the BHS/JBS plot of all Statin trials , back in 2005.

see http://heart.bmj.com/content/91/suppl_5/v1/F5.large.jpg

Though it can be improved to incorporate weightings, sample size etc., in use in my lectures I note that my audience is not instinctively orientated, and always require an explanation of the plot and axial orientations.

Thus I feel the single biggest improvement is to do a left-right mirror reversal, such that Arrows point downwards and rightwards, as a biomarker is improving.

This would then implicitly fit with scientific convention that change/time runs left to right.

Dr Sam Lewis

Competing interests: None declared

L Sam Lewis, GP Trainer

Surgery, Newport, Pembrokeshire, SA42 oTJ

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Thank you for publishing our arrow plot. However, we note that the version of the graphic made by the BMJ contains an error. The ACCORD study showed significant increase in mortality and so its arrow should be solid. (PMID: 18539917)

Competing interests: None declared

Robert G. Badgett, Professor of Medicine

Kansas University School of Medicine - Wichita

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We agree with the strong conclusion by Boussageon et al regarding diabetes mellitus type II, "relying on surrogate end points for treating people is a fallacy." 1 However, Forest plots in meta-analyses do not well show the relationship between a surrogate outcome such as a biomarker and a clinical outcome such as mortality. We offer a two-dimensional arrow plot 2 as an additional display for meta-analyses of biomarkers and clinical outcomes to increase the information garnered from meta-analysis. In the Figure, the arrows start with the results of the control groups and end with the results of the intervention groups. The slopes of the arrows represent the relationship between change in the biomarker (HbA1c) and the change in clinical outcome (mortality).

In this arrow plot, there is no relationship between changes in the HbA1c and the mortality. No definite clinical recommendation is possible. However, based on the metformin versus diet portion of the UKPDS 34 trial, metformin, when used in patients with increased risk of mortality and when not combined with a sulfonylurea, may significantly reduce mortality.3

References:

Competing interests: None declared

Robert G. Badgett, Professor of Medicine

Frank Dong, KoKo Aung

Kansas University School of Medicine - Wichita

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16 August 2011

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: None declared

Mark J Bolland, Senior Research Fellow

Andrew Grey

University of Auckland

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The research paper (1) and the editorial (2) on the intensive glucose lowering treatment in type 2 diabetes, show that this has a very limited effect on all cause mortality, cardiovascular (CVS) deaths, non-fatal myocardial infarction and microvascular events. However, they both conclude that such treatment results in more than a doubling of severe hypoglycaemia and serious hypoglycaemic events.

This does raise the question of the mechanism by which diabetes results in cardiovascular (and microvascular) damage. Catecholamines are known to play a major role in the aeliology and pathogenesis of ischaemic heart disease (3) and may also be the cause of cardiovascular system damage in diabetes. This is due to the mutually antagonistic actions of insulin and the catecholamines (4).

Insulin antagonises the harmful actions of non-adrenalin on the heart muscle (5) and vascular reactivity (6). But the catecholamines inhibit the cell-mediated uptake of insulin and the secretion of insulin by the pancreas (7). In diabetes there are either very low blood insulin levels (type 1) or insulin resistance (type 2). But it is reasonable to conclude that the catecholamines' action in both types could well be enhanced resulting in cardiovascular damage. In addition, severe hypoglycaemia will result in stimulation of the catecholamines (to raise blood sugar levels) with further damage to the CVS.

Unless the harmful effects of increased catecholamines can be reduced by lifestyle changes such as regular exercise, smoking cessation and weight reduction, all of which will decrease catecholamine levels (3), intensive lowering of blood glucose will not result in an improvement in cardiovascular events and deaths.

I believe this shows the need to understand fully the pathophysiology of diabetes and the drugs used to reduce its vascular complications. Last year intensive glucose-lowering by rosiglitazone was found to have increased cardiovascular events in the treatment of diabetes (8). This also emphasises the need for a translational or inter-disciplinary approach to research and practice as set out by Geoff Watts (9) a year ago.

