The effect of interventions to prevent cardiovascular disease in patients with type 2 diabetes mellitus

SPECIAL ARTICLE

The Effect of Interventions to Prevent Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus Elbert S. Huang, MD, MPH, James B. Meigs, MD, MPH, Daniel E. Singer, MD PURPOSE: Cardiovascular complications account for over 50% of mortality among patients with type 2 diabetes mellitus. We quantify the cardiovascular benefit of lowering cholesterol, blood pressure, and glucose levels in these patients. METHODS: We conducted a meta-analysis of randomized controlled trials in type 2 diabetes or diabetes subgroups, comparing the cardiovascular effects of intensive medication control of risk factor levels in standard therapy or placebo. We identified trials by searching MEDLINE (1966 to 2000) and review articles. Treatment details, patient characteristics, and outcome events were obtained using a specified protocol. Data were pooled using fixed-effects models. RESULTS: Seven serum cholesterol-lowering trials, six blood pressure–lowering trials, and five blood glucose-lowering trials met eligibility criteria. For aggregate cardiac events (coronary heart disease death and nonfatal myocardial infarction), cholesterol lowering [rate ratio (RR) ⫽ 0.75; 95% confidence interval

(CI): 0.61 to 0.93) and blood pressure lowering (RR ⫽ 0.73; 95% CI: 0.57 to 0.94) produced large, significant effects, whereas intensive glucose lowering reduced events without reaching statistical significance (RR ⫽ 0.87; 95% CI: 0.74 to 1.01). We observed this pattern for all individual cardiovascular outcomes. For cholesterol-lowering and blood pressure–lowering therapy, 69 to 300 person-years of treatment were needed to prevent one cardiovascular event. CONCLUSIONS: The evidence from these clinical trials demonstrates that lipid and blood pressure lowering in patients with type 2 diabetes is associated with substantial cardiovascular benefits. Intensive glucose lowering is essential for the prevention of microvascular disease, but improvements in cholesterol and blood pressure levels are central to reducing cardiovascular disease in these patients. Am J Med. 2001;111:633– 642. 䉷2001 by Excerpta Medica, Inc.

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Recommendations for the control of hypercholesterolemia, hypertension, and hyperglycemia in diabetes have been widely promulgated by expert panels (10 –12). However, physicians are still neither aggressively diagnosing nor treating hypercholesterolemia or hypertension in diabetic patients (13). We sought to quantify the effects of different risk factor interventions on cardiovascular disease in patients with type 2 diabetes. Whereas most earlier trials excluded diabetic patients, several recent, randomized, controlled trials of cholesterol-lowering and blood pressure–lowering agents have included these patients. In this study, we aggregate the published outcomes for these diabetic subgroups to illustrate the effect of risk factor reduction, as well as quantitatively summarize the effect of improving glucose control, on cardiovascular outcomes.

atients with type 2 diabetes mellitus are at a markedly increased risk of cardiovascular disease than are nondiabetic persons, with a 1.5-fold to 4.0-fold higher risk of death from coronary heart disease and a 2.8-fold higher risk of stroke (1,2). Approximately 50% to 75% of deaths in patients with diabetes are attributable to cardiovascular disease (3,4). Hypercholesterolemia and hypertension are important modifiable cardiovascular risk factors, whereas cardiovascular risk attributable to hyperglycemia remains uncertain (5–7). Observational studies suggest a relation between mean glucose levels and risk of cardiovascular disease (8,9), but the degree to which this risk is modifiable by improved glycemic control remains unclear (7).

From the General Medicine Division (ESH), University of Chicago, Chicago, Illinois; and the General Medicine Division (JBM, DES), Massachusetts General Hospital, Boston, Massachusetts. This study was supported by Public Health National Research Service Award PE-11001; the American Diabetes Association; SmithKline Beecham, Research Triangle Park, North Carolina; and Health Resources and Service Administration Award 2D08-PE-50018. Requests for reprints should be addressed to Elbert S. Huang, MD, MPH, General Medicine Division, University of Chicago, 5841 S. Maryland Avenue, MC 2007, Chicago, Illinois 60637. Manuscript submitted March 19, 2001, and accepted in revised form August 23, 2001. 䉷2001 by Excerpta Medica, Inc. All rights reserved.

