- Email: [email protected]
Effect of intensive glycemic control on cardiovascular outcomes and all-cause mortality in type 2 diabetes: Overview and metaanalysis of five trials
DIABETES RESEARCH A N D CLINICAL PRACTICE
86S (2009) S57–S6 2
Effect of intensive glycemic control on cardiovascular outcomes and all-cause mortality in type 2 diabetes: Overview and metaanalysis of five trials Ivan Tkáˇc * Department of Internal Medicine 4, Šafárik University, Faculty of Medicine, L. Pasteur Faculty Hospital, Košice, Slovakia
AR TI C L E
I NF O
A B S T R A C T
Keywords:
More intensive diabetes control prevents microangiopathy in patients with both type 1 di-
Type 2 diabetes mellitus
abetes and type 2 diabetes. The data related to prevention of macrovascular disease in
Glucose lowering treatment
patients with type 2 diabetes are controversial. The data confirming benefit of the HbA1c
Cardiovascular disease
levels below 6.5% came almost exclusively from epidemiological studies. The following ar-
Metaanalysis of randomized trials
ticle reviews the data from five large clinical randomized trials which compared the more intensive glucose lowering strategy with the standard antidiabetic treatment i.e. UKPDS, PROactive, ACCORD, ADVANCE and VADT. Metaanalysis of five trials showed a highly significant reduction of the incidence of nonfatal myocardial infarction [OR 0.84 (95% CI 0.75–0.93), p = 0.001] in patients with intensive glycemic control. No significant differences were observed by combined analysis for the non-fatal stroke, cardiovascular mortality and all-cause mortality between the compared groups. The reason for the discordance of the results of the epidemiological and interventional studies is not clear. The possible explanations could include short duration of the trials to show effect of glucose lowering, as well as attenuating of the beneficial effect of better glycemic control by increased hypoglycemia-related mortality in patients with preexisting cardiovascular disease. © 2009 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
More intensive diabetes control prevents microangiopathy in patients with type 1 diabetes, as it was observed in the Diabetes Control and Complications Trial (DCCT) [1]. A similar finding in patients with type 2 diabetes was confirmed in the United Kingdom Prospective Diabetes Study (UKPDS) [2]. However, the majority of patients with type 2 diabetes die because of macrovascular complications, such as myocardial infarction or stroke. Data related to prevention of
* Address for correspondence: Prof. Ivan Tkáˇc, MD, PhD, Department of Internal Medicine 4, Šafárik University, Faculty of Medicine, L. Pasteur Faculty Hospital, Rastislavova 43, SK-04190 Košice, Slovakia. Tel.: +421 55 615 2230, fax: +421 55 615 2249. E-mail address: [email protected]
macrovascular disease in patients with type 2 diabetes are controversial. The data confirming benefit of the HbA1c levels below 6.5% came almost exclusively from epidemiological studies. Epidemiological analysis of the UKPDS showed that HbA1c lower by 1% was associated with significantly lower incidence of both myocardial infarction (by 14%) and of stroke (by 12%) [3]. Analysis from the Atherosclerosis Risk in the Communities Study (ARIC) showed that diabetic patients with HbA1c in the range of 6.0–7.4% had increased risk of the development for peripheral arterial disease by 53% when compared with diabetic patients with HbA1c <6% [4]. The metaanalysis of 10 studies which included patients with type 2 diabetes showed that increase in HbA1c level by 1% is associated with significantly increased risk of coronary artery disease or stroke by 18% [5]. A similar relationship between the HbA1c level and the in-
0168-8227/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
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DIABETES RESEARCH A N D CLINICAL PRACTICE
cidence of cardiovascular disease was observed also in nondiabetic patients, even after statistical adjustment for other cardiovascular risk factors. From this aspect the most important data could be considered the results of the prospective epidemiological study European Perspective Into Cancer in Norfolk (EPIC-Norfolk), which showed that risk of cardiovascular disease and total mortality increases from the level of HbA1c >5%. Thus, the males with HbA1c level in the range of 6.0–6.4% had three times increased incidence of coronary event when compared with males with HbA1c <5% [6]. Similar findings were observed in epidemiological studies that examined the incidence of atherosclerosis in different vessel trees. In the Tromso study the subjects with HbA1c in the range of 6.0–6.4% had increased incidence of carotid plaques by 58% in comparison with subjects whose HbA1c was <5% [7]. The analysis from the National Health and Nutrition Epidemiological Survey (NHANES) has analogically shown that subjects with HbA1c in the range of 5.7–6.0% had increased risk of peripheral vascular disease by 57% when compared with subjects with HbA1c <5.3% [8].
2.
Overview of clinical randomized studies
2.1.
