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, com-
paring the cardiovascular effects of intensive medication con-
trol of risk factor levels in standard therapy or placebo. We
identified trials by searching MEDLINE (1966 to 2000) and re-
view articles. Treatment details, patient characteristics, and out-
come 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), choles-
terol lowering [rate ratio (RR) ⫽ 0.75; 95% confidence interval
P
atients with type 2 diabetes mellitus are at a mark-
edly 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 cardiovascu-
lar 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 con-
trol remains unclear (7).
From the General Medicine Division (ESH), University of Chicago,
Chicago, Illinois; and the General Medicine Division (JBM, DES), Mas-
sachusetts 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 Re-
sources 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. Mary-
land 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.
(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–lower-
ing therapy, 69 to 300 person-years of treatment were needed to
prevent one cardiovascular event.
CONCLUSIONS: The evidence from these clinical trials dem-
onstrates 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 preven-
tion 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.
Recommendations for the control of hypercholester-
olemia, hypertension, and hyperglycemia in diabetes
have been widely promulgated by expert panels (10 –12).
However, physicians are still neither aggressively diag-
nosing nor treating hypercholesterolemia or hyperten-
sion 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 dia-
betic patients, several recent, randomized, controlled tri-
als of cholesterol-lowering and blood pressure–lowering
agents have included these patients. In this study, we ag-
gregate the published outcomes for these diabetic sub-
groups to illustrate the effect of risk factor reduction, as
well as quantitatively summarize the effect of improving
glucose control, on cardiovascular outcomes.
MATERIAL AND METHODS
Study Selection
From a MEDLINE database (1966 to 2000), we identified
randomized controlled trials, published in English, in-
volving 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
 Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al
We used specific terms to identify trials of cholesterol-
lowering, blood pressure–lowering, and glucose-lower-
ing therapies. Search details are available upon request.
We supplemented the search with an examination of ref-
erence lists from initially identified trials and recent re-
view 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; compari-
son 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 out-
come. 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 mortal-
ity, 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 au-
thors independently reviewed the identified articles for pos-
sible inclusion; disagreements were resolved by consensus.
Seven cholesterol-lowering trials (5,21–26), six blood pres-
sure–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 Myo-
cardial Infarction (DIGAMI) study, despite its focus on an
acute intervention, because it also included long-term ef-
forts 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, spe-
cial diets, 28% of excluded glucose-lowering trials), absence
of prespecified outcomes (68% of excluded glucose-lower-
ing 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 tri-
als) (37– 40).
Data Abstraction
We collected information on treatment characteristics,
patient demographics, cardiovascular disease history,
and diabetes duration. We documented the mean base-
line 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 December 1, 2001 THE AMERICAN JOURNAL OF MEDICINE威
Statistical Analysis
To assess intervention effects on risk factor levels, we de-
scribe the mean follow-up risk factor levels in the treat-
ment 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 estimat-
ing 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 incor-
porates treatment duration, assuming a constant effect
over time (41). Both measures were calculated by pooling
data from multiple trials. Each pooled analysis was exam-
ined for significant heterogeneity of effect using chi-
squared statistics (42– 44). No statistically significant het-
erogeneity was found. Hence, we used fixed-effects model
equations to generate summary rate ratio and person-
years needed to treat values (42). To calculate person-
years needed to treat, we pooled incidence rate differ-
ences and inverted this value. We present the summary
estimates with 95% confidence intervals (CI). All statisti-
cal 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 preven-
tion studies. Blood pressure medication studies were di-
vided 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, anal-
yses were repeated without the older University Group
Diabetes Program (UGDP) and the Hypertension Detec-
tion 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 choles-
terol 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
Volume 111
 Table 1. Cholesterol-lowering Trials
Primary Prevention Trials Secondary Prevention Trials
Helsinki Heart AFCAPS/TexCAPS* 4S CARE LIPID* Post-CABG VA-HIT*
Characteristic (21) (22) (23) (5) (24) (25) (26)

Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al

Subjects with diabetes (% of total) 135 (3) 155 (2) 202 (5) 586 (14) 782 (9) 116 (9) 627 (25)
Mean follow-up (years) 5 5.2 5.4 5 6.1 4.3 5.1
Treatment arm drug Gemfibrozil Lovastatin Simvastatin Pravastatin Pravastatin Lovastatin/ Gemfibrozil
cholestyramine
Control arm drug Placebo Placebo Placebo Placebo Placebo Lovastatin Placebo
Baseline data
Mean age (years) 49 58 60 61 52 63 64
Male sex (%) 100 85 72 80 83 85 100
December 1, 2001