MATERIAL AND METHODS Study Selection From a MEDLINE database (1966 to 2000), we identified randomized controlled trials, published in English, involving adults with type 2 diabetes. Diabetic patients were either the focus of studies or subgroups of larger trials. 0002-9343/01/$–see front matter 633 PII S0002-9343(01)00978-0

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We used specific terms to identify trials of cholesterollowering, blood pressure–lowering, and glucose-lowering therapies. Search details are available upon request. We supplemented the search with an examination of reference lists from initially identified trials and recent review articles (14 –20). Trials had to meet the following criteria: a prospective, randomized, controlled design; patients older than 18 years; more than 10 patients in each trial arm; comparison of intensive risk factor reduction using drug therapy versus placebo, or routine risk factor reduction; at least 1 year of follow-up; presentation of treatment effect on risk factor levels; and report of at least one prespecified outcome. Such outcomes included aggregate cardiac events (coronary heart disease death and nonfatal myocardial infarction), cardiovascular mortality (sudden death, fatal myocardial infarction, and fatal stroke), all-cause mortality, myocardial infarction, and stroke. A total of 45 serum cholesterol management studies, 171 blood pressure management studies, and 629 blood glucose management studies were found on initial search. Two authors independently reviewed the identified articles for possible inclusion; disagreements were resolved by consensus. Seven cholesterol-lowering trials (5,21–26), six blood pressure–lowering trials (6,27–31), and five glucose-lowering trials (7,32–35) met the inclusion criteria. We included the Diabetes mellitus Insulin-Glucose infusion in Acute Myocardial Infarction (DIGAMI) study, despite its focus on an acute intervention, because it also included long-term efforts at intensive glucose lowering (35). Several well-known trials were excluded because they did not report outcomes on diabetic patients (36). Other reasons for exclusion were an examination of nonpharmaceutical treatments (eg, special diets, 28% of excluded glucose-lowering trials), absence of prespecified outcomes (68% of excluded glucose-lowering trials and 47% of excluded cholesterol-lowering trials), and comparison of therapeutic agents rather than mean risk factor levels (52% of excluded blood pressure–lowering trials) (37– 40).

Data Abstraction We collected information on treatment characteristics, patient demographics, cardiovascular disease history, and diabetes duration. We documented the mean baseline and follow-up risk factor levels (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, and hemoglobin A1c [HbA1c]). Outcome event frequencies were also recorded. If the aggregate outcome of cardiac events was not reported, we used the sum of the number of patients with sudden death and myocardial infarction. 634

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Statistical Analysis To assess intervention effects on risk factor levels, we describe the mean follow-up risk factor levels in the treatment and control arms for each trial group, which could be the levels found at the end of a study or the average levels for the study duration. We evaluated risk factor change as the absolute difference between treatment arm and control arm levels. We calculated means, weighted by study population size, and assessed baseline severity of illness across trials by comparing control arm outcome event rates, expressed as the average number of events per 1000 person-years of treatment. These averages were weighted by the person-years observed for each trial. Treatment outcome effects were examined by estimating incidence rate ratio (RR) and person-years needed to treat to prevent one cardiovascular event. Person-years needed to treat is a measure of absolute effect, which is similar to the number needed to treat except that it incorporates treatment duration, assuming a constant effect over time (41). Both measures were calculated by pooling data from multiple trials. Each pooled analysis was examined for significant heterogeneity of effect using chisquared statistics (42– 44). No statistically significant heterogeneity was found. Hence, we used fixed-effects model equations to generate summary rate ratio and personyears needed to treat values (42). To calculate personyears needed to treat, we pooled incidence rate differences and inverted this value. We present the summary estimates with 95% confidence intervals (CI). All statistical analyses were performed using Microsoft Excel 97 (Microsoft Corporation, Redmond, Washington). We also conducted subgroup and sensitivity analyses. Trials of reducing serum cholesterol and blood glucose levels were divided into primary and secondary prevention studies. Blood pressure medication studies were divided into intensive blood pressure–lowering trials and angiotensin-converting enzyme (ACE) inhibitor effect trials (comparing low-dose ACE inhibitors and placebo). To eliminate the potential impact of secular trends, analyses were repeated without the older University Group Diabetes Program (UGDP) and the Hypertension Detection and Follow-up Program (HDFP) (27,32).