United Kingdom Prospective Diabetes Study (UKPDS)
UKPDS study included 4203 patients with newly diagnosed type 2 diabetes. The median follow-up of patients was 10 years. The main results of the UKPDS study were published 1998 in two papers. UKPDS 33 paper reports results of 3867 patients with newly diagnosed type 2 diabetes who were randomised to intensive glycemic control policy with sulfonylureas or insulin, or to conventional treatment policy primarily with diet. Further drugs were allowed to have been added in both groups of patients, if fasting plasma glucose was ≥15 mmol/l. Patients in the intensive group had median HbA1c of 7.0% during 10-year follow-up, while patients in the conventional group achieved median HbA1c of 7.9%. Three aggregate endpoints were used for comparison of intensive and conventional group – any diabetes related endpoint (all-cause death, macrovascular and microvascular), diabetes related death and all-cause mortality. Significant risk reduction by 12% (p = 0.029) in the incidence of any diabetesrelated endpoint in the intensive treatment group was observed. The diabetes-related death and all-cause mortality were both not significantly reduced by 10% and 6%, respectively. Non-fatal and fatal myocardial myocardial infarction incidence was reduced almost significantly (p = 0.052) by 16% [2]. The results of subgroup analysis of 1704 overweight (>120% ideal body weight) patients with type 2 diabetes randomized to intensive treatment by metformin, sulfonylurea/insulin or to conventional treatment were published separately in the UKPDS 34 paper. Patients treated primarily by intensive metformin treatment had median HbA1c level of 7.4% during the follow-up, while patients in conventional treatment group had median HbA1c level of 8.0%. Patients allocated to metformin compared with the conventional group had significantly reduced risk for any diabetesrelated endpoint by 32% (p = 0.002), for diabetes related
86S (2009) S57–S6 2
death by 42% (p = 0.017), for all-cause mortality by 36% (p = 0.011) and for fatal/non-fatal myocardial infarction by 39% (p = 0.01). Patients allocated to metformin when compared to patients allocated to insulin/sulfonylurea had lower risk for any diabetes-related endpoint (p = 0.0034), for all-cause mortality (p = 0.021) and for stroke (p = 0.032) [9]. 2.2. Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) The PROactive study included 5238 patients with developed macrovascular (coronary, cerebral or peripheral arterial) disease. The interventional study group patients were given pioglitazone in addition to the previous treatment. This treatment resulted in on-study difference of HbA1c level by 0.6% between the treatment groups. The patients on pioglitazone had non-significantly reduced the incidence of widely defined primary endpoint (the composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular and surgical interventions in the coronary or leg arteries, and amputations above ankle) by 10% (p = 0.095). The incidence of more commonly used main secondary endpoint (total mortality, non-fatal myocardial infarction, and stroke), which was not predefined in the design of the study was significantly reduced by 16% (p = 0.027) in the pioglitazone-treated patients [10]. In the post-hoc analyses, the effect of intervention seemed to be more pronounced in the patients with already developed macrovascular complications. Thus, in patients with previous stroke, pioglitazone treatment reduced fatal and non-fatal stroke by 47% (p = 0.0085) and in patients with previous myocardial infarction pioglitazone reduced fatal and non-fatal myocardial infarction by 28% (p = 0.045) [11,12]. 2.3. Action to Control Cardiovascular Risk in Diabetes (ACCORD) In the ACCORD trial, 10251 patients with a mean age of 62 years and median diabetes duration of 10 years were randomised to recieve intensive glucose-lowering treatment aiming for HbA1c <6% or standard diabetes treatment targeting HbA1c level in the range 7.0–7.9%. No specific treatment was requested in neither of study groups and multiple drug combinations were allowed to achieve the defined target. In the intensive treatment group a median HbA1c of 6.4% and in standard treatment group a median of 7.5% were achieved, respectively. The study was prematurely stopped after 3.5 years of follow-up in 2008 because of observed 22% significant increase in all-cause mortality (p = 0.04) and 35% increase in cardiovascular mortality (p = 0.02) in patients with intensive glycemic control. The primary endpoint of the study (non-fatal myocardial infarction, nonfatal stroke or death from cardiovascular causes) was non-significantly reduced in the intensivetreatment group by 10% (p = 0.16). Significant reduction in the incidence of nonfatal myocardial infarction by 24% (p = 0.004) was observed in the intensive-therapy group. The subgroup analysis revealed a significantly more beneficial effect on primary endpoint reduction in the intensive-treat-
DIABETES RESEARCH A N D CLINICAL PRACTICE
ment group in the patients without previous cardiovascular disease and with better diabetes control (HbA1c <8%) [13]. 2.4. Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) The design of the ADVANCE study was very similar to the design of ACCORD. 11,140 patients with the mean age of 66 years and mean diabetes duration of 8 years were randomised to intensive treatment defined as the use of gliclazide modified release with other drugs with a target of HbA1c <6.5% or standard treatment. The standard treatment strategy was based on local guidelines. Median follow-up of patients was 5 years. Primary endpoint of combined major macrovascular and microvascular events was reduced significantly by 10% in the intensive-treatment group (p = 0.01). There was observed a non-significant 6% reduction in the incidence of macrovascular events (nonfatal myocardial infarction, nonfatal stroke and death from cardiovascular causes). In contrast with the ACCORD trial, no significant increase in all-cause and cardiovascular mortality was observed. The most pronounced effect in this study was a 21% reduction (p = 0.006) of the development of new or worsening nephropathy. Subgroup analysis suggested there might be a more pronounced effect on primary endpoint reduction in the subgroup of patients with no history of macrovascular disease. However, the test of heterogeneity between the groups with and without history of macrovascular disease was not significant [14]. 2.5.
Veterans Affairs Diabetes Trial (VADT)
The VADT trial had similar design to ACCORD and ADVANCE trials. 1791 patients with mean age of 60 years and mean diabetes duration of 11.5 years were randomised to intensive diabetes treatment aiming for HbA1c <6% and standard-treatment group aiming for HbA1c <9%. The goal for HbA1c between-group difference was 1.5%. The ontreatment median HbA1c was 6.9% for the intensive-treatment group and 8.4% for the standard treatment group. The primary endpoint was any major cardiovascular event (a composite of myocardial infarction, stroke, death from cardiovascular disease, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene). After of the median follow-up of 5.6 years there was observed a nonsignificant reduction of
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primary endpoint in the intensive-therapy group by 12% (p = 0.14). Incidence of none of the endpoints included in the primary outcome did not differ significantly between the study groups. The patients treated with intensive regimen had reduced any worsening in albuminuria by 38% with borderline significance (p = 0.05) [15].
