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Re:Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseWe are responding to the revised letter of Yudkin and Richter, which we did not see before its publication. Although methods of pooling trials with shared controls have been developed, each has its own limitations. We would like to point out some serious limitations related to simply combining the UKPDS 33 and 34 into one study, as done by Yudkin and Richter in their letter. The UKPDS 34 only included overweight participants at high risk for cardiovascular outcomes. Simply summing the numbers of events from the UKPDS 33 and UKPDS 34 would make the intensive and conventional treatment groups non-comparable, introducing bias to the conclusion. For example, in the UKPDS 33, the proportion overweight was similar between the intensive and conventional treatment groups (34.8% and 36.2%, respectively). By combining the UKPDS 33 and 34, the proportion overweight of the conventional treatment group would remain 36.2% (as the controls from UKPDS 34 were originally included in the UKPDS 33 control group), but the proportion overweight in the intensive treatment group would increase to 47.4% (as only overweight patients were included in the UKPDS 34). This imbalance in overweight status and other associated cardiovascular risk factors between the intensive treatment and conventional treatment groups threatens the internal validity of the 'combined analysis' and leads to bias in their conclusions.
Conflict of Interest:
None declared
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Re:Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseWe would like to thank Drs. Yudkin and Richter for their interest in our meta-analysis. The decision to conduct subgroup analyses of early and more recent trials was an a priori determination based on important differences in patient populations, targeted HbA1c levels, and treatment regimens (1). Specifically, the early UKPDS trials included only newly diagnosed diabetes patients while the more recent ACCORD, ADVANCE, and VADT included prevalent diabetes patients. The targeted intensive glucose control level in the UKPDS was similar to that of the targeted conventional glucose control level in the more recent trials. Finally, the UKPDS used diet as the primary method of conventional treatment while the more recent trials used hypoglycemic agents. We included the UKPDS 34 in our meta-analysis because the 342 patients that were assigned to metformin for intensive treatment were completely independent to the 2,729 patients assigned to sulfonylureas or insulin for intensive treatment in the UKPDS 33 (2).
Combining results from different treatment arms of clinical trials that share a common control group is sometimes done though ideally estimates should account for underlying correlation between the effect size which we did not do (3, 4). The UKPDS 34 control group comprises a relatively small proportion of the UKPDS 33 control group (approximately 36%), and meta-analytic methods to account for correlations in binary endpoints of trials using partially shared control groups have not been developed. We believe that the UKPDS 34 provides important information regarding the effects of intensive glucose control on cardiovascular disease, and any correlation it may have with the UKPDS 33 due to a partially shared control group does not warrant its exclusion from the meta-analysis. Yudkin et al raised an issue about different definitions of outcomes among individual trials. However, all-cause mortality and cardiovascular disease mortality are two “hard clinical outcomes," which should be comparable among trials. Our meta-analysis indicated that there was significant heterogeneity in these outcomes between individual trials, which supported our decision to conduct subgroup analyses. We appreciate the concerns of Yudkin et al, but stand by our methods and conclusions.
References
1. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K and He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med (2009) 151: 394-403.
2. 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: 837-853.
3. Glesser LJ, Olkin I. Stochastically dependent effect sizes. In: Cooper H, Hedges LV. The Handbook of Research Synthesis. New York: Russel Sage Foundation. (1994) 339-356.
4. Generalized synthesis of evidence – Combining different sources of evidence. In: Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for Meta-analysis in Medical Research. New York: Wiley & Sons, LTD. (2000) 259-276.
Conflict of Interest:
None
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Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseThe issue of the impact of glucose lowering on cardiovascular risk in patients with type 2 diabetes is one of great public health significance. While recognising the importance of the paper by Kelly et al (1), we would like to draw attention to errors in their meta-analysis that we believe affect the conclusions reached.