RESULTS Study and Patient Characteristics In all lipid-lowering trials, diabetic patients were a small subset of the study population (Table 1). Baseline cholesterol levels varied, ranging from LDL cholesterol 135 mg/dL or lower in the Cholesterol and Recurrent Events Trial (CARE) (5) and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) (26) to higher than 200 mg/dL in the Helsinki Heart Study (21). In the Helsinki Heart Study, Air Force/Texas

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Table 1. Cholesterol-lowering Trials Primary Prevention Trials AFCAPS/TexCAPS* (22)

Subjects with diabetes (% of total) Mean follow-up (years) Treatment arm drug

135 (3) 5 Gemfibrozil

Control arm drug Baseline data Mean age (years) Male sex (%) Mean cholesterol level (mg/dL)† Total cholesterol LDL cholesterol HDL cholesterol Triglycerides Difference (treatment minus control) in follow-up lipids (mg/dL)† Total cholesterol LDL cholesterol HDL cholesterol Triglycerides

Placebo

Characteristic

Secondary Prevention Trials

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4S (23)

CARE (5)

LIPID* (24)

Post-CABG (25)

VA-HIT* (26)

155 (2) 5.2 Lovastatin

202 (5) 5.4 Simvastatin

586 (14) 5 Pravastatin

782 (9) 6.1 Pravastatin

627 (25) 5.1 Gemfibrozil

Placebo

Placebo

Placebo

Placebo

116 (9) 4.3 Lovastatin/ cholestyramine Lovastatin

49 100

58 85

60 72

61 80

52 83

63 85

64 100

291 201 46 238

221 150 37 158

259 186 44 153

206 136 38 164

218 150 36 131

225 152 36 185

175 112 32 160

⫺21 ⫺10 2.3 ⫺87

⫺44 ⫺41 1 ⫺20

⫺71 ⫺67 2.6 ⫺25

⫺36 ⫺40 1.5 ⫺21

⫺7 NA NA NA

⫺40 ⫺30 0 ⫺10

⫺7 0 2 ⫺51

Placebo

* Numbers derived from overall study population. † To convert total cholesterol, LDL cholesterol, and HDL cholesterol from mg/dL to mmol/L, multiply by 0.0259. To convert triglycerides from mg/dL to mmol/L, multiply by 0.0113. 4S ⫽ Scandinavian Simvastatin Survival Study; AFCAPS/TexCAPS ⫽ Air Force/Texas Coronary Arteriosclerosis Prevention Study; CARE ⫽ Cholesterol and Recurrent Events; HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein; LIPID ⫽ Long-term Intervention with Pravastatin in Ischaemic Disease; NA ⫽ not applicable; Post-CABG ⫽ Post Coronary Artery Bypass Graft; VA-HIT ⫽ Veterans Affairs Cooperative Studies Program High-density Lipoprotein Cholesterol Intervention Trial.

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Helsinki Heart (21)

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Baseline data Mean age (years) Male sex (%) History of coronary artery disease (%) Mean blood pressure (mm Hg) Systolic blood pressure Diastolic blood pressure Difference (treatment minus control) in follow-up blood pressure (mm Hg) Systolic blood pressure Diastolic blood pressure

Blood Pressure–lowering Trials Characteristic Subjects with diabetes (% of total) Mean follow-up (years) Intensive treatment arm drug Control arm drug

HDFP* (27)

SHEP (28)

HOT*(29)

UKPDS 38 (6)

772 (7) 5 Chlorthalidone/ reserpine Referred (“usual”) care

583 (12) 5 Chlorthalidone/ atenolol Placebo

1000 (5) 3.8 Felodipine

1148 (100) 8.4 Captopril/ atenolol “Avoid study drugs”

Felodipine

ACE Inhibitor Trial Syst-Eur (30) 492 (10) 2 Nitrendipine/enalapril/ hydrochlorothiazide Placebo

MICRO-HOPE (31) 3,577 (38) 4.5 Ramipril Placebo

51 54 5

70 50 5

62 53 6

56 55 0

70* 33* 35

65 63 60

159 101

170.2 76

170 105

159 94

175.3 84.5

142 80

NA ⫺5

⫺6 ⫺5

⫺2 ⫺4

⫺6 ⫺5

⫺5 ⫺5

⫺2 ⫺1

* Numbers derived from overall study population. ACE ⫽ angiotensin-converting enzyme; HDFP ⫽ Hypertension Detection and Follow-up Program; HOT ⫽ Hypertension Optimal Treatment; MICRO-HOPE ⫽ Microalbuminuria, Cardiovascular, and Renal Outcomes in the Heart Outcomes Prevention Evaluation [substudy]; NA ⫽ not applicable; SHEP ⫽ Systolic Hypertension in the Elderly Program; Syst-Eur ⫽ Systolic Hypertension in Europe; UKPDS ⫽ United Kingdom Prospective Diabetes Study.