3.
Metaanalysis of five large trials
It is not surprising that the conflicting results of the abovementioned studies led to some confusion among clinicians, whether it is needed to revise current HbA1c goal for glycemic control or rather the treatment strategies leading to the defined goal. Thus, to elucidate the effect of more intensive glycemic control on cardiovascular events and mortality we decided to perform combined analysis of five above-mentioned trials comparing intensive with conventional treatment strategies in patients with type 2 diabetes i.e. UKPDS, PROactive, ACCORD, ADVANCE, and VADT. The above studies were selected, since they are five main studies comparing more intensive with conventional treatment strategies in patients with type 2 diabetes. Each of this studies included more than 1500 patients who were followed-up at least for 3 years. In every of these studies median HbA1c of 7% or less was achieved in the group of patients with intensive treatment (range 6.4–7.0%) and the difference between intensive and conventional treatment groups in median HbA1c was at least 0.6% (range 0.6–1.5%). More detailed characteristics of the study populations included in these studies is shown in Table 1. The five large trials included in total 32649 patients, among them 17267 were assigned to intensive diabetes control and 15382 patients were assigned to less intensive (convential) glucose control. Data from combined analysis of the five trials by the Mantel–Haenszel method for the endpoint of cardiovascular and all-cause mortality are shown in Table 2. No significant effect of intensive glycemic control on cardiovascular mortality was detected [OR 1.03 (95% CI 0.84– 1.26)], although significant heterogeneity (p = 0.015) among the results of studies was observed. Similarly, no effect of intensive diabetes control on all-cause mortality was shown [OR 1.02 (95% CI 0.89–1.16)] with no significant heterogeneity among the trials. Metaanalysis of five trials for the endpoints of non-fatal myocardial infarction and non-fatal stroke is shown in Table 3. A highly significant reduction in the incidence of non-
Table 1 – Characteristics of patients in the studies of antidiabetic treatment.
UKPDS PROactive ADVANCE ACCORD VADT
Number of patients (intensive/conventional treatment group)
Mean age at study start (years)
Median/mean * duration of follow-up (years)
Median HbA1c (%) in intensive vs. conventional treatment group
4209 (3071/1138) 5238 (2605/2633) 11140 (5571/5569) 10251 (5128/5123) 1791 (892/899)
54 ± 8 62 ± 8 66 ± 6 62 ± 7 60 ± 9
10.0 2.9 * 5.0 3.4 5.6
7.0 vs. 7.9 7.0 vs. 7.6 6.3 vs. 7.0 6.4 vs. 7.5 6.9 vs. 8.4
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Table 2 – Effect of more intensive diabetes control on the endpoints of cardiovascular mortality and all-cause mortality. Intensive group events (% patients) (n = 17,267)
Control group events (% patients) (n = 15,382)
OR (95% CI)
p
Cardiovascular mortality UKPDS PROactive ADVANCE ACCORD VADT Combined
299 (9.7) 119 (4.9) 253 (4.5) 135 (2.6) 38 (4.3) 852 (5.2)
123 (10.8) 144 (5.2) 289 (5.2) 94 (1.8) 29 (3.2) 671 (4.6)
0.89 (0.71–1.11) 0.94 (0.73–1.21) 0.87 (0.73–1.03) 1.45 (1.11–1.89) 1.34 (0.82–2.18) 1.03 (0.84–1.26)
0.304 0.631 0.112 0.007 0.250 0.762
All-cause mortality UKPDS PROactive ADVANCE ACCORD VADT Combined
539 (17.6) 177 (6.8) 498 (8.9) 257 (5.0) 102 (11.4) 1573 (9.0)
213 (18.7) 186 (7.1) 533 (9.6) 203 (4.0) 95 (10.6) 1230 (8.5)
0.92 (0.78–1.10) 0.96 (0.78–1.19) 0.93 (0.82–1.05) 1.28 (1.06–1.54) 1.09 (0.81–1.47) 1.02 (0.89–1.16)
0.381 0.701 0.250 0.010 0.557 0.801
Random effect models. Q-test for heterogeneity: p = 0.015 for cardiovascular mortality; p > 0.05 for all-cause mortality
Table 3 – Effect of more intensive diabetes control on the endpoints of non-fatal myocardial infarction and non-fatal stroke. Intensive group events (% patients) (n = 17,267)
Control group events (% patients) (n = 15,382)
OR (95% CI)
p
Non-fatal myocardial infarction UKPDS 221 (7.2) PROactive 119 (4.6) ADVANCE 153 (2.7) ACCORD 186 (3.6) VADT 64 (7.1) Combined 743 (4.3)
101 (8.9) 144 (5.5) 156 (2.8) 235 (4.6) 78 (8.7) 714 (4.6)
0.80 (0.62–1.02) 0.83 (0.65–1.06) 0.98 (0.78–1.23) 0.78 (0.64–0.95) 0.81 (0.58–1.15) 0.84 (0.75–0.93)
0.069 0.136 0.860 0.015 0.240 0.001
Non-fatal stroke UKPDS PROactive ADVANCE ACCORD VADT Combined
44 (3.9) 107 (4.1) 209 (3.8) 61 (1.2) 36 (4.0) 457 (3.0)
1.01 (0.71–1.44) 0.81 (0.60–1.08) 1.02 (0.84–1.24) 1.10 (0.78–1.56) 0.78 (0.47–1.28) 0.97 (0.85–1.10)
0.951 0.144 0.807 0.598 0.325 0.595
120 (3.9) 86 (3.3) 214 (3.8) 67 (1.3) 28 (3.1) 515 (3.0)
Random effect models. Q-test for heterogeneity: p > 0.05 for both endpoints
fatal myocardial infarction was observed [OR 0.84 (95% CI 0.75–0.93), p = 0.001] in patients treated towards more intensive glycemic control. No effect on reduction of non-fatal stroke was observed [OR 0.97 (95% CI 0.85–1.10)] in the intensive glycemic control group. For both evaluated endpoints there was no significant heterogeneity among the trials.
