- Email: [email protected]
Extent of glycemic control in type 2 diabetes mellitus: Close, but no cigar
Nutrition, Metabolism & Cardiovascular Diseases (2009) 19, 593e595
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
EDITORIAL COMMENT
Extent of glycemic control in type 2 diabetes mellitus: Close, but no cigar In June 2008, two large randomized controlled trials [1,2] were published on the probably most important, yet unanswered question for the care of patients with type 2 diabetes mellitus: Is a rather tight glycemic control beneficial regarding cardiovascular outcomes and all-cause mortality? Since then, a subsequent, smaller randomized controlled trial [3] and the first [4] and second [5] metaanalysis on this subject were published. These two metaanalyses and also the systematic review by Mannucci et al. [6] in this issue included a similar set of studies. Before we move on to the two systematic reviews on this hot topic published in Nutrition, Metabolism & Cardiovascular Diseases [6,7], one should contemplate about a study design which would help answer the question in focus. To assess whether differences in glycemic control cause differences in the investigated outcomes, the respective groups have to be similar for every other known or unknown factor that influences the investigated outcomes. Metaphorically speaking, the only screw that can be adjusted is glycemic control, all else is fixed. Possible approaches to study the effects of intensive versus non-intensive metabolic control by means of randomized controlled trials should first try to mirror clinical practice where glycated hemoglobin (HbA1c) levels are used to adjust antihyperglycemic therapy. Other possible yet less validated approaches are pre- or postprandial blood glucose guided antihyperglycemic treatments. The above mentioned strategies might be achieved through application of monotherapy of hypoglycemic drugs or a step-wise addition of further antidiabetic compounds. Table 1 provides an overview of the glycemic targets of the primary studies investigated in the two systematic reviews [6,7]. Levels of HbA1c cannot be interpreted in isolation from the particular drug treatment. It is known that there are drug-specific (adverse) effects, for example congestive heart failure due to pioglitazone [8]. Therefore, group comparability also demands similar, ideally identical drug treatments. Reasonable approaches include dose escalation of a single hypoglycemic drug, though often difficult to
achieve in oral antidiabetic therapy, as upper allowed doses may soon be reached and frequency of adverse effects may rise. This approach, however, is feasible in insulin therapy. To ensure comparability, number of drug combinations should be restricted. Moreover, drug schemes and principles should be similar between intervention and control groups. The last major point in thinking about an adequate study design is consideration of concomitant treatment of cardiovascular risk factors. Cardiovascular mortality accounts for a major part of death in patients with type 2 diabetes mellitus [9]. Therefore, treatment of cardiovascular risk factors should also be similar. In the STENO-2 trial [10] for example, the multifactorial intervention applied different treatment of cardiovascular risk factors to the intervention and control groups, thus the effect attributed to contrasting glycemic control remained unclear. Let us now examine the two systematic reviews in this issue which show two major differences: First, while Ma et al. stated in their selection criteria only to include studies that compared ‘intensive and standard glycemic control’, Mannucci et al. accepted any study with a ‘between-group difference in mean HbA1c during the trial of at least 0.5%’. They gave no explicit justification for this criterion, however a 0.5% change in HbA1c is commonly considered as a clinically relevant difference and often used for sample size calculations [11]. Second, Ma et al. chose to differentiate their meta-analyses by different HbA1c levels. Though they gave no rationale for this approach, it is generally acknowledged that some threshold exists below which lowering of HbA1c does not increase beneficial but adverse effects of antihyperglycemic treatment. The approach by Mannucci et al. relies on the very strong assumption of a linear relationship of HbA1c with any of the considered cardiovascular outcomes. For their meta-analysis they used expected reductions in the incidence of cardiovascular events depicted from yet another metaanalysis of cohort studies, itself relying on another set of strong statistical assumptions [12]. Furthermore, as
0939-4753/$ - see front matter ª 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2009.08.009
594 Table 1
Editorial Comment Used approaches by the included studies.