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Table 2. Blood Pressure Medication Trials

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Coronary Arteriosclerosis Prevention Study (AFCAPS)/ TexCAPS, and CARE trial, diabetic patients with poorly controlled glucose levels (HbA1c higher than 10%) or those requiring insulin therapy were excluded. Of the blood pressure medication studies, five were designed to compare improved blood pressure control with placebo or conventional blood pressure control (Table 2). Investigators used a variety of antihypertensive agents, including diuretics, beta blockers, calcium channel blockers, and ACE inhibitors. The Microalbuminuria, Cardiovascular, and Renal Outcomes in the Heart Outcomes Prevention Evaluation (MICRO-HOPE) study was an ACE inhibitor effect trial (31). Subjects in the MICRO-HOPE study had a lower baseline blood pressure (142/80 mm Hg) than did those (165/94 mm Hg) in the other trials. The Systolic Hypertension in the Elderly Program (SHEP) (28) and Systolic Hypertension in Europe (Syst-Eur) trial (30) were specifically designed for older subjects. The United Kingdom Prospective Diabetes Study (UKPDS) was the only blood pressure study specifically designed for diabetic patients (6). In the Syst-Eur trial, diabetic subjects were excluded if their glucose was not “adequately controlled.” The MICRO-HOPE study patients who had diabetic nephropathy were also not eligible to participate. Of the glucose control studies, the DIGAMI study, UGDP, and Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VACSDM) deserve special mention (Table 3). In the DIGAMI study, which also included subjects with type 1 diabetes (20%), patients in the treatment arm received a glucose-insulin infusion within 24 hours of a myocardial infarction (35). During the subsequent 3 months, they received subcutaneous insulin four times daily, whereas those in the control arm received insulin only if necessary. The UGDP was the only study published before 1980. Because it had five arms, we limited our analysis to a comparison of the placebo and variable insulin arms when examining the effect of the largest glucose difference (45). The VACSDM was a pilot feasibility trial (33). Across trial group populations, the mean ages of the participants were 58 years in cholesterol-lowering trials, 63 years in blood pressure–lowering trials, and 55 years in glucose-lowering trials (Tables 1–3). The majority of subjects were men, especially in the cholesterol-lowering studies where 89% were men. The percentage of patients with diagnosed coronary artery disease was higher among cholesterol-lowering trial subjects (89%), compared with patients in the blood pressure medication (32%) and glucose-lowering (13%) trials. Baseline total cholesterol levels from cholesterol-lowering studies covered a broader range (175 to 292 mg/dL) than those from blood pressure medication and glucose-lowering trials (200 to 240 mg/ dL). Baseline blood pressure levels were by design higher among patients in the blood pressure medication studies

(142 to 175/76 to 105 mm Hg) than among those in the other two groups (121 to 147/70 to 91 mm Hg). Reported mean fasting plasma glucose levels also overlapped across trial groups, but the upper range was highest among glucose-lowering studies (139 to 213 mg/dL).

Effects of Treatment on Risk Factor Levels Among lipid-lowering trials, the mean differences (treatment minus control) in fasting lipid levels were ⫺23 mg/dL for total cholesterol, ⫺27 mg/dL for LDL cholesterol, ⫹2 mg/dL for HDL cholesterol, and ⫺36 mg/dL for triglycerides. Treatment arm subjects achieved average lipid levels of 179 mg/dL for total cholesterol, 112 mg/dL for LDL cholesterol, 39 mg/dL for HDL cholesterol, and 134 mg/dL for triglycerides. In blood pressure–lowering trials, the mean difference was ⫺5 mm Hg for systolic blood pressure and ⫺2 mm Hg for diastolic blood pressure. In the glucose control studies, the mean reduction in fasting plasma glucose level was 29 mg/dL (treatment arm fasting plasma glucose level, 147 mg/dL), whereas the mean reduction in HbA1c level was 0.9% (treatment arm HbA1c level, 7%).