4.
Implications for clinical practice
In summary, based on the metaanalysis of five most important trials comparing intensive to conventional glycemic control, more intensive glycemic control led in average to reduction in the incidence of nonfatal myocardial infarctions by one sixth, while it had no significant effect on the incidence of nonfatal stroke and both cardiovascular or all-cause mortality. Significant heterogeneity among the studies was observed for cardiovascular mortality. While in UKPDS, PROactive and ADVANCE studies a nonsignificant
trend for decreased cardiovascular mortality in intensivetreatment group was observed, in ACCORD study the cardiovascular mortality was significantly increased and a trend for increased mortality was observed in VADT study in intensively treated patients. In the ACCORD study, the intensivetreatment group was given aggresive treatment with up to 4–5 glucose-lowering drugs and high percentage of patients using insulin, sulfonylurea, rosiglitazone or even the combinations of these drugs. These treatment regimens in ACCORD were associated with much higher incidence of hypoglycemic episodes, as well as significant weight gain. What are the possible explanations for the observed heterogeneity of the mentioned study results and less than expected (from the epidemiological studies) effect on cardiovascular morbidity and mortality? First, the beneficial effect of long-term glucose control might be observed after the longer time than in cholesterol and blood pressure lowering studies, in which it was observed usually in 5-year treatment period. Indeed, long-term follow-up of patients included into
DIABETES RESEARCH A N D CLINICAL PRACTICE
the DCCT – Epidemiology of Diabetes Complications (DCTTEDIC) and UPKDS studies showed that the effect on prevention of macrovascular events become significant after 10-years of follow-up after the study end, despite the lack of difference in glycemic control during the follow-up period [16,17]. Moreover, the effects of better glycemic control or multifactorial interventions on all-cause mortality became significant during the follow-up phases of the UKPDS and Steno 2 trials, respectively [17,18]. This effect called “legacy” by the UKPDS investigators might have been associated by slower progression of vascular disease related to the accumulation of advanced glycation endproducts, in contrast to faster mechanism of atherosclerosis related to LDL particles. Another explanation for the delayed effect on prevention could be that better glycemic control during the trials prevented the development of diabetic nephropathy, which is associated with increased incidence of cardiovascular disease. In the EDIC-DCCT trial the presence of nephropathy or albuminuria were along with HbA1c levels the only significant predictors for development of macrovascular complications in type 1 diabetes [16]. Similar mechanism might participate in atherosclerosis prevention also in patients with type 2 diabetes. Further explanation for the less than expected effect of intensive glycemic control might be related to the side effects of antidiabetic treatment, first of all to increased incidence of hypoglycemia and weight gain. While hypoglycemia might be related to increased incidence of cardiovascular mortality (for sudden death, myocardial infarction and stroke), increased weight is a well established risk factor for atherosclerosis in non-diabetic, as well as in diabetic patients. Thus, adverse effects of treatment could have reduced the beneficial effect of HbA1c lowering in UKPDS, PROactive, ADVANCE and VADT studies and even be related to increased cardiovascular mortality observed in the ACCORD study. Furthermore, the adverse effect of long-term hyperglycemia could be genetically determined. A recently published study observed that an interaction between poor glycemic control and a polymorphism in 9p21 locus (close to CDKN2A-2B genes) resulted in more frequent development of coronary artery disease in carriers of two risk alleles [19]. The results of the above-mentioned studies might lead to an individualisation of diabetes control goals as reflected also in the recent joint statement of American Diabetes Association, American College of Cardiology Foundation and American Heart Association. According to the statement the general goal of HbA1c <7% should be maintained, but for certain groups of patients more stringent goal could be recommended based on the subgroup analysis of the mentioned studies. Those patients include diabetic patients with short duration of diabetes, longer life expectancy a no significant cardiovascular disease. In contrast, less stringent than the general goal of <7% might be considered in patients with history of severe hypoglycemia, limited life expectancy, longer duration of diabetes, advanced microvascular and macrovascular complications or extensive comorbid conditions [20].
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Acknowledgements The present study was supported in part by research grants from the Research Grant Agency (VEGA 1/4304/07) and from the Research and Development Agency (APVV-0122-06) of the Ministry of Education, Slovakia.
Conflict of interest The author received lecture fees from sanofi-aventis, Eli Lilly, Servier, Novartis, Merck-Sharp-Dohme, and Wörwag Pharma.