Mean cholesterol level (mg/dL)†

Total cholesterol 291 221 259 206 218 225 175
LDL cholesterol 201 150 186 136 150 152 112
HDL cholesterol 46 37 44 38 36 36 32
Triglycerides 238 158 153 164 131 185 160
Difference (treatment minus control)
THE AMERICAN JOURNAL OF MEDICINE威

in follow-up lipids (mg/dL)†

Total cholesterol ⫺21 ⫺44 ⫺71 ⫺36 ⫺7 ⫺40 ⫺7
LDL cholesterol ⫺10 ⫺41 ⫺67 ⫺40 NA ⫺30 0
HDL cholesterol 2.3 1 2.6 1.5 NA 0 2
Triglycerides ⫺87 ⫺20 ⫺25 ⫺21 NA ⫺10 ⫺51
* 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.
Volume 111 635
 636
December 1, 2001
THE AMERICAN JOURNAL OF MEDICINE威

Table 2. Blood Pressure Medication Trials

Blood Pressure–lowering Trials ACE Inhibitor Trial

Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al

Syst-Eur MICRO-HOPE
Characteristic HDFP* (27) SHEP (28) HOT*(29) UKPDS 38 (6) (30) (31)
Subjects with diabetes (% of total) 772 (7) 583 (12) 1000 (5) 1148 (100) 492 (10) 3,577 (38)
Mean follow-up (years) 5 5 3.8 8.4 2 4.5
Intensive treatment arm drug Chlorthalidone/ Chlorthalidone/ Felodipine Captopril/ Nitrendipine/enalapril/ Ramipril
reserpine atenolol atenolol hydrochlorothiazide
Control arm drug Referred (“usual”) care Placebo Felodipine “Avoid study Placebo Placebo
drugs”
Baseline data
Volume 111

Mean age (years) 51 70 62 56 70* 65

Male sex (%) 54 50 53 55 33* 63
History of coronary artery disease (%) 5 5 6 0 35 60
Mean blood pressure (mm Hg)
Systolic blood pressure 159 170.2 170 159 175.3 142
Diastolic blood pressure 101 76 105 94 84.5 80
Difference (treatment minus control)
in follow-up blood pressure (mm Hg)
Systolic blood pressure NA ⫺6 ⫺2 ⫺6 ⫺5 ⫺2
Diastolic blood pressure ⫺5 ⫺5 ⫺4 ⫺5 ⫺5 ⫺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.
 Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al
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 (Ta-
ble 2). Investigators used a variety of antihypertensive
agents, including diuretics, beta blockers, calcium chan-
nel blockers, and ACE inhibitors. The Microalbuminuria,
Cardiovascular, and Renal Outcomes in the Heart Out-
comes Prevention Evaluation (MICRO-HOPE) study
was an ACE inhibitor effect trial (31). Subjects in the MI-
CRO-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 Pro-
gram (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 spe-
cifically 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 el-
igible to participate.
Of the glucose control studies, the DIGAMI study,
UGDP, and Veterans Affairs Cooperative Study on Gly-
cemic 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 neces-
sary. 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 differ-
ence (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 sub-
jects 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 glu-
cose-lowering (13%) trials. Baseline total cholesterol lev-
els 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
December 1, 2001
(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 glu-
cose-lowering studies (139 to 213 mg/dL).
Effects of Treatment on Risk Factor Levels
Among lipid-lowering trials, the mean differences (treat-
ment minus control) in fasting lipid levels were ⫺23
mg/dL for total cholesterol, ⫺27 mg/dL for LDL choles-
terol, ⫹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 pres-
sure. 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 con-
sistently 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 compar-
ing primary prevention trial data, we observed that base-
line event rates for cholesterol-lowering and glucose-low-
ering trials were similar (Table 4). However, when com-
paring 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 choles-
terol 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 second-
ary 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 person-
years needed to treat, we found the same pattern. The
pooled-effect point estimates suggest that 106 to 157 per-
son-years of cholesterol or blood pressure lowering were
required to prevent one aggregate cardiac event. Statisti-
cal significance aside, the point estimate from glucose-
lowering studies suggests that 419 person-years of treat-
ment were necessary to prevent an event.
Individual cardiovascular outcomes. The results among
individual cardiovascular outcomes had the same general
THE AMERICAN JOURNAL OF MEDICINE威 Volume 111 637
 638
December 1, 2001