First, the authors combined data from 3 recent studies (2-4) with two sub-studies of the UKPDS (5,6) to suggest that many outcomes differ between the ‘early’ and ‘late’ studies. In so doing, they failed to notice that the 411 participants and their associated events in the conventional treatment (diet) limb of the metformin sub-study UKPDS34 (6) were also included in the conventional treatment arm in the main study UKPDS33 (5). Using the same studies and methodology as Kelly et al, but without double-counting, we appropriately analysed UKPD 33 and 34 as one study including the additional data from the intensive treatment arm of the metformin treated patients in UKPDS34. Thus, the relative risk for cardiovascular death and all cause mortality is 1.05 (0.82-1.33) instead of 0.97 (0.76-1.24), and 1.03 (0.89-1.19) instead of 0.98 (0.84-1.15), and the reduction in risk of cardiovascular events is 8% (1%-14%) instead of 10% (2%-17%). The recalculation reduces the difference between the early and late trials of Kelly et al's categorisation, with the only end-points now showing substantial heterogeneity in overall pooled effect estimates being cardiovascular death ( I2 = 75%) , all-cause mortality ( I2 = 67% ) and severe hypoglycaemia (I2 = 79%).
Second, one might debate whether UKPDS34 was appropriate to include in the meta-analysis; trialists involved in the originally studies recently performed a similar meta-analysis without its inclusion (7).
Third, the use of different definitions of end-points (such as including or not including sudden death as cardiovascular disease) is a problem that cannot be solved unless an individual patient data meta-analysis is done.
Given all of the above, we conclude that there is little evidence of differences in outcomes between early and late studies. We think that current epidemiologic and trial evidence suggests that intensive glycemic control will reduce coronary heart disease by about two-thirds, and will not significantly affect stroke, cardiovascular mortality or total mortality. Moreover, we think that data suggest that treating 100 people with intensive glycemic control for 10 years would prevent around 3 cardiovascular events, at the expense of inducing 8 serious hypoglycemic ones.
References
1. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K and He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med (2009) 151: (published on-line 21 July 2009).
2. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med (2008) 358: 2545-2559.
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med (2008) 358: 2560-2572.
4. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG and Huang GD for the VADT Investigators. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med (2009) 360: 129-139.
5. 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: 837-853.
6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet (1998) 352: 854-865.
7. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, Evans GW, Gerstein HC, Holman RR, Moritz TE, Neal BC, Ninomiya T, Patel AA, Paul SK, Travert F and Woodward M. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia (2009) DOI 10.1007/s00125-009-1470-0 (published on-line 5th August 2009).
Conflict of Interest:
None declared
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Editors Correction: Systematic Review: Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseIn the recent meta-analysis by Kelly and colleagues (1), Tables and Figures presented data from two UKPDS studies that compared intensive glucose lowering therapy with diet: the UKPDS 33 and 34. The UKPDS 34 was actually a substudy of 33, limited to overweight patients who had been randomized to metformin or diet in the parent study. However, in UKPDS 33 overweight patients randomized to diet in the 34 substudy (N=411) were included in a combined diet comparison group (N=1138). Thus, the comparison group of 411 overweight patients in the UKPDS 34 study was already included in the analysis of UKPDS 33. The Kelly meta-analysis considered the two studies as separate trials and, as such, double-counted those 411 overweight patients. Authors of a letter to the editor pointed out the double counting and provided effect estimates that avoided double counting by merging 33 and 34 into one study (2). For interested readers, several other approaches that minimize the bias introduced when comparisons use a common control arm are available (3-5).
References
1. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K and He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med 2009;151:394-403.
References
2. Yudkin JS, Richter B. Glucose control and cardiovascular disease correction. Ann Intern Med 2009;
3 Higgins JPT, Whitehead A. Borrowing strength from external trials in a meta-analysis. Stat Med. 1996; 15: 2733-2749.
4. Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D'Amico R, Bradburn M, Eastwood AJ: International Stroke Trial Group. Indirect comparisons of competing interventions. Health Technol Assess. 2005;9:1 134.
5. Chootrakool H, Shi JQ. Meta-analysis of multi-arm trials using empirical logistic transform. Open Med Inform J. 2008;2:112 - 116.