references [1] Diabetes Control and Complicatins Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:304–309. [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] Stratton IM, Adler AI, Neil AW, Matthews DR, Manley SE, Cull CA et al, on behalf of the UK Prospective Diabetes Study Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. Br Med J 2000;321:405–412. [4] Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett AR. HbA1c and peripheral arterial disease in diabetes. The Atherosclerosis Risk in Communities study. Diabetes Care 2006;29:877–882. [5] 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;141:421–431. [6] Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: The European Prospective Investigation into Cancer in Norfolk. Ann Intern Med 2004; 141:413–420. [7] Jorgensen L, Jenssen T, Joakimsen O, Heuch I, Ingebretsen OC, Jacobsen BK. Glycated hemoglobin is strongly related to the prevalence of carotid artery plaques with high echogenicity in nondiabetic individuals. The Tromso Study. Circulation 2004;110:466–470. [8] Muntner P, DeSalvo KB, Wildman RP, Desalvo KB, Chen J, Fonseca V. Relationship between HbA1c level and peripheral arterial disease. Diabetes Care 2005;28:1981–1987. [9] 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;352:854–865. [10] Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti M, Moules IK et al, on behalf of the PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascuar Events): a randomised controlled trial. Lancet 2005;366:1279–1289. [11] Wilcox R, Bousser MG, Betteridge J, Schernthaner G, Pirags V, Kupfer S et al, on behalf of the PROactive Investigators. Effects of pioglitazone in patients with type 2 diabetes with
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or without previous stroke. Results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38:865–873. Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, on behalf of the PROactive Investigators. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction. Results from the PROactive (PROactive 5) Study. J Am Coll Cardiol 2007; 49:1772–1780. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–2559. The ADVANCE Collaborative Group. Intensive blood glucose and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560–2572. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD et al, for the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129–139. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC)
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Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–1589. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effects of multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580–591. Doria A, Wojcik J, Xu R, Gervino EV, Hauser TH, Johnstone MT et al. Interaction between poor glycemic control and 9p21 locus on risk of coronary artery disease in type 2 diabetes. J Am Med Assoc 2008;300:2389–2297. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EM et al. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE and VA Diabetes trials. A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009; 32:187–192.
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Effect of intensive glycemic control on cardiovascular outcomes and all-cause mortality in type 2 diabetes: Overview and metaanalysis of five trials Ivan Tkáˇc * Department of Internal Medicine 4, Šafárik University, Faculty of Medicine, L. Pasteur Faculty Hospital, Košice, Slovakia
AR TI C L E
I NF O
A B S T R A C T
Keywords:
More intensive diabetes control prevents microangiopathy in patients with both type 1 di-
Type 2 diabetes mellitus
abetes and type 2 diabetes. The data related to prevention of macrovascular disease in
Glucose lowering treatment
patients with type 2 diabetes are controversial. The data confirming benefit of the HbA1c
Cardiovascular disease
levels below 6.5% came almost exclusively from epidemiological studies. The following ar-
Metaanalysis of randomized trials
ticle reviews the data from five large clinical randomized trials which compared the more intensive glucose lowering strategy with the standard antidiabetic treatment i.e. UKPDS, PROactive, ACCORD, ADVANCE and VADT. Metaanalysis of five trials showed a highly significant reduction of the incidence of nonfatal myocardial infarction [OR 0.84 (95% CI 0.75–0.93), p = 0.001] in patients with intensive glycemic control. No significant differences were observed by combined analysis for the non-fatal stroke, cardiovascular mortality and all-cause mortality between the compared groups. The reason for the discordance of the results of the epidemiological and interventional studies is not clear. The possible explanations could include short duration of the trials to show effect of glucose lowering, as well as attenuating of the beneficial effect of better glycemic control by increased hypoglycemia-related mortality in patients with preexisting cardiovascular disease. © 2009 Elsevier Ireland Ltd. All rights reserved.
1.
Introduction
More intensive diabetes control prevents microangiopathy in patients with type 1 diabetes, as it was observed in the Diabetes Control and Complications Trial (DCCT) [1]. A similar finding in patients with type 2 diabetes was confirmed in the United Kingdom Prospective Diabetes Study (UKPDS) [2]. However, the majority of patients with type 2 diabetes die because of macrovascular complications, such as myocardial infarction or stroke. Data related to prevention of
* Address for correspondence: Prof. Ivan Tkáˇc, MD, PhD, Department of Internal Medicine 4, Šafárik University, Faculty of Medicine, L. Pasteur Faculty Hospital, Rastislavova 43, SK-04190 Košice, Slovakia. Tel.: +421 55 615 2230, fax: +421 55 615 2249. E-mail address: [email protected]
macrovascular disease in patients with type 2 diabetes are controversial. The data confirming benefit of the HbA1c levels below 6.5% came almost exclusively from epidemiological studies. Epidemiological analysis of the UKPDS showed that HbA1c lower by 1% was associated with significantly lower incidence of both myocardial infarction (by 14%) and of stroke (by 12%) [3]. Analysis from the Atherosclerosis Risk in the Communities Study (ARIC) showed that diabetic patients with HbA1c in the range of 6.0–7.4% had increased risk of the development for peripheral arterial disease by 53% when compared with diabetic patients with HbA1c <6% [4]. The metaanalysis of 10 studies which included patients with type 2 diabetes showed that increase in HbA1c level by 1% is associated with significantly increased risk of coronary artery disease or stroke by 18% [5]. A similar relationship between the HbA1c level and the in-
0168-8227/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
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DIABETES RESEARCH A N D CLINICAL PRACTICE
cidence of cardiovascular disease was observed also in nondiabetic patients, even after statistical adjustment for other cardiovascular risk factors. From this aspect the most important data could be considered the results of the prospective epidemiological study European Perspective Into Cancer in Norfolk (EPIC-Norfolk), which showed that risk of cardiovascular disease and total mortality increases from the level of HbA1c >5%. Thus, the males with HbA1c level in the range of 6.0–6.4% had three times increased incidence of coronary event when compared with males with HbA1c <5% [6]. Similar findings were observed in epidemiological studies that examined the incidence of atherosclerosis in different vessel trees. In the Tromso study the subjects with HbA1c in the range of 6.0–6.4% had increased incidence of carotid plaques by 58% in comparison with subjects whose HbA1c was <5% [7]. The analysis from the National Health and Nutrition Epidemiological Survey (NHANES) has analogically shown that subjects with HbA1c in the range of 5.7–6.0% had increased risk of peripheral vascular disease by 57% when compared with subjects with HbA1c <5.3% [8].