Study UKPDS [14,15] Intensive
Non-intensive Abraira [16,17] Intensive
Non-intensive
Kumamoto [18] Intensive
Non-intensive
Glycemic targets -FPG < 6 mmol/l - in insulin-treated patients: ac glucose 4-7 mmol/l FPG < 15 mmol/l without symptoms of hyperglycemia HbA1c 4e6.1%d and FBG 4.48e6.44 mmol/ld and ac glucose 7.28 mmol/ld HbA1c < 12.9% without excessive hyperglycemia, excessive glycosuria, ketonuria and hypoglyecmia FBG < 7.8 mmol/l and 2 h-pc glucose < 11.1 mmol/l and MAGE < 5.6 mmol/l FBG < 7.8 mmol/l without symptoms of hypoor hyperglcemia
STENO-2 [10] Intensive Non-intensive
HbA1c < 6.5% HbA1c < 7.5/6.5%a
PROactive [19] Intensive Non-intensive
HbA1c < 6.5% (þpioglitazone) HbA1c < 6.5% (þplacebo)
ACCORD [1,20] Intensive Non-intensive
HbA1c < 6.0%b HbA1c 7e7.9%c
ADVANCE [2] Intensive Non-intensive
VADT [3,21] Intensive Non-intensive
HbA1c < 6.5% HbA1c target levels ‘defined on local guidelines’ HbA1c < 6%d HbA1c 8e9% without glycosuria, hypoglycemia and ketonuria
ac: antecibal; FBG: fasting blood glucose; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; MAGE: mean amplitude of glycemic excursion; (2 h-)pc: (2 h) postcibal. a The target was lowered for the last two years of the 9 years study. b If fasting/ac glucose > 5.6 mmol/l or pc glucose > 7.7 mmol/l in >50% of the results of the four days selfmonitoring of blood glucose, antihyperglycemic treatment was increased. c If fasting/ac glucose < 5 mmol/l in >50% of the results of the four days self-monitoring of blood glucose, antihyperglycemic treatment was decreased. d ‘A priority is to avoid hypoglycemia, even if asymptomatic.’
acknowledged by the authors, this linearity assumption is the basis for the later performed meta-regression. Because of this unproved assumption, the observational character of meta-regression and the low number of included studies results should be interpreted with great caution. Both systematic reviews aggregate trials with markedly different populations. To name two, the mean age of study participants was 49.5 years in the Kumamoto trial compared to 66 years in the ADVANCE trial (with comparable diabetes duration). The mean diabetes duration was 11.5 years in the VADT trial compared to newly diagnosed patients in the UKPDS. Furthermore, there is no information given to assess the role of the recently postulated and still debatable concept of ‘legacy effects’ (a kind of body memory of former good metabolic control with associated positive outcomes even if HbA1c levels deteriorate later on). In our view, such an extent of clinical heterogeneity (which is not inevitably associated with nor necessarily detected by statistical heterogeneity) questions the validity of the resulting meta-analyses. After these words of caution, the findings regarding cardiovascular outcomes and severe hypoglycemia should be scrutinized: For both all-cause and cardiovascular (that is due to myocardial infarction, stroke and peripheral artery disease) mortality, there were no statistically significant differences for all three comparisons (one by Mannucci et al. and two by Ma et al.), with point estimates of relative risk or odds ratio around 1.0. In other words: there is currently no evidence that intensive glucose control reduces mortality in type 2 diabetes mellitus. Risk or odds of severe hypoglycemia were found to be significantly increased. The possible cardiovascular adverse consequences of severe hypoglycemia have been discussed by Mannucci et al.; in addition, a recently published cohort study evaluated the association between the long-term consequences of severe hypoglycemia and the development of dementia [13]. For two comparisons, Mannucci et al. found significant benefits of intensive glucose control on cardiovascular events (which incorporated myocardial infarction, stroke and peripheral artery diseases, each fatal or non-fatal) and its subset fatal and non-fatal myocardial infarction (odds ratio 0.9 and 0.85, respectively). As a caveat one should critically appraise all endpoints reported in the primary studies since definition and adjudication varied widely. All other investigated cardiovascular outcomes showed statistically non-significant results. Which conclusions can be drawn and which recommendations can be given from these two systematic reviews? Current population-wide treatment targets of less than 6.5% HbA1c appear to be too restrictive, putting many patients (especially elderly individuals) at risk of severe hypoglycemia without an apparent benefit regarding overall or cardiovascular mortality. Drug-specific treatment effects and possible drugedrug interactions should be considered. This implies to prefer antihyperglycemic drugs for which there is evidence of benefit for patient-relevant outcomes. It also means not to combine certain drugs (like metformin þ sulfonylureas) as well as to avoid inadequately
Editorial Comment studied combinations for which interactions cannot be foreseen. Diabetes is just one item in an assembly of risk factors for cardiovascular events in patients with type 2 diabetes mellitus. How and which risk factor (for example blood pressure, lipids) to treat is determined by the best currently available evidence, clinical expertise and patient values and preferences. In our opinion, the question to what extent hyperglycemia should be treated in type 2 diabetes mellitus remains unanswered. Apart from further studies applying the principles mentioned above, individual patient data analysis of key randomized controlled trials with transparent reporting of definition and adjudication of single endpoints could shed some light on this central question of therapy for type 2 diabetes.