Table 3. Glucose-lowering Trials

THE AMERICAN JOURNAL OF MEDICINE威

Trial
Characteristic UGDP (32) VACSDM (33) Kumamoto (34) DIGAMI (35) UKPDS 33 (7)

Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al

Number of participants 409 153 110 620 3867
(all had diabetes)
Mean follow-up (years) 12.5 2.25 8 1 10
Treatment arm drug Variable insulin Insulin/ Multiple insulin Insulin-glucose infusion Sulphonylureas (chlorpropamide
glipizide injection therapy and subcutaneous insulin glibenclamide glipizide)/
insulin/metformin
Control arm drug Placebo Insulin Conventional insulin Usual care Diet/sulphonylureas (chlorpropamide
injection therapy glibenclamide)/insulin/metformin
Baseline data
Volume 111

Mean age (years) 53 60 50 68 53

Male sex (%) 27 100 49 63 61
History of coronary artery 4.4 19 0 100 0
disease (%)
Mean HbA1c NA 9.4 9.2 8.1 7.1
(% of total hemoglobin)
Mean fasting plasma glucose 139 213 160 NA 145
(mg/dL)*
Difference (treatment ⫺45 ⫺95 ⫺40 NA ⫺24
minus control) in follow-up fasting plasma
glucose (mg/dL)*
Difference (treatment minus control) NA ⫺2.1 ⫺2.2 ⫺0.3 ⫺0.9
in follow-up reported HbA1c (%)
* 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.
 Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al

Table 4. Summary Effects on Aggregate Cardiac Events*

Treatment Arm Control Arm
Event Rates Event Rates Person-years
Number of (Events/1000 (Events/1000 Summary Rate Ratio Needed to Treat
Variable Studies Person-years) Person-years) (95% Confidence Interval) (95% Confidence Interval)
Cholesterol lowering 5 30 41 0.75 (0.61–0.93) 106 (62–366)
Primary prevention 2 8 19 0.44 (0.17–1.20) 97 (45–NM)
Secondary prevention 3 34 44 0.77 (0.62–0.96) 120 (61–4856)
Blood pressure lowering 3 17 23 0.73 (0.57–0.94) 157 (88–726)
Glucose lowering
Primary prevention 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 tri-
als reported individual outcomes), summary rate ratios
across complications were between 0.59 and 0.80, indi-
cating 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

Treatment Arm Control Arm Summary Person-years
Event Rates Event Rates Rate Ratio Needed to Treat
Number (Events/1000 (Events/1000 (95% Confidence (95% Confidence
Outcome of Studies Person-years) Person-years) Interval) Interval)
Cardiovascular mortality
Cholesterol lowering*
Secondary prevention 2 20 24 0.80 (0.53–1.20) 265 (78–NM)
Blood pressure medication 4 12 20 0.59 (0.49–0.71) 121 (90–184)
Blood pressure lowering 3 10 19 0.51 (0.38–0.69) 115 (79–212)
ACE inhibitor 1 14 22 0.64 (0.50–0.81) 128 (84–268)
Glucose lowering† 5 10 12 0.89 (0.74–1.08) 4392 (470–NM)
Primary prevention† 4 10 11 0.94 (0.78–1.14) 8091 (494–NM)
Secondary prevention 1 39 83 0.47 (0.24–0.92) 23 (12–209)
Myocardial infarction
Cholesterol lowering*
Secondary prevention 3 20 35 0.60 (0.41–0.87) 69 (42–210)
Blood pressure medication 3 18 24 0.78 (0.67–0.92) 215 (131–590)
Blood pressure lowering 2 14 16 0.76 (0.51–1.01) 257 (132–4847)
ACE inhibitor 1 23 29 0.79 (0.65–0.96) 166 (91–937)
Glucose lowering 4 16 20 0.91 (0.78–1.05) 550 (229–NM)
Primary prevention 3 14 16 0.89 (0.76–1.05) 550 (229–NM)
Secondary prevention 1 173 175 0.99 (0.68–1.44) 511 (15–NM)
Stroke
Cholesterol lowering*
Secondary prevention 2 12 17 0.74 (0.44–1.25) 221 (84–NM)
Blood pressure medication 5 9 14 0.65 (0.53–0.80) 228 (140–611)
Blood pressure lowering 4 8 14 0.61 (0.46–0.83) 222 (108–NM)
ACE inhibitor 1 9 14 0.69 (0.51–0.92) 237 (133–1092)
Glucose lowering
Primary prevention† 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 THE AMERICAN JOURNAL OF MEDICINE威 Volume 111 639

 Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al
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 ex-
ception, showing a substantial reduction in cardiovascu-
lar 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 person-
years (69 to 300 person-years) of lipid-lowering and
blood pressure–lowering therapy was necessary to pre-
vent one cardiovascular event. With statistical signifi-
cance 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, be-
cause 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-lower-
ing 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 antihyperten-
sive 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 in-
vestigators 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 cardiovascu-
lar events. Although nonsignificant, the point estimates
from glucose-lowering trials suggest that 419 to 4392 per-
son-years of therapy were required to prevent one cardio-
vascular event. In addition to appreciating the overall
magnitude of benefits, we must consider the initial tim-
ing of effect of preventive strategies (46). Cumulative in-
cidence 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 December 1, 2001 THE AMERICAN JOURNAL OF MEDICINE威
themselves comparable. Control arm subjects in the lip-
id-lowering studies consistently had the highest cardio-
vascular outcome event rates, whereas patients in the glu-
cose-lowering studies had the lowest. This difference is
attributable to the large proportion of cholesterol-lower-
ing study subjects with established coronary artery dis-
ease. In several cases, we directly compared primary and
secondary prevention populations. For aggregate cardiac
events, the control arm event rates for primary preven-
tion lipid-lowering and glucose-lowering trials were sim-
ilar, with glucose lowering continuing to have a smaller
benefit. For cardiovascular mortality and myocardial in-
farction, the control arm event rates for secondary pre-
vention 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 reduc-
tion 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. Cur-
rent guidelines recommend even lower lipid (LDL cho-
lesterol 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 observa-
tional 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 magni-
tude, 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 inten-
sive glucose lowering in secondary prevention popula-
tions 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-
Volume 111
 Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al
cular disease prevention in type 2 diabetes. Furthermore,
specific exclusion of patients on insulin and with existing
complications limits the extent to which diabetic sub-
populations of the trials are representative of the average
diabetic patient (49). Several trials funded by the Na-
tional Institutes of Health that are in development will
address these needs (50).
Nonetheless, current trial evidence indicates that treat-
ment of hyperlipidemia and hypertension results in large
cardiovascular benefits for patients with type 2 diabetes.
Whereas aggressive glucose lowering is needed for pre-
vention 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.
REFERENCES
1. Nathan DM, Meigs J, Singer DE. The epidemiology of cardiovascu-
lar disease in type 2 diabetes mellitus: how sweet it is. . .or is it?
Lancet. 1997;350(suppl 1):SI4 –SI9.
2. Kuller LH. Stroke, and Diabetes. In: Harris MI, ed. Diabetes in
America. 2nd ed. Bethesda: National Institutes of Health; 1995:
449 –456.
3. Morrish NJ, Stevens LK, Head J, et al. A prospective study of mor-
tality among middle-aged diabetic patients (the London cohort of
the WHO Multinational Study of Vascular Disease in Diabetics) I:
causes and death rates. Diabetologia. 1990;33:538 –541.
4. Moss SE, Klein R, Klein BEK. Cause-specific mortality in a popula-
tion-based study of diabetes. Am J Public Health. 1991;81:1158 –
1162.
5. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events
and their reduction with pravastatin in diabetic and glucose-intol-
erant myocardial infarction survivors with average cholesterol
levels: subgroup analyses in the Cholesterol and Recurrent Events
Trial. Circulation. 1998;98:2513–2519.
6. UK Prospective Diabetes Study Group. Tight blood pressure con-
trol and risk of cardiovascular and microvascular complications in
type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–713.