The Editors
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Author's Reply: Errors in Calculating Benefits of Glucose Control in Type 2 Diabetes
Submit responseThe Authors Reply:
We would like to thank Drs. Yudkin and Richter for their interest in our meta-analysis. The decision to conduct subgroup analyses of ‘early’ and ‘more recent’ trials was an a priori determination based on important differences in patient populations, targeted HbA1c levels, and treatment regimens (1). Specifically, the early UKPDS trials included only newly diagnosed diabetes patients while the more recent ACCORD, ADVANCE, and VADT included prevalent diabetes patients. The targeted intensive glucose control level in the UKPDS was similar to that of the targeted conventional glucose control level in the more recent trials. Finally, the UKPDS used diet as the primary method of conventional treatment while the more recent trials used hypoglycemic agents. We included the UKPDS 34 in our meta-analysis because the intensive treatment group was completely independent to that of the UKPDS 33 (2). Combining results from different treatment arms of clinical trials that share a common control group is a widely accepted practice (3, 4).
Yudkin et al raised an issue about different definitions of outcomes among individual trials. However, all-cause mortality and cardiovascular disease mortality are two “hard clinical outcomes”, which should be comparable among trials. Our meta-analysis indicated that there was significant heterogeneity in these outcomes between individual trials, which supported our decision to conduct subgroup analyses. We appreciate the concerns of Yudkin et al, but stand by our methods and conclusions.
References
1. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K and He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med (2009) 151: 394-403.
2. 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: 837-853.
3. Glesser LJ, Olkin I. Stochastically dependent effect sizes. In: Cooper H, Hedges LV. The Handbook of Research Synthesis. New York: Russel Sage Foundation. (1994) 339-356.
4. Generalized synthesis of evidence – Combining different sources of evidence. In: Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for Meta-analysis in Medical Research. New York: Wiley & Sons, LTD. (2000) 259-276.
Conflict of Interest:
None declared
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More than one target to prevent cardiovascular (CV) mortality in type 2 diabetes?
Submit responseMore than one target to prevent cardiovascular (CV) mortality in type 2 diabetes?
The importance of glycaemic control in the prevention of long-term macro-vascular complications and mortality of type 2 diabetes (T2DM) is debated. A recent commentary (1) focuses on features of blood glucose control, on different ways to reach glycaemic targets; obesity of these patients is never considered, in spite of the fact that in all the studies considered, subjects were obese, and in spite of the fact that obesity adds significantly in terms of cardiovascular (CV) mortality (2). A quite recent meta-analysis, based on five mega-trials, indicates that intensified hypoglycaemic treatment does not affect incidence of CV mortality in T2DM (3).
This suggets that probably tight glycaemic control is not enough. Bariatric surgery, probably due to weight loss, and to improvement of glucose and lipid metabolism, prevented CV mortality in obese T2DM patients (4). Intentional weight loss reduced CV mortality in obese T2DM patients, when compared with non-intentional weight loss, weight gain, and no change of weight (5). The UKPDS 75 (6)] showed that tight glycaemic control together with tight blood pressure control prevented macro- vascular complications and CV mortality in newly diagnosed obese T2DM patients, as it was the case for multifactorial interventions (aimed at control of glucose and lipid metabolism, of blood pressure, and of other risk factors)(7).
Our aim was to analyze the above studies to evaluate the possible role of different targets alone or in combination. It was possible to enumerate targets of each study from declared aims; tight glycaemic control or intentional weight loss was the aim of studies Proactive (8), Advance, Accord, VADT (1, 3), and study [5]; tight glycaemic control plus blood pressure control was the aim of one study (6); multifactorial intervention was the aim of one study (7); bariatric surgery was allocated to this group as it controls body weight, blood glucose and lipid levels, and blood pressure (4). CV mortality rate was derived from each study; delta-CV mortality rate was calculated for each study as the difference between treated and control subjects. Pairwise correlations between delta-CV mortality rate (dependent variable) and number of targets and age of patients (independent variables) were computed. p < 0.005 was considered statistically significant.