Control Arm Event Rates Control arm event rates of lipid-lowering trials were consistently the highest; conversely, glucose-lowering trial rates were consistently the lowest (Tables 4 and 5). Higher cholesterol-lowering trial rates were driven by secondary prevention study data. When directly comparing primary prevention trial data, we observed that baseline event rates for cholesterol-lowering and glucose-lowering trials were similar (Table 4). However, when comparing secondary prevention trial data, we observed higher control arm event rates for the glucose-lowering DIGAMI trial than for the lipid-lowering trials (Table 5).

Magnitude of Effect Aggregate cardiac events. Studies of lowering cholesterol levels (RR ⫽ 0.75; 95% CI: 0.61 to 0.93) and blood pressure (RR ⫽ 0.73; 95% CI: 0.57 to 0.94) reported large, statistically significant reductions in cardiac event rates (Table 4). In subgroup analyses, lipid lowering in secondary prevention also produced a significant reduction in cardiac events but not in primary prevention. The pooled effect from glucose-lowering trials suggested a smaller, nonsignificant reduction in adverse events (RR ⫽ 0.87; 95% CI: 0.74 to 1.01). From the perspective of personyears needed to treat, we found the same pattern. The pooled-effect point estimates suggest that 106 to 157 person-years of cholesterol or blood pressure lowering were required to prevent one aggregate cardiac event. Statistical significance aside, the point estimate from glucoselowering studies suggests that 419 person-years of treatment were necessary to prevent an event. Individual cardiovascular outcomes. The results among individual cardiovascular outcomes had the same general

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Table 3. Glucose-lowering Trials Characteristic

UGDP (32)

UKPDS 33 (7)

620

3867 10 Sulphonylureas (chlorpropamide glibenclamide glipizide)/ insulin/metformin Diet/sulphonylureas (chlorpropamide glibenclamide)/insulin/metformin

2.25 Insulin/ glipizide

8 Multiple insulin injection therapy

1 Insulin-glucose infusion and subcutaneous insulin

Control arm drug

Placebo

Insulin

Conventional insulin injection therapy

Usual care

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NA

60 100 19 9.4

110

DIGAMI (35)

12.5 Variable insulin

53 27 4.4

153

Kumamoto (34)

Number of participants (all had diabetes) Mean follow-up (years) Treatment arm drug

Baseline data Mean age (years) Male sex (%) History of coronary artery disease (%) Mean HbA1c (% of total hemoglobin) Mean fasting plasma glucose (mg/dL)* Difference (treatment minus control) in follow-up fasting plasma glucose (mg/dL)* Difference (treatment minus control) in follow-up reported HbA1c (%)

409

VACSDM (33)

50 49 0 9.2

68 63 100 8.1

53 61 0 7.1

139

213

160

NA

145

⫺45

⫺95

⫺40

NA

⫺24

NA

⫺2.1

⫺2.2

⫺0.3

⫺0.9

* To convert fasting plasma glucose from mg/dL to mmol/L, multiply by 0.0555. DIGAMI ⫽ Diabetes mellitus Insulin-Glucose infusion in Acute Myocardial Infarction; HbA1c ⫽ hemoglobin A1c; NA ⫽ not available; UGDP ⫽ University Group Diabetes Program; UKPDS ⫽ United Kingdom Prospective Diabetes Study; VACSDM ⫽ Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes.

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Trial

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Table 4. Summary Effects on Aggregate Cardiac Events*

Variable

Treatment Arm Control Arm Event Rates Person-years Event Rates (Events/1000 Summary Rate Ratio Needed to Treat Number of (Events/1000 Person-years) Person-years) (95% Confidence Interval) (95% Confidence Interval) Studies

Cholesterol lowering Primary prevention Secondary prevention Blood pressure lowering Glucose lowering Primary prevention

5 2 3 3

30 8 34 17

41 19 44 23

0.75 (0.61–0.93) 0.44 (0.17–1.20) 0.77 (0.62–0.96) 0.73 (0.57–0.94)

106 (62–366) 97 (45–NM) 120 (61–4856) 157 (88–726)

2

15

18

0.87 (0.74–1.01)

419 (197–NM)

* Death from coronary heart disease, and nonfatal myocardial infarction. NM ⫽ not meaningful, because person-years needed to treat value is negative.