7. UK Prospective Diabetes Study Group. Intensive blood-glucose
control with sulphonylureas or insulin compared with conven-
tional treatment and risk of complications in patients with type 2
diabetes: UKPDS 33. Lancet. 1998;352:837–853.
8. Coutinho M, Gerstein HC, Wang YC, Yusuf S. The relationship
between glucose and incident cardiovascular events: a meta-regres-
sion analysis of published data from 20 studies of 95,783 individuals
followed for 12.4 years. Diabetes Care. 1999;22:233–240.
9. Stratton IM, Adler AI, Neil AW, et al. Association of glycaemia with
macrovascular and microvascular complications of type 2 diabetes
(UKPDS 35): prospective observational study. BMJ. 2000;321:405–
412.
10. American Diabetes Association. Detection and management of
lipid disorders in diabetes (consensus statement). Diabetes Care.
1993;16:828 –834.
11. National Cholesterol Education Program (NCEP) Expert Panel.
Summary of the third report of the NCEP expert panel on detection
evaluation, and treatment of high blood cholesterol in adults (adult
treatment panel III). JAMA. 2001;285:2486 –2497.
12. The sixth report of the Joint National Committee on prevention,
detection, evaluation, and treatment of high blood pressure. Arch
Intern Med. 1997;157:2413–2446.
December 1, 2001
13. Meigs JB, Stafford RS. Cardiovascular disease prevention practices
by U.S. physicians for patients with diabetes. J Gen Intern Med.
2000;15:220 –228.
14. Savage PJ. Cardiovascular complications of diabetes mellitus: what
we know and what we need to know about their prevention. Ann
Intern Med. 1996;124:123–126.
15. Fagan TC, Sowers J. Type 2 diabetes mellitus: greater cardiovascular
risks and greater benefits of therapy. Arch Intern Med. 1999;159:
1033–1034.
16. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus.
Ann Intern Med. 1999;131:281–303.
17. Boyne MS, Saudek CD. Effect of insulin therapy on cardiovascular
risk factors in type 2 diabetes. Diabetes Care. 1999;22:45–53.
18. Lebovitz HE. Effects of oral antihyperglycemic agents in modifying
cardiovascular risk factors in type 2 diabetes. Diabetes Care. 1999;
22:41–44.
19. Garber AJ. Vascular disease and lipids in diabetes. Med Clin North
Am. 1998;82:931–948.
20. Ruilope LM, Garcia-Robles R. How far should blood pressure be
reduced in diabetic hypertensive patients? J Hypertens. 1997;
15(suppl 2):S63–S65.
21. Koskinen P, Manttari M, Manninen V, et al. Coronary heart disease
incidence in NIDDM patients in the Helsinki Heart Study. Diabetes
Care. 1992;15:820 –825.
22. Downs JR, Clearfield M, Weis D, et al. Primary prevention of acute
coronary events with lovastatin in men and women with average
cholesterol levels. JAMA. 1998;279:1615–1622.
23. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering with
simvastatin improves prognosis of diabetic patients with coronary
heart disease: a subgroup analysis of the Scandinavian Simvastatin
Survival Study (4S). Diabetes Care. 1997;20:614 –620.
24. The Long-Term Intervention with Pravastatin in Ischaemic Disease
(LIPID) Study Group. Prevention of cardiovascular events and
death with pravastatin in patients with coronary heart disease and a
broad range of initial cholesterol levels. N Engl J Med. 1998;339:
1349 –1357.
25. Hoogwerf BJ, Waness A, Cressman M, et al. Effects of aggressive
cholesterol lowering and low-dose anticoagulation on clinical and
angiographic outcomes in patients with diabetes. The Post Coro-
nary Artery Bypass Graft Trial. Diabetes. 1999;48:1289 –1294.
26. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the second-
ary prevention of coronary heart disease in men with low levels of
high-density lipoprotein cholesterol. Veterans Affairs High-Den-
sity Lipoprotein Cholesterol Intervention Trial Study Group.
N Engl J Med. 1999;341:410 –418.
27. The Hypertension Detection, and Follow-up Program Cooperative
Research Group. Mortality findings for stepped-care and referred-
care participants in the Hypertension Detection and Follow-up
Program stratified by other risk factors. Prev Med. 1985;14:312–
335.
28. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based anti-
hypertensive treatment on cardiovascular disease risk in older dia-
betic patients with isolated systolic hypertension. Systolic Hyper-
tension in the Elderly Program Cooperative Research Group.
JAMA. 1996;276:1886 –1892.
29. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive
blood-pressure lowering and low-dose aspirin in patients with
hypertension: principal results of the Hypertension Optimal Treat-
ment (HOT) randomised trial. HOT Study Group. Lancet. 1998;
351:1755–1762.
30. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calci-
um-channel blockade in older patients with diabetes and systolic
hypertension. N Engl J Med. 1999;340:677–684.
31. Heart Outcomes Prevention Evaluation Study Investigators. Effects
of ramipril on cardiovascular and microvascular outcomes in peo-
THE AMERICAN JOURNAL OF MEDICINE威 Volume 111 641
 Preventing Cardiovascular Disease in Type 2 Diabetes Mellitus/Huang et al
ple with diabetes mellitus: results of the HOPE study and MICRO-
HOPE substudy. Lancet. 2000;355:253–259.
32. Knatterud GL, Klimt CR, Goldner MG, et al. Effects of hypoglyce-
mic agents on vascular complications in patients with adult-onset
diabetes: VIII. Evaluation of insulin therapy: final report. Diabetes.
1982;21(suppl 5):S1–S81.
33. Abraira C, Colwell J, Nuttall F, et al. Cardiovascular events and
correlates in the Veterans Affairs Diabetes Feasibility trial. Veterans
Affairs Cooperative Study on Glycemic Control and Complications
in Type II Diabetes. Arch Intern Med. 1997;157:181–188.
34. Shichiri M, Kishikawa H, Ohkubo Y, WakeN Long-term results of
the Kumamoto study on optimal diabetes control in type 2 diabetic
patients. Diabetes Care. 2000;23(suppl 2):B21–B29.
35. Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-
glucose infusion followed by subcutaneous insulin treatment in
diabetic patients with acute myocardial infarction (DIGAMI
study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26:57–
65.
36. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart
disease with pravastatin in men with hypercholesterolemia. N Engl
J Med. 1995;333:1301–1307.
37. Tatti P, Pahor M, Byington RP, et al. Outcome results of the fosi-
nopril versus amlodipine cardiovascular events randomized trial
(FACET) in patients with hypertension and NIDDM. Diabetes
Care. 1998;21:597–603.
38. UK Prospective Diabetes Study Group. Efficacy of atenolol and
captopril in reducing risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713–
720.
39. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-
converting-enzyme inhibition compared with conventional ther-
apy on cardiovascular morbidity and mortality in hypertension: the
Captopril Prevention Project (CAPPP) randomised trial. Lancet.
1999;353:611–616.
642 December 1, 2001 THE AMERICAN JOURNAL OF MEDICINE威 Volume 111
40. Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as
compared with enalapril on cardiovascular outcomes in patients
with non-insulin dependent diabetes and hypertension. N Engl
J Med. 1998;338:645–652.
41. Laupacis A, Sackett DL, Robert RS. An assessment of clinically use-
ful measures of the consequences of treatment. N Engl J Med. 1988;
318:1728 –1733.
42. Ioannidis JPA, Cappelleri JC, Lau J, et al. Early or deferred zidovu-
dine therapy in HIV-infected patients without an AIDS-defining
illness. Ann Intern Med. 1995;122:856 –866.
43. Petiti DB. Statistical methods in meta-analysis. In: Petiti DB, ed.
Meta-Analysis, Decision Analysis, and Cost-Effectiveness Analysis.
New York: Oxford University Press; 2000:94 –118.
44. Thompson SG. Why sources of heterogeneity in meta-analysis
should be investigated. BMJ. 1994;309:1351–1355.
45. University Group Diabetes Program. A study of the effects of hy-
poglycemic agents on vascular complications in patients with
adult-onset diabetes: I. Design, methods, and baseline characteris-
tics. Diabetes. 1970;19(suppl 2):747–783.
46. Weinstein MC, Siegel JE, Gold MR, et al. Recommendations of the
panel on cost-effectiveness in health and medicine. JAMA. 1996;
276:1253–1258.
47. Adler AI, Stratton IM, Neil AW, et al. Association of systolic blood
pressure with macrovascular and microvascular complications of
type 2 diabetes (UKPDS 36): prospective observational study. BMJ.
2000;321:412–419.
48. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of met-
formin and rosiglitazone combination therapy in patients with type
2 diabetes mellitus. JAMA. 2000;283:1695–1702.
49. Harris MI. Summary. In: Harris MI, ed. Diabetes in America. 2nd
ed. Bethesda: National Institutes of Health; 1995:1–13.
50. Action to control cardiovascular risk in diabetes ACCORD. Avail-
able at: http://www.accordtrial.org.html. Accessed July 9, 2001.