References

1. Remy Boussageon, Theodora Bejan-Angoulvant, Mitra Saadatian-Elahi, Sandrine Lafont, Claire Bergeonneau, Behrouz Kassai, Sylvie Erpeldinger, James M Wright, Francois Gueyffier, Catherine Cornu. 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 doi: 10.1136/bmj.d4169 p.244 (30 July).

2. David Preiss, Kausik K Ray. Intensive glucose lowering treatment in type 2 diabetes. BMJ2011;343:d4243 doi:10.1136/bmj.d4243 p.215 (30 July).

3. Lee, J.A. The role of the sympathetic nervous system in ischaemic heart disease: A review of epidemiological features and risk factors, integration with clinical and experimental evidence and hypothesis. Activ. Nerv. Sup. (Praha). 25, 1983, No.2 p.110-121.

4. Lee, J.A. Insulin, catecholamines and heart disease. Lancet 1978; 2, p.794.

5. Lee, J.A., Downing, S.E. Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine. Amer. J. Physiol. 1976: 230; 1360-1365.

6. Alexander, W.D., Oake, R.J. The effect of insulin on vascular reactivity to norepinephrine. Diabetes 1977, 26, 611-614.

7. David S. Goldstein. Stress, catecholamines and cardiovascular disease. Oxford University Press 1995.

8. Rosiglitazone: what went wrong? Deborah Cohen. BMJ 2010: c4848 p.530-534 (11 September).

9. Geoff Watts. Lost without translation. BMJ 2010; 341: c4363, p428-429 (28 August).

Competing interests: None declared

John A Lee, Retired Consultant in Public Health

Hereford

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Dear Editor,

I have read the meta-analysis by Boussageon et al. (1) The authors clearly show that intensive, HbA1c-dependent therapy is not superior to standard therapy. This means that hyperglycaemia per se is not the only factor contributing to morbidity and mortality of type 2 diabetes mellitus (T2DM) patients. Another contributing factor is endothelial dysfunction which plays a major role in the pathophysiology of cardiovascular events in the setting of T2DM. (2) On the top of that is the activation of oxidative stress which occurs in both glucose-intolerance and diabetic patients. (3)

In other words, even mild hyperglycaemia contributes to activation of oxidative stress. These findings are consistent and imply that management of T2DM should not be based only on HbA1c but more importantly is to address all cardiovascular risk factors.

Yours sincerely,
Moayed Alawami

References:

1. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M 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. Hartge MM, Kintscher U, Unger T. Endothelial dysfunction and its role in diabetic vascular disease. Endocrinol Metab Clin North Am. 2006;35:551- 60, viii-ix.

3. Zheng F, Lu W, Jia C, Li H, Wang Z, Jia W. Relationships between glucose excursion and the activation of oxidative stress in patients with newly diagnosed type 2 diabetes or impaired glucose regulation. Endocrine. 2010;37:201-208.

Competing interests: None declared

Moayed A Alawami, Trainee Intern

University of Auckland

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27 July 2011

Dear Editor,

There appears to be a typographical error in the abstract published for this article. Where it reads "more than twofold increase in the risk of severe hypoglycaemia (2.33, 21.62 to 3.36, P<0.001)," the confidence interval is said to be 1.62 to 3.36 in the main article.

Competing interests: None declared

Saiji Nageshwaran, Medical Student

University College London Medical School

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Dear Fellows:

Type 2 diabetes is much more than just a disease of carbohydrates. Actually, hyperglycemia is only a secondary by-product of much deeper metabolic derangements.

If hyperglycemia was that important as a therapeutic target in type 2 diabetes we would not be seeing all these failures and increased death rates(!!!) in clinical trials trying to achieve a normal Glycated Hemoglobin.

Even in pure observational studies there is no direct relationship between glycemic levels and cardiovascular mortality, contrary to what happens with blood pressure levels, and also LDL-Cholesterol levels.

Competing interests: None declared

Jose Mario Franco de Oliveira, Associate Professor of Medicine

Universidade Federal Fluminense

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