Delta-CV mortality rate was directly related to number of targets (r2 = .724, p = 0.007), and inversely related to age (r2 = .846, p = 0.0012). Since two studies [4, 5] were different (they were not randomized clinical trials), we computed again regressions after their exclusion; the former regression was still statistically significant (r2 = .847, p = 0.0093).
This analysis suggests that treatments aimed at more than one target are more effective in reducing CV mortality than intensified hypoglycaemic treatment. Bariatric surgery has been shown to reduce CV mortality in non-diabetic subjects (9), as well as in T2DM (4). In contrast, older age is associated with a lower beneficial effect of interventions, and this is in line with the concept of frailty patients, meaning that treatments aimed at reducing CV mortality should be implemented early in the course of disease (1, 3).
References
1. Del Prato S. Megatrials in type 2 diabetes. From excitement to frustration? Diabetologia 2009; 52: 1219-1226.
2. Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009; 373: 1083- 1096.
3. 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; 151: 394-4903
4. MacDonald KG Jr, Long SD, Swanson MS. The gastric bypass operation reduces the progression and mortality of non-insulin-dependent diabetes mellitus. J Gastrointest Surg 1997; 1: 213-220.
5. Williamson DF, Thompson TJ, Thun M. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000; 23: 1499-1504.
6. Stratton IM, Cull CA, Adler AI. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia. 2006; 49: 1761-1769.
7. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580-591.
8. Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive investigators. 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: 1279-1289.
9. Sjöström L, Narbro K, Sjöström CD; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357: 741 752.
Conflict of Interest:
None declared
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Errors in Calculating Benefits of Glucose Control in Type 2 Diabetes
Submit responseThe Editor
Glucose Control and Cardiovascular Disease in Type 2 DiabetesThe issue of the impact of glucose lowering on cardiovascular risk in patients with type 2 diabetes is one of great public health significance. While recognising the importance of the paper by Kelly et al ((1) published on line on 21 July), we would like to draw attention to some serious errors in their meta-analysis which substantially affect the conclusions reached.
The authors have combined the data from the 3 recent studies (ACCORD (2), ADVANCE (3) and VADT (4)) with two sub-studies of the UKPDS (5,6), to suggest that many of the outcomes differ between the ‘early’ and ‘late’ studies. In so doing, however, they have failed to notice that the subjects in the conventional treatment limb of the metformin sub-study UKPDS34 (6) were also included in the 3867 subjects in the main study UKPDS33 (5). This error is apparent by comparing Figures 1 in the two papers (5,6), where it is seen that the total population in the study was 4209 subjects. As we have pointed out (7), this error was also made by Ray et al in their meta-analysis (8). One might debate the validity in the definition of UKPDS34 as appropriate for inclusion in such a meta-analysis (7), noting in particular that the trialists involved in the studies have recently performed a similar meta-analysis without its inclusion (9). However, the decision is now of little consequence because its inclusion, with a study weighting appropriate for 411, and not 1704, subjects, makes little difference to virtually all the estimates of relative risk.
We have recalculated the relative risks in Kelly et al's study, and show the main results in the Table . The relative risk estimates for cardiovascular death and all cause mortality are now 1.05 (0.82-1.33) instead of 0.97 (0.76-1.24), and 1.03 (0.89-1.19) instead of 0.98 (0.84-1.15), and the reduction in risk of cardiovascular events is 8% (1%-14%) instead of 10% (2%-17%). Moreover, the recalculation substantially reduces the difference between the early and late trials of Kelly et al's categorisation, with the only end-points showing important heterogeneity being cardiovascular death ( I2 = 75%) and all cause mortality ( I2 = 67% ).