pattern observed for aggregate cardiac events (Table 5). For lipid-lowering trials (only secondary prevention trials reported individual outcomes), summary rate ratios across complications were between 0.59 and 0.80, indicating a sizeable reduction in cardiovascular events. This result was significant for myocardial infarction. The ben-

efits of blood pressure medication trials in aggregate and in subgroup analyses were large (RR ⫽ 0.51 to 0.79) for each outcome. All results were significant, except for the subgroup analysis of the effect of blood pressure lowering on myocardial infarction. For intensive glucose lowering, pooled rate ratios indicated either a benefit smaller than

Table 5. Summary Effects Across Individual Cardiovascular Outcomes

Outcome Cardiovascular mortality Cholesterol lowering* Secondary prevention Blood pressure medication Blood pressure lowering ACE inhibitor Glucose lowering† Primary prevention† Secondary prevention Myocardial infarction Cholesterol lowering* Secondary prevention Blood pressure medication Blood pressure lowering ACE inhibitor Glucose lowering Primary prevention Secondary prevention Stroke Cholesterol lowering* Secondary prevention Blood pressure medication Blood pressure lowering ACE inhibitor Glucose lowering Primary prevention†

Number of Studies

Treatment Arm Event Rates (Events/1000 Person-years)

Control Arm Event Rates (Events/1000 Person-years)

Summary Rate Ratio (95% Confidence Interval)

Person-years Needed to Treat (95% Confidence Interval)

2 4 3 1 5 4 1

20 12 10 14 10 10 39

24 20 19 22 12 11 83

0.80 (0.53–1.20) 0.59 (0.49–0.71) 0.51 (0.38–0.69) 0.64 (0.50–0.81) 0.89 (0.74–1.08) 0.94 (0.78–1.14) 0.47 (0.24–0.92)

265 (78–NM) 121 (90–184) 115 (79–212) 128 (84–268) 4392 (470–NM) 8091 (494–NM) 23 (12–209)

3 3 2 1 4 3 1

20 18 14 23 16 14 173

35 24 16 29 20 16 175

0.60 (0.41–0.87) 0.78 (0.67–0.92) 0.76 (0.51–1.01) 0.79 (0.65–0.96) 0.91 (0.78–1.05) 0.89 (0.76–1.05) 0.99 (0.68–1.44)

69 (42–210) 215 (131–590) 257 (132–4847) 166 (91–937) 550 (229–NM) 550 (229–NM) 511 (15–NM)

2 5 4 1

12 9 8 9

17 14 14 14

0.74 (0.44–1.25) 0.65 (0.53–0.80) 0.61 (0.46–0.83) 0.69 (0.51–0.92)

221 (84–NM) 228 (140–611) 222 (108–NM) 237 (133–1092)

3

5

5

1.16 (0.85–1.57)

NM

* Cholesterol-lowering primary prevention trials did not present data on these outcomes. † When there were no events in a given trial arm, 0.000001 was used in place of zero in the analysis. ACE ⫽ angiotensin-converting enzyme; NM ⫽ not meaningful, because person-years needed to treat value is negative. December 1, 2001

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that of the other two trial groups, or no benefit at all; none of these results were significant. In subset analyses, the DIGAMI secondary prevention study results were the exception, showing a substantial reduction in cardiovascular mortality (RR ⫽ 0.47; 95% CI: 0.24 to 0.92) but not in myocardial infarction (RR ⫽ 0.99; 95% CI: 0.68 to 1.44). In terms of absolute effects, a similar range of personyears (69 to 300 person-years) of lipid-lowering and blood pressure–lowering therapy was necessary to prevent one cardiovascular event. With statistical significance aside, the glucose-lowering trial analyses showed that a minimum 550 person-years of treatment would prevent a myocardial infarction.

Sensitivity Analysis Exclusion of data from the UGDP did not affect any pooled results substantially. In the analysis of aggregate cardiac events, the exclusion of UGDP left UKPDS as the only study available. Because UKPDS did not originally report on aggregate cardiac events, we used the sum of the number of patients with sudden death and myocardial infarction. The point estimate for this outcome did not change, but the upper bound of the confidence intervals became 0.99, most likely reflecting double counting, because patients who died suddenly could also have had myocardial infarction. For blood pressure medication trials, removal of the HDFP results from the all-cause mortality analysis also did not change results.