References [1] Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545e59. [2] 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;358:2560e72. [3] 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;360:129e39. [4] 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;373:1765e72. doi:10.1016/ S0140-6736(09)60697-8. [5] Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med 2009; July 20. [Epub ahead of print]. [6] Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention of cardiovascular disease through glycemic control in type 2 diabetes. Nutr Metab Cardiovasc Dis 2009. [7] Jian M, Weiwei Y, Ningyuan F, Wei Z, Meng W. The association between intensive glycemic control and vascular complications in type 2 diabetes mellitus: a meta-analysis. Nutr Metab Cardiovasc Dis 2009. [8] Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006;4. CD006060. [9] Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28:1769e78. [10] Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383e93. [11] U.S. Department of Health and Human Services - Food and Drug Administration. Guidance for industry e diabetes
595
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
mellitus: developing drugs and therapeutic biologics for treatment and prevention, http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm071624.pdf; 2008 [accessed July 09.07.09]. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421e31. Whitmer RA, Karter AJ, Yaffe K, Quesenberry Jr CP, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009;301:1565e72. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854e65. doi:10.1016/S0140-6736(98)07037-8. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: 837e53. doi:10.1016/S0140-6736(98)07019-6. 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;157:181e8. Abraira C, Emanuele N, Colwell J, Henderson W, Comstock J, Levin S, et al. Glycemic control and complications in type II diabetes. Design of a feasibility trial. VA CS Group (CSDM). Diabetes Care 1992;15:1560e71. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(Suppl. 2):B21e9. Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care 2004;27(7): 1647e53. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial e Protocol. URL: http://www.accordtrial.org/public/ protocol_2005-05-11.pdf [accessed 09.07.09]. Abraira C, Duckworth W, McCarren M, Emanuele N, Arca D, Reda D, et al. Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: veterans affairs diabetes trial. J Diabet Complications 2003; 17:314e22. doi:10.1016/S1056-8727(02)00277-5.
Christian Lerch Bernd Richter Du¨sseldorf University Hospital, Cochrane Metabolic and Endocrine Disorders Review Group, Department of General Practice, Moorenstraße 5, 40225 Du¨sseldorf, Germany E-mail address: [email protected] (C. Lerch)
9 July 2009
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
EDITORIAL COMMENT
Extent of glycemic control in type 2 diabetes mellitus: Close, but no cigar In June 2008, two large randomized controlled trials [1,2] were published on the probably most important, yet unanswered question for the care of patients with type 2 diabetes mellitus: Is a rather tight glycemic control beneficial regarding cardiovascular outcomes and all-cause mortality? Since then, a subsequent, smaller randomized controlled trial [3] and the first [4] and second [5] metaanalysis on this subject were published. These two metaanalyses and also the systematic review by Mannucci et al. [6] in this issue included a similar set of studies. Before we move on to the two systematic reviews on this hot topic published in Nutrition, Metabolism & Cardiovascular Diseases [6,7], one should contemplate about a study design which would help answer the question in focus. To assess whether differences in glycemic control cause differences in the investigated outcomes, the respective groups have to be similar for every other known or unknown factor that influences the investigated outcomes. Metaphorically speaking, the only screw that can be adjusted is glycemic control, all else is fixed. Possible approaches to study the effects of intensive versus non-intensive metabolic control by means of randomized controlled trials should first try to mirror clinical practice where glycated hemoglobin (HbA1c) levels are used to adjust antihyperglycemic therapy. Other possible yet less validated approaches are pre- or postprandial blood glucose guided antihyperglycemic treatments. The above mentioned strategies might be achieved through application of monotherapy of hypoglycemic drugs or a step-wise addition of further antidiabetic compounds. Table 1 provides an overview of the glycemic targets of the primary studies investigated in the two systematic reviews [6,7]. Levels of HbA1c cannot be interpreted in isolation from the particular drug treatment. It is known that there are drug-specific (adverse) effects, for example congestive heart failure due to pioglitazone [8]. Therefore, group comparability also demands similar, ideally identical drug treatments. Reasonable approaches include dose escalation of a single hypoglycemic drug, though often difficult to
