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Diabetes and Cardiovascular Risk
treatment led to a 39% reduction in MI (p=0.01) and a 36% reduction in Patients on metformin were randomized to rosiglitazone or a
total mortality (p=0.01); there was no increase in severe hypoglycemia.
23
sulfonylurea and patients on a sulfonylurea were randomized to
Importantly, during the subsequent 10-year observational follow-up, the rosiglitazone or metformin. The analytical structure was a non-inferiority
reduction in MI (33%; p=0.005) and total mortality (27%; p=0.002) with trial with an upper HR boundary of 1.20, comparing rosiglitazone with a
metformin persisted.
17
combined active control group of metformin and sulfonylurea. The
primary outcome was CVD hospitalization or death.
The  Hyperinsulinaemia: the Outcome of Its Metabolic Effects (HOME)
trial randomized 390 insulin-treated patients with type 2 diabetes to After 5.5 years of follow-up, rosiglitazone was not inferior to the control
metformin or placebo for a mean follow-up of 4.3 years.
24
Although the group (HR <1.20) for the primary outcome, MI, or stroke.
34
Nor was any
same glycemic level was targeted, mean HbA
1c
was 0.4% lower in CVD benefit shown for rosiglitazone, though HDL cholesterol was
the metformin group. Mean daily insulin dose was 20 units less with a increased and HbA
1c
was decreased by 0.3%. Both heart failure and
corresponding lower plasma insulin level. The addition of metformin to lower-limb fractures were increased by rosiglitazone.
34
insulin treatment resulted in no difference in the primary outcome, a
composite of macro- and microvascular events. There was, however, a BARI 2D
substantial reduction in the macrovascular outcome (hazard ratio [HR] Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes
0.60, 95% CI 0.40–0.92; p=0.04).
24
(BARI 2D) tested a cardiology and glycemic management question
simultaneously in a factorial design with total mortality as the primary
Thiazolidinedione Drugs outcome and a composite of death, MI, or stroke as a principal
The two currently marketed agents in this class are rosiglitazone secondary outcome.
35
The investigation included 2,368 patients with
(Avandia) and pioglitazone (Actos). There is some debate about their type 2 diabetes (mean age 62 years, 70% male, diabetic duration 10
relative effectiveness and safety with regard to CVD.
25–30
years, baseline HbA
1c
7.7%). All patients included had angiographically
documented CAD and clinical or stress test evidence of ischemia.
Pioglitazone
PROACTIVE included 5,238 patients with type 2 diabetes (mean age 62 Patients were randomly assigned to primary treatment, targeted at HbA
1c
years, 67% male), all with prior evidence of CVD. Patients were randomly <7.0%, with insulin-sensitizing drugs (metformin and/or rosiglitazone) or
assigned to titrated doses of pioglitazone or placebo in addition to their insulin-providing drugs (insulin, sulfonylureas, meglitinides). They were
usual glycemic therapy. They were followed for three years.
31
simultaneously randomly assigned to either aggressive medical therapy
for CAD or the addition of prompt revascularization by coronary artery
Median baseline HbA
1c
(7.8%) decreased by -0.8% with pioglitazone bypass graft (CABG) or percutaneous coronary intervention (PCI). The
and by -0.3% with placebo. Pioglitazone had no significant effect on revascularization group was stratified by the cardiologist’s choice of
the primary outcome—a composite of total mortality, non-fatal MI, CABG or PCI prior to randomization, the CABG group having more severe
stroke, acute coronary syndrome, revascularization of coronary or leg CAD by angiographic and clinical characteristics. There was no direct
arteries, and above-ankle amputation (HR 0.90, 95% CI 0.80–1.02) comparison of CABG versus PCI in like patients.
compared with placebo. For a secondary end-point of total mortality,
non-fatal MI, and stroke, there was a significant reduction (HR 0.84, No difference emerged in the primary or principal secondary outcomes
95% CI 0.72–0.98; p=0.027).
31
over a five-year follow-up period between the insulin-sensitization and
insulin-provision groups or between the revascularization and medical
In subgroup analyses, pioglitazone reduced the pre-specified outcome therapy control groups.
35
In the CABG stratum, however, there was a 12%
of fatal and non-fatal MI by 28% (p=0.045) and acute coronary syndrome reduction in the composite of death, MI, or stroke compared with
by 37% (p=0.035) in 2,445 patients with a previous MI.
32
Moreover, in medical therapy (p=0.01). This was largely accounted for by a significant
patients with a previous history of stroke, pioglitazone reduced 49% reduction in non-fatal MI.
35
Strikingly, the composite outcome was
recurrent stroke (HR 0.53, 95% CI 0.34–0.85; p=0.009) and a composite reduced by 42% (p=0.002) in the insulin-sensitization group of those
end-point of CVD death, non-fatal MI, or stroke (HR 0.72, 95% CI randomized to CABG, but only 10% in the insulin-provision group
0.53–1.00; p=0.047).
33
Pioglitazone increased high-density lipoprotein (p=0.58). Within the CABG stratum, the composite outcome was 18.7%
(HDL) cholesterol, which along with lowering HbA
1c
may have for insulin sensitization versus 26% for insulin provision (p=0.066). Severe
contributed to its beneficial effect. It did, however, increase the risk of hypoglycemia was 36% less frequent with insulin-sensitization than with
heart failure, with or without hospitalization (HR 1.43, 95% CI 1.20–1.70; insulin-provision treatment (p=0.003), and was largely accounted for by
p<0.001). There was no effect on total mortality.
31
the addition of insulin to improve HbA
1c
.
35
The mechanism for the unique
beneficial interaction between CABG and insulin sensitization remains to
Rosiglitazone be elucidated, but this interaction suggests a pathogenetic relationship
The RECORD Trial between metabolic and anatomical abnormalities in diabetic CAD.
Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent
Combination Therapy for Type 2 Diabetes (RECORD) was an open-label Meta-analysis
randomized trial. It included 2,222 patients already taking Pioglitazone
metformin and 2,225 on a sulfonylurea (mean age 59 years, 50% male, Nineteen trials involving 16,390 patients with type 2 diabetes followed
mean HbA
1c
7.9%).
34
for between four months and 3.5 years were analyzed.
36
For the primary
92 US ENDOCRINOLOGY
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