DISCUSSION In our analysis of diabetic subpopulations in lipid-lowering trials, the point estimates for all outcomes indicated large reductions in cardiovascular events. These effects were statistically significant for aggregate cardiac events and myocardial infarction. The benefits of antihypertensive agents were large and significant across all outcomes and for the majority of substudy analyses. In contrast, glucose lowering had a marginally significant effect on cardiovascular outcomes. Of note, the DIGAMI study investigators reported a large and significant reduction in cardiovascular mortality. In terms of absolute effects, we found that 69 to 300 person-years of lipid-lowering and blood pressure–lowering therapy prevented cardiovascular events. Although nonsignificant, the point estimates from glucose-lowering trials suggest that 419 to 4392 person-years of therapy were required to prevent one cardiovascular event. In addition to appreciating the overall magnitude of benefits, we must consider the initial timing of effect of preventive strategies (46). Cumulative incidence curves from lipid-lowering and blood pressure– lowering trials indicate that cardiovascular benefits began 2 to 4 years from onset of treatment. Our ability to weigh the effects of different treatments depends on whether patients from the trial groups are 640

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themselves comparable. Control arm subjects in the lipid-lowering studies consistently had the highest cardiovascular outcome event rates, whereas patients in the glucose-lowering studies had the lowest. This difference is attributable to the large proportion of cholesterol-lowering study subjects with established coronary artery disease. In several cases, we directly compared primary and secondary prevention populations. For aggregate cardiac events, the control arm event rates for primary prevention lipid-lowering and glucose-lowering trials were similar, with glucose lowering continuing to have a smaller benefit. For cardiovascular mortality and myocardial infarction, the control arm event rates for secondary prevention data were the highest in the DIGAMI study. Whereas the benefits of cholesterol lowering in secondary prevention were consistent across outcomes, treatment in the DIGAMI study was associated with a large reduction in cardiovascular mortality but with no effect on myocardial infarction. The magnitude of the treatment benefits is also related to the risk factor reduction achieved. If any risk factor level difference had been larger, the size of demonstrable cardiovascular benefit might have been more substantial. We may also have underestimated potential benefits when risk factors did not reach specific target levels. Current guidelines recommend even lower lipid (LDL cholesterol less than 100 mg/dL) and blood pressure (systolic blood pressure, 135 mm Hg) levels than those observed in the selected trials (LDL cholesterol, 112 mg/dL; systolic blood pressure, 142 mm Hg). Similarly, glucose-lowering trials reported only an absolute change in glucose levels of 0.9%, reaching a mean HbA1c level of 7%. While the relation between traditional cardiovascular risk factors and complications demonstrated in observational epidemiologic analyses is consistent with results from randomized controlled trials, the association is less consistent for hyperglycemia (47). Secondary analyses of the UKPDS data suggest that a continuous relation exists between mean glucose levels and complication rates. For every 1% decrease in HbA1c level, investigators estimated a 14% decrease in myocardial infarction, 12% decrease in stroke, and 14% reduction in all-cause mortality (9). Our analysis of myocardial infarction and cardiac events in glucose-lowering trials yielded results of similar magnitude, but with no suggestion of prevention of stroke or all-cause mortality. The degree to which glucose lowering might reduce cardiovascular risk thus remains unclear. Trials of intensive glucose lowering in secondary prevention populations are needed to confirm the DIGAMI study results. New trials that improve mean glucose levels further or use such insulin sensitizing agents as thiazolidinediones might demonstrate cardiovascular benefits (48). Even for lipid-lowering and blood pressure–lowering agents, our study illustrates the dearth of trials evaluating cardiovas-

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cular disease prevention in type 2 diabetes. Furthermore, specific exclusion of patients on insulin and with existing complications limits the extent to which diabetic subpopulations of the trials are representative of the average diabetic patient (49). Several trials funded by the National Institutes of Health that are in development will address these needs (50). Nonetheless, current trial evidence indicates that treatment of hyperlipidemia and hypertension results in large cardiovascular benefits for patients with type 2 diabetes. Whereas aggressive glucose lowering is needed for prevention of microvascular complications, aggressive lipid and blood pressure lowering is central to prevention of macrovascular complications. Efforts to improve the management of these risk factors should be vigorously supported.

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