achieve in oral antidiabetic therapy, as upper allowed doses may soon be reached and frequency of adverse effects may rise. This approach, however, is feasible in insulin therapy. To ensure comparability, number of drug combinations should be restricted. Moreover, drug schemes and principles should be similar between intervention and control groups. The last major point in thinking about an adequate study design is consideration of concomitant treatment of cardiovascular risk factors. Cardiovascular mortality accounts for a major part of death in patients with type 2 diabetes mellitus [9]. Therefore, treatment of cardiovascular risk factors should also be similar. In the STENO-2 trial [10] for example, the multifactorial intervention applied different treatment of cardiovascular risk factors to the intervention and control groups, thus the effect attributed to contrasting glycemic control remained unclear. Let us now examine the two systematic reviews in this issue which show two major differences: First, while Ma et al. stated in their selection criteria only to include studies that compared ‘intensive and standard glycemic control’, Mannucci et al. accepted any study with a ‘between-group difference in mean HbA1c during the trial of at least 0.5%’. They gave no explicit justification for this criterion, however a 0.5% change in HbA1c is commonly considered as a clinically relevant difference and often used for sample size calculations [11]. Second, Ma et al. chose to differentiate their meta-analyses by different HbA1c levels. Though they gave no rationale for this approach, it is generally acknowledged that some threshold exists below which lowering of HbA1c does not increase beneficial but adverse effects of antihyperglycemic treatment. The approach by Mannucci et al. relies on the very strong assumption of a linear relationship of HbA1c with any of the considered cardiovascular outcomes. For their meta-analysis they used expected reductions in the incidence of cardiovascular events depicted from yet another metaanalysis of cohort studies, itself relying on another set of strong statistical assumptions [12]. Furthermore, as
0939-4753/$ - see front matter ª 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2009.08.009
594 Table 1
Editorial Comment Used approaches by the included studies.
Study UKPDS [14,15] Intensive
Non-intensive Abraira [16,17] Intensive
Non-intensive
Kumamoto [18] Intensive
Non-intensive
Glycemic targets -FPG < 6 mmol/l - in insulin-treated patients: ac glucose 4-7 mmol/l FPG < 15 mmol/l without symptoms of hyperglycemia HbA1c 4e6.1%d and FBG 4.48e6.44 mmol/ld and ac glucose 7.28 mmol/ld HbA1c < 12.9% without excessive hyperglycemia, excessive glycosuria, ketonuria and hypoglyecmia FBG < 7.8 mmol/l and 2 h-pc glucose < 11.1 mmol/l and MAGE < 5.6 mmol/l FBG < 7.8 mmol/l without symptoms of hypoor hyperglcemia
STENO-2 [10] Intensive Non-intensive
HbA1c < 6.5% HbA1c < 7.5/6.5%a
PROactive [19] Intensive Non-intensive
HbA1c < 6.5% (þpioglitazone) HbA1c < 6.5% (þplacebo)
ACCORD [1,20] Intensive Non-intensive
HbA1c < 6.0%b HbA1c 7e7.9%c
ADVANCE [2] Intensive Non-intensive
VADT [3,21] Intensive Non-intensive
HbA1c < 6.5% HbA1c target levels ‘defined on local guidelines’ HbA1c < 6%d HbA1c 8e9% without glycosuria, hypoglycemia and ketonuria
ac: antecibal; FBG: fasting blood glucose; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; MAGE: mean amplitude of glycemic excursion; (2 h-)pc: (2 h) postcibal. a The target was lowered for the last two years of the 9 years study. b If fasting/ac glucose > 5.6 mmol/l or pc glucose > 7.7 mmol/l in >50% of the results of the four days selfmonitoring of blood glucose, antihyperglycemic treatment was increased. c If fasting/ac glucose < 5 mmol/l in >50% of the results of the four days self-monitoring of blood glucose, antihyperglycemic treatment was decreased. d ‘A priority is to avoid hypoglycemia, even if asymptomatic.’