It is clear that different definitions of end-points might create problems in such meta-analyses, and without individual patient data, this issue remains even after the publication of the Trialists' meta-analysis (9). This is clear by comparing the results of Kelly's study (1) with that of Ray et al (8) who did not include sudden death in their definition of cardiovascular disease. We would conclude, however, that there is little evidence of differences in outcomes between early and late studies. In the context of the epidemiological relationships between glycaemia and cardiovascular disease, around two-thirds of that of CHD is reversible with intensive control, but virtually none of that of stroke (7). There is no evidence of benefit on reducing either cardiovascular or total mortality, or, by extrapolation, life expectancy. Moreover, the data suggest that treating 100 people with intensive glycaemic control for 10 years would prevent around 3 cardiovascular events (7), at the expense of inducing 8 serious hypoglycaemic ones.References
1. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K and He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med (2009) 151: (published on-line 21 July 2009).
2. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med (2008) 358: 2545-2559.
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med (2008) 358: 2560-2572.
4. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG and Huang GD for the VADT Investigators. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med (2009) 360: 129-139.
5. 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: 837-853.
6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet (1998) 352: 854-865.
7. Yudkin JS and Richter B. Intensive glucose control and cardiovascular outcomes. Lancet (2009) 374: 522.
8. Ray KK, Seshasai SRK, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S and 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 373: 1765-72.
9. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, Evans GW, Gerstein HC, Holman RR, Moritz TE, Neal BC, Ninomiya T, Patel AA, Paul SK, Travert F and Woodward M. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia (2009) DOI 10.1007/s00125-009-1470-0 (published on-line 5th August 2009).
Table: Relative Risks (95% Confidence Intervals) for major endpoints overall and in early (E) and late (L) studies as in original paper and recalculated without double-counting
Kelly total
Kelly early-late
BR and JY total
BR and JY early-late
Cardiovascular disease
0.90 (0.83-0.98)
E 0.79 (0.57-1.09)
L 0.94 (0.86-1.02)
0.92 (0.86-0.99)
E 0.89 (0.78-1.01)
L 0.94 (0.86-1.01)
Coronary heart disease
0.89 (0.81-0.96)
E 0.78 (0.59-1.04)
L 0.91 (0.83-1.01)
0.89 (0.82-0.97)
E 0.85 (0.72-0.99)
L 0.91 (0.83-1.01)
Stroke
0.98 (0.86-1.11)
E 0.91 (0.53-1.58)
L 0.97 (0.84-1.12)
0.99 (0.87-1.13)
E1.08 (0.80-1.45)
L 0.97 (0.83-1.12)
Cardiovascular death
0.97 (0.76-1.24)
E 0.75 (0.48-1.19)
L 1.13 (0.79-1.63)
1.05 (0.82-1.33)
E 0.89 (0.73-1.08)
L 1.13 (0.79-1.62)
All cause mortality
0.98 (0.84-1.15)
E 0.83 (0.59-1.16)
L 1.08 (0.88-1.32)
1.03 (0.89-1.19)
E 0.94 (0.81-1.08)
L 1.08 (0.88-1.32)
Fatal myocardial infarction
0.94 (0.75-1.18)
E 0.74 (0.46-1.18)
L 1.08 (0.80-1.46)
1.01 (0.83-1.23)
E 0.92 (0.73-1.16)
L 1.08 (0.80-1.46)
Severe hypoglycaemia
2.03 (1.46-2.81)
E 1.37 (0.58-3.27)
L 2.48 (1.78-3.47)
2.32 (1.77 - 3.06)
E 1.94 (1.54-2.44)
L 2.48 (1.78-3.46)
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Glucose Control and Cardiovascular Disease in Type 2 Diabetes: a reply to Tanika N. Kelly
Submit responseTo the Editor,
Tanika N. Kelly and colleagues (July 21st, vol 151)(1)reported the results from a meta-analysis of five randomised trials and concluded that intensive glucose control reduced the risk of some, but not all, cardiovascular events at the expense of an increased risk of severe hypoglycaemia. If this statement is true globally, it is worth analysing separately the clinical benefits demonstrated in ADVANCE (2) where a significant 10% decrease was seen in the composite end point of macrovascular and microvascular events. Moreover, the significant 21% risk reduction for new or worsening nephropathy must be considered for its predictive value on cardiovascular events. Moreover, it is important not to globalize results regarding cardiovascular and all-cause mortality, as ADVANCE was the only study showing a favorable trend in these outcomes as compared with ACCORD and VADT. It is a matter of fact that it takes time to demonstrate a significant clinical benefit on macrovascular events as seen in the UKPDS long term follow up (3). As alluded by Kelly et al., the lack of significant effect was mainly due to an insufficient duration of follow up within the 5-year time frame. In addition, ADVANCE showed the best efficacy/safety ratio in terms of severe hypoglycaemic episodes (2.7% in comparison with a six-fold increase in ACCORD (4) and VADT (5) when we use the standard definition of severe hypoglycemias and not only those requiring external medical assistance) and absence of weight gain (compared with more than 3.5kg in the other trials). We acknowledge the clear need for multifactorial interventions which combine optimal controls of blood glucose, blood pressure, and lipid profile to minimize the risk of cardiovascular events in the high-risk population of type 2 diabetes.