2.
Overview of clinical randomized studies
2.1.
United Kingdom Prospective Diabetes Study (UKPDS)
UKPDS study included 4203 patients with newly diagnosed type 2 diabetes. The median follow-up of patients was 10 years. The main results of the UKPDS study were published 1998 in two papers. UKPDS 33 paper reports results of 3867 patients with newly diagnosed type 2 diabetes who were randomised to intensive glycemic control policy with sulfonylureas or insulin, or to conventional treatment policy primarily with diet. Further drugs were allowed to have been added in both groups of patients, if fasting plasma glucose was ≥15 mmol/l. Patients in the intensive group had median HbA1c of 7.0% during 10-year follow-up, while patients in the conventional group achieved median HbA1c of 7.9%. Three aggregate endpoints were used for comparison of intensive and conventional group – any diabetes related endpoint (all-cause death, macrovascular and microvascular), diabetes related death and all-cause mortality. Significant risk reduction by 12% (p = 0.029) in the incidence of any diabetesrelated endpoint in the intensive treatment group was observed. The diabetes-related death and all-cause mortality were both not significantly reduced by 10% and 6%, respectively. Non-fatal and fatal myocardial myocardial infarction incidence was reduced almost significantly (p = 0.052) by 16% [2]. The results of subgroup analysis of 1704 overweight (>120% ideal body weight) patients with type 2 diabetes randomized to intensive treatment by metformin, sulfonylurea/insulin or to conventional treatment were published separately in the UKPDS 34 paper. Patients treated primarily by intensive metformin treatment had median HbA1c level of 7.4% during the follow-up, while patients in conventional treatment group had median HbA1c level of 8.0%. Patients allocated to metformin compared with the conventional group had significantly reduced risk for any diabetesrelated endpoint by 32% (p = 0.002), for diabetes related
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death by 42% (p = 0.017), for all-cause mortality by 36% (p = 0.011) and for fatal/non-fatal myocardial infarction by 39% (p = 0.01). Patients allocated to metformin when compared to patients allocated to insulin/sulfonylurea had lower risk for any diabetes-related endpoint (p = 0.0034), for all-cause mortality (p = 0.021) and for stroke (p = 0.032) [9]. 2.2. Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) The PROactive study included 5238 patients with developed macrovascular (coronary, cerebral or peripheral arterial) disease. The interventional study group patients were given pioglitazone in addition to the previous treatment. This treatment resulted in on-study difference of HbA1c level by 0.6% between the treatment groups. The patients on pioglitazone had non-significantly reduced the incidence of widely defined primary endpoint (the composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular and surgical interventions in the coronary or leg arteries, and amputations above ankle) by 10% (p = 0.095). The incidence of more commonly used main secondary endpoint (total mortality, non-fatal myocardial infarction, and stroke), which was not predefined in the design of the study was significantly reduced by 16% (p = 0.027) in the pioglitazone-treated patients [10]. In the post-hoc analyses, the effect of intervention seemed to be more pronounced in the patients with already developed macrovascular complications. Thus, in patients with previous stroke, pioglitazone treatment reduced fatal and non-fatal stroke by 47% (p = 0.0085) and in patients with previous myocardial infarction pioglitazone reduced fatal and non-fatal myocardial infarction by 28% (p = 0.045) [11,12]. 2.3. Action to Control Cardiovascular Risk in Diabetes (ACCORD) In the ACCORD trial, 10251 patients with a mean age of 62 years and median diabetes duration of 10 years were randomised to recieve intensive glucose-lowering treatment aiming for HbA1c <6% or standard diabetes treatment targeting HbA1c level in the range 7.0–7.9%. No specific treatment was requested in neither of study groups and multiple drug combinations were allowed to achieve the defined target. In the intensive treatment group a median HbA1c of 6.4% and in standard treatment group a median of 7.5% were achieved, respectively. The study was prematurely stopped after 3.5 years of follow-up in 2008 because of observed 22% significant increase in all-cause mortality (p = 0.04) and 35% increase in cardiovascular mortality (p = 0.02) in patients with intensive glycemic control. The primary endpoint of the study (non-fatal myocardial infarction, nonfatal stroke or death from cardiovascular causes) was non-significantly reduced in the intensivetreatment group by 10% (p = 0.16). Significant reduction in the incidence of nonfatal myocardial infarction by 24% (p = 0.004) was observed in the intensive-therapy group. The subgroup analysis revealed a significantly more beneficial effect on primary endpoint reduction in the intensive-treat-
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ment group in the patients without previous cardiovascular disease and with better diabetes control (HbA1c <8%) [13]. 2.4. Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) The design of the ADVANCE study was very similar to the design of ACCORD. 11,140 patients with the mean age of 66 years and mean diabetes duration of 8 years were randomised to intensive treatment defined as the use of gliclazide modified release with other drugs with a target of HbA1c <6.5% or standard treatment. The standard treatment strategy was based on local guidelines. Median follow-up of patients was 5 years. Primary endpoint of combined major macrovascular and microvascular events was reduced significantly by 10% in the intensive-treatment group (p = 0.01). There was observed a non-significant 6% reduction in the incidence of macrovascular events (nonfatal myocardial infarction, nonfatal stroke and death from cardiovascular causes). In contrast with the ACCORD trial, no significant increase in all-cause and cardiovascular mortality was observed. The most pronounced effect in this study was a 21% reduction (p = 0.006) of the development of new or worsening nephropathy. Subgroup analysis suggested there might be a more pronounced effect on primary endpoint reduction in the subgroup of patients with no history of macrovascular disease. However, the test of heterogeneity between the groups with and without history of macrovascular disease was not significant [14]. 2.5.