acknowledged by the authors, this linearity assumption is the basis for the later performed meta-regression. Because of this unproved assumption, the observational character of meta-regression and the low number of included studies results should be interpreted with great caution. Both systematic reviews aggregate trials with markedly different populations. To name two, the mean age of study participants was 49.5 years in the Kumamoto trial compared to 66 years in the ADVANCE trial (with comparable diabetes duration). The mean diabetes duration was 11.5 years in the VADT trial compared to newly diagnosed patients in the UKPDS. Furthermore, there is no information given to assess the role of the recently postulated and still debatable concept of ‘legacy effects’ (a kind of body memory of former good metabolic control with associated positive outcomes even if HbA1c levels deteriorate later on). In our view, such an extent of clinical heterogeneity (which is not inevitably associated with nor necessarily detected by statistical heterogeneity) questions the validity of the resulting meta-analyses. After these words of caution, the findings regarding cardiovascular outcomes and severe hypoglycemia should be scrutinized: For both all-cause and cardiovascular (that is due to myocardial infarction, stroke and peripheral artery disease) mortality, there were no statistically significant differences for all three comparisons (one by Mannucci et al. and two by Ma et al.), with point estimates of relative risk or odds ratio around 1.0. In other words: there is currently no evidence that intensive glucose control reduces mortality in type 2 diabetes mellitus. Risk or odds of severe hypoglycemia were found to be significantly increased. The possible cardiovascular adverse consequences of severe hypoglycemia have been discussed by Mannucci et al.; in addition, a recently published cohort study evaluated the association between the long-term consequences of severe hypoglycemia and the development of dementia [13]. For two comparisons, Mannucci et al. found significant benefits of intensive glucose control on cardiovascular events (which incorporated myocardial infarction, stroke and peripheral artery diseases, each fatal or non-fatal) and its subset fatal and non-fatal myocardial infarction (odds ratio 0.9 and 0.85, respectively). As a caveat one should critically appraise all endpoints reported in the primary studies since definition and adjudication varied widely. All other investigated cardiovascular outcomes showed statistically non-significant results. Which conclusions can be drawn and which recommendations can be given from these two systematic reviews? Current population-wide treatment targets of less than 6.5% HbA1c appear to be too restrictive, putting many patients (especially elderly individuals) at risk of severe hypoglycemia without an apparent benefit regarding overall or cardiovascular mortality. Drug-specific treatment effects and possible drugedrug interactions should be considered. This implies to prefer antihyperglycemic drugs for which there is evidence of benefit for patient-relevant outcomes. It also means not to combine certain drugs (like metformin þ sulfonylureas) as well as to avoid inadequately
Editorial Comment studied combinations for which interactions cannot be foreseen. Diabetes is just one item in an assembly of risk factors for cardiovascular events in patients with type 2 diabetes mellitus. How and which risk factor (for example blood pressure, lipids) to treat is determined by the best currently available evidence, clinical expertise and patient values and preferences. In our opinion, the question to what extent hyperglycemia should be treated in type 2 diabetes mellitus remains unanswered. Apart from further studies applying the principles mentioned above, individual patient data analysis of key randomized controlled trials with transparent reporting of definition and adjudication of single endpoints could shed some light on this central question of therapy for type 2 diabetes.
References [1] Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545e59. [2] 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;358:2560e72. [3] 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;360:129e39. [4] 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;373:1765e72. doi:10.1016/ S0140-6736(09)60697-8. [5] Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med 2009; July 20. [Epub ahead of print]. [6] Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention of cardiovascular disease through glycemic control in type 2 diabetes. Nutr Metab Cardiovasc Dis 2009. [7] Jian M, Weiwei Y, Ningyuan F, Wei Z, Meng W. The association between intensive glycemic control and vascular complications in type 2 diabetes mellitus: a meta-analysis. Nutr Metab Cardiovasc Dis 2009. [8] Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006;4. CD006060. [9] Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28:1769e78. [10] Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383e93. [11] U.S. Department of Health and Human Services - Food and Drug Administration. Guidance for industry e diabetes
595
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
mellitus: developing drugs and therapeutic biologics for treatment and prevention, http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm071624.pdf; 2008 [accessed July 09.07.09]. Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421e31. Whitmer RA, Karter AJ, Yaffe K, Quesenberry Jr CP, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009;301:1565e72. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854e65. doi:10.1016/S0140-6736(98)07037-8. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: 837e53. doi:10.1016/S0140-6736(98)07019-6. 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;157:181e8. Abraira C, Emanuele N, Colwell J, Henderson W, Comstock J, Levin S, et al. Glycemic control and complications in type II diabetes. Design of a feasibility trial. VA CS Group (CSDM). Diabetes Care 1992;15:1560e71. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(Suppl. 2):B21e9. Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care 2004;27(7): 1647e53. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial e Protocol. URL: http://www.accordtrial.org/public/ protocol_2005-05-11.pdf [accessed 09.07.09]. Abraira C, Duckworth W, McCarren M, Emanuele N, Arca D, Reda D, et al. Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2: veterans affairs diabetes trial. J Diabet Complications 2003; 17:314e22. doi:10.1016/S1056-8727(02)00277-5.
Christian Lerch Bernd Richter Du¨sseldorf University Hospital, Cochrane Metabolic and Endocrine Disorders Review Group, Department of General Practice, Moorenstraße 5, 40225 Du¨sseldorf, Germany E-mail address: [email protected] (C. Lerch)
9 July 2009