References
1. Kelly TN, Bazzano LA, Fonseca VA et al. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern medicine 2009;151(online)
2. Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
3. Holman R, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.
4. Gerstein HC, Miller ME, Byington RP et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59.
5. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360: 129-39.
Conflict of Interest:
I have received fees for lectures and consultations from Eli Lilly, GlaxoSmithKline, Novartis, Roche, Servier, and Takeda.
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Far from the metabolic targets in type 2 diabetes
Submit responseWe read with interest the review of Kelly et al (1) on glucose control and cardiovascular disease in type 2 diabetes. Quite surprisingly, a 3-month distance separates the paper of Kelly et al (1) from that of Montori & Fernandez-Balsells (2) on the same topic. However, important topics merit important and hopefully definite answers. The importance of glucose control on cardiovascular outcomes in type 2 diabetes has long been debated. Ironically, the very recent trials aimed at definitely proven the promising results of the old UKPDS Study left a feeling of embarrass. The analysis of the same five trials led Montori & Fernandez-Balsells (2) to recommend selecting diabetes medications based on burden of administration and side effects (Primum non nocere); Kelly et al (1) recommend a global approach which takes into account all benefits coming to the diabetic patients by other interventions that have demonstrated to reduce the cardiovascular burden associated with diabetes. Another recent meta-analysis (3) agrees that blood pressure and lipid control reduce cardiovascular events and all-cause mortality in individuals with type 2 diabetes. However, the benefit of glucose control on coronary heart disease in type 2 diabetes will not be as great as that produced by blood pressure control or statin treatment. Not unexpected, the blood pressure and LDL-cholesterol targets known to have benefits in diabetics are suboptimal. In the Look AHEAD trial (4), for example, which is a multicentered, randomized, controlled trial of 5,145 individuals with type 2 diabetes, the baseline prevalence of meeting ADA goals for blood pressure (<130/80 mm Hg), LDL cholesterol (<100 mg/dL) and HbA1c (<7%) was 52%, 37%, and 42%, respectively. The prevalence of simultaneously meeting all three goals was 10%; only one out of ten diabetic may hope to have its residual risk comparable to that of the non diabetic population. The current uncertainty about the optimal drugs to achieve glycemic targets should be a stimulus for reaching as many metabolic targets as possible in type 2 diabetes in order to reduce its cardiovascular burden.
References
1. 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;151:online 21 July 2009.
2. Montori VM, Fernandez-Balsells M. Glycemic control in type 2 diabetes: time for an evidence-based about-face? Ann Intern Med. 2009;150:803-8.
3. Ray K, Kondapally Seshasai SR, Wijesuriya R, Nethercott S, Preiss D, Erqou S. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomized controlled trials. Lancet. 2009;373:1765-72.
4. The Look AHEAD Research Group. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes. One-year results of the Look AHEAD trial Diabetes Care. 2007;30:1374-83.
Conflict of Interest:
None declared