Veterans Affairs Diabetes Trial (VADT)
The VADT trial had similar design to ACCORD and ADVANCE trials. 1791 patients with mean age of 60 years and mean diabetes duration of 11.5 years were randomised to intensive diabetes treatment aiming for HbA1c <6% and standard-treatment group aiming for HbA1c <9%. The goal for HbA1c between-group difference was 1.5%. The ontreatment median HbA1c was 6.9% for the intensive-treatment group and 8.4% for the standard treatment group. The primary endpoint was any major cardiovascular event (a composite of myocardial infarction, stroke, death from cardiovascular disease, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene). After of the median follow-up of 5.6 years there was observed a nonsignificant reduction of
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primary endpoint in the intensive-therapy group by 12% (p = 0.14). Incidence of none of the endpoints included in the primary outcome did not differ significantly between the study groups. The patients treated with intensive regimen had reduced any worsening in albuminuria by 38% with borderline significance (p = 0.05) [15].
3.
Metaanalysis of five large trials
It is not surprising that the conflicting results of the abovementioned studies led to some confusion among clinicians, whether it is needed to revise current HbA1c goal for glycemic control or rather the treatment strategies leading to the defined goal. Thus, to elucidate the effect of more intensive glycemic control on cardiovascular events and mortality we decided to perform combined analysis of five above-mentioned trials comparing intensive with conventional treatment strategies in patients with type 2 diabetes i.e. UKPDS, PROactive, ACCORD, ADVANCE, and VADT. The above studies were selected, since they are five main studies comparing more intensive with conventional treatment strategies in patients with type 2 diabetes. Each of this studies included more than 1500 patients who were followed-up at least for 3 years. In every of these studies median HbA1c of 7% or less was achieved in the group of patients with intensive treatment (range 6.4–7.0%) and the difference between intensive and conventional treatment groups in median HbA1c was at least 0.6% (range 0.6–1.5%). More detailed characteristics of the study populations included in these studies is shown in Table 1. The five large trials included in total 32649 patients, among them 17267 were assigned to intensive diabetes control and 15382 patients were assigned to less intensive (convential) glucose control. Data from combined analysis of the five trials by the Mantel–Haenszel method for the endpoint of cardiovascular and all-cause mortality are shown in Table 2. No significant effect of intensive glycemic control on cardiovascular mortality was detected [OR 1.03 (95% CI 0.84– 1.26)], although significant heterogeneity (p = 0.015) among the results of studies was observed. Similarly, no effect of intensive diabetes control on all-cause mortality was shown [OR 1.02 (95% CI 0.89–1.16)] with no significant heterogeneity among the trials. Metaanalysis of five trials for the endpoints of non-fatal myocardial infarction and non-fatal stroke is shown in Table 3. A highly significant reduction in the incidence of non-
Table 1 – Characteristics of patients in the studies of antidiabetic treatment.
UKPDS PROactive ADVANCE ACCORD VADT
Number of patients (intensive/conventional treatment group)
Mean age at study start (years)
Median/mean * duration of follow-up (years)
Median HbA1c (%) in intensive vs. conventional treatment group
4209 (3071/1138) 5238 (2605/2633) 11140 (5571/5569) 10251 (5128/5123) 1791 (892/899)
54 ± 8 62 ± 8 66 ± 6 62 ± 7 60 ± 9
10.0 2.9 * 5.0 3.4 5.6
7.0 vs. 7.9 7.0 vs. 7.6 6.3 vs. 7.0 6.4 vs. 7.5 6.9 vs. 8.4
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Table 2 – Effect of more intensive diabetes control on the endpoints of cardiovascular mortality and all-cause mortality. Intensive group events (% patients) (n = 17,267)
Control group events (% patients) (n = 15,382)
OR (95% CI)
p
Cardiovascular mortality UKPDS PROactive ADVANCE ACCORD VADT Combined
299 (9.7) 119 (4.9) 253 (4.5) 135 (2.6) 38 (4.3) 852 (5.2)
123 (10.8) 144 (5.2) 289 (5.2) 94 (1.8) 29 (3.2) 671 (4.6)
0.89 (0.71–1.11) 0.94 (0.73–1.21) 0.87 (0.73–1.03) 1.45 (1.11–1.89) 1.34 (0.82–2.18) 1.03 (0.84–1.26)
0.304 0.631 0.112 0.007 0.250 0.762
All-cause mortality UKPDS PROactive ADVANCE ACCORD VADT Combined
539 (17.6) 177 (6.8) 498 (8.9) 257 (5.0) 102 (11.4) 1573 (9.0)
213 (18.7) 186 (7.1) 533 (9.6) 203 (4.0) 95 (10.6) 1230 (8.5)
0.92 (0.78–1.10) 0.96 (0.78–1.19) 0.93 (0.82–1.05) 1.28 (1.06–1.54) 1.09 (0.81–1.47) 1.02 (0.89–1.16)
0.381 0.701 0.250 0.010 0.557 0.801
Random effect models. Q-test for heterogeneity: p = 0.015 for cardiovascular mortality; p > 0.05 for all-cause mortality
Table 3 – Effect of more intensive diabetes control on the endpoints of non-fatal myocardial infarction and non-fatal stroke. Intensive group events (% patients) (n = 17,267)
Control group events (% patients) (n = 15,382)
OR (95% CI)
p
Non-fatal myocardial infarction UKPDS 221 (7.2) PROactive 119 (4.6) ADVANCE 153 (2.7) ACCORD 186 (3.6) VADT 64 (7.1) Combined 743 (4.3)
101 (8.9) 144 (5.5) 156 (2.8) 235 (4.6) 78 (8.7) 714 (4.6)
0.80 (0.62–1.02) 0.83 (0.65–1.06) 0.98 (0.78–1.23) 0.78 (0.64–0.95) 0.81 (0.58–1.15) 0.84 (0.75–0.93)
0.069 0.136 0.860 0.015 0.240 0.001
Non-fatal stroke UKPDS PROactive ADVANCE ACCORD VADT Combined
44 (3.9) 107 (4.1) 209 (3.8) 61 (1.2) 36 (4.0) 457 (3.0)
1.01 (0.71–1.44) 0.81 (0.60–1.08) 1.02 (0.84–1.24) 1.10 (0.78–1.56) 0.78 (0.47–1.28) 0.97 (0.85–1.10)
0.951 0.144 0.807 0.598 0.325 0.595
120 (3.9) 86 (3.3) 214 (3.8) 67 (1.3) 28 (3.1) 515 (3.0)
Random effect models. Q-test for heterogeneity: p > 0.05 for both endpoints
fatal myocardial infarction was observed [OR 0.84 (95% CI 0.75–0.93), p = 0.001] in patients treated towards more intensive glycemic control. No effect on reduction of non-fatal stroke was observed [OR 0.97 (95% CI 0.85–1.10)] in the intensive glycemic control group. For both evaluated endpoints there was no significant heterogeneity among the trials.
4.
Implications for clinical practice
In summary, based on the metaanalysis of five most important trials comparing intensive to conventional glycemic control, more intensive glycemic control led in average to reduction in the incidence of nonfatal myocardial infarctions by one sixth, while it had no significant effect on the incidence of nonfatal stroke and both cardiovascular or all-cause mortality. Significant heterogeneity among the studies was observed for cardiovascular mortality. While in UKPDS, PROactive and ADVANCE studies a nonsignificant
trend for decreased cardiovascular mortality in intensivetreatment group was observed, in ACCORD study the cardiovascular mortality was significantly increased and a trend for increased mortality was observed in VADT study in intensively treated patients. In the ACCORD study, the intensivetreatment group was given aggresive treatment with up to 4–5 glucose-lowering drugs and high percentage of patients using insulin, sulfonylurea, rosiglitazone or even the combinations of these drugs. These treatment regimens in ACCORD were associated with much higher incidence of hypoglycemic episodes, as well as significant weight gain. What are the possible explanations for the observed heterogeneity of the mentioned study results and less than expected (from the epidemiological studies) effect on cardiovascular morbidity and mortality? First, the beneficial effect of long-term glucose control might be observed after the longer time than in cholesterol and blood pressure lowering studies, in which it was observed usually in 5-year treatment period. Indeed, long-term follow-up of patients included into
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the DCCT – Epidemiology of Diabetes Complications (DCTTEDIC) and UPKDS studies showed that the effect on prevention of macrovascular events become significant after 10-years of follow-up after the study end, despite the lack of difference in glycemic control during the follow-up period [16,17]. Moreover, the effects of better glycemic control or multifactorial interventions on all-cause mortality became significant during the follow-up phases of the UKPDS and Steno 2 trials, respectively [17,18]. This effect called “legacy” by the UKPDS investigators might have been associated by slower progression of vascular disease related to the accumulation of advanced glycation endproducts, in contrast to faster mechanism of atherosclerosis related to LDL particles. Another explanation for the delayed effect on prevention could be that better glycemic control during the trials prevented the development of diabetic nephropathy, which is associated with increased incidence of cardiovascular disease. In the EDIC-DCCT trial the presence of nephropathy or albuminuria were along with HbA1c levels the only significant predictors for development of macrovascular complications in type 1 diabetes [16]. Similar mechanism might participate in atherosclerosis prevention also in patients with type 2 diabetes. Further explanation for the less than expected effect of intensive glycemic control might be related to the side effects of antidiabetic treatment, first of all to increased incidence of hypoglycemia and weight gain. While hypoglycemia might be related to increased incidence of cardiovascular mortality (for sudden death, myocardial infarction and stroke), increased weight is a well established risk factor for atherosclerosis in non-diabetic, as well as in diabetic patients. Thus, adverse effects of treatment could have reduced the beneficial effect of HbA1c lowering in UKPDS, PROactive, ADVANCE and VADT studies and even be related to increased cardiovascular mortality observed in the ACCORD study. Furthermore, the adverse effect of long-term hyperglycemia could be genetically determined. A recently published study observed that an interaction between poor glycemic control and a polymorphism in 9p21 locus (close to CDKN2A-2B genes) resulted in more frequent development of coronary artery disease in carriers of two risk alleles [19]. The results of the above-mentioned studies might lead to an individualisation of diabetes control goals as reflected also in the recent joint statement of American Diabetes Association, American College of Cardiology Foundation and American Heart Association. According to the statement the general goal of HbA1c <7% should be maintained, but for certain groups of patients more stringent goal could be recommended based on the subgroup analysis of the mentioned studies. Those patients include diabetic patients with short duration of diabetes, longer life expectancy a no significant cardiovascular disease. In contrast, less stringent than the general goal of <7% might be considered in patients with history of severe hypoglycemia, limited life expectancy, longer duration of diabetes, advanced microvascular and macrovascular complications or extensive comorbid conditions [20].
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Acknowledgements The present study was supported in part by research grants from the Research Grant Agency (VEGA 1/4304/07) and from the Research and Development Agency (APVV-0122-06) of the Ministry of Education, Slovakia.
Conflict of interest The author received lecture fees from sanofi-aventis, Eli Lilly, Servier, Novartis, Merck-Sharp-Dohme, and Wörwag Pharma.
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