PROactive

In Review

Dormandy JA, et al. "Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial". The Lancet. 2005. 366(9493):1279-1289.
PubMed • Full text

Clinical Question

In patients with type 2 diabetes mellitus (DM) and high risk for macrovascular complications, does pioglitazone reduce the risk of macrovascular complications as compared to placebo.

Bottom Line

In high-risk patients with T2DM, pioglitazone did not reduce the risk of the pre-defined primary and secondary macrovascular endpoints. However, the authors reported a significant reduction in a main secondary endpoint (all-cause mortality, non-fatal MI, and stroke). Pioglitazone demonstrated good overall safety but increased the risk of heart failure.

Major Points

The thiazolidinediones (eg, pioglitazone, rosiglitazone) are oral antihyperglycemic agents. They are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist to increase insulin sensitivity in the liver, muscle, and adipose tissue. Intensive glycemic control has been shown to decrease the risk of microvascular complications but not macrovascular complications significantly. However, a retrospective analysis of the UKPDS reported that metformin reduced the risk of CV disease and mortality. Therefore the PROACTIVE ascertained the effect of pioglitazone on macrovascular disease.

The "PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive)" trial randomized 5,238 patients with T2DM at high-risk for macrovascular disease to receive pioglitazone or placebo. The primary endpoint was the composite of all-cause mortality, non fatal MI (including silent MI), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and above-ankle amputation.

While the reduction in primary endpoint did not reach statistical significance, pioglitazone significantly reduced the risk of the main secondary endpoint (all-cause mortality, non-fatal MI, and stroke). In the pioglitazone and placebo groups, 301 and 358 patients reached this endpoint respectively (0·84, 95%CI 0·72-0·98, P=0·027).

Several studies have raised concerns regarding the cardiovascular safety of thiazolidinediones. In 2003, the AHA/ADA published a consensus statement regarding thiazolidinedione, fluid retention and heart failure. Heart failure requiring admission occurred in 6% of pioglitazone-treated patients as compared to 4% in placebo (P=0.007).

A Cochrane analysis concluded that pioglitazone treatment did not improve all-cause mortality or morbidity significantly but an increased risk of edema was noted. However, the authors suggested that the results of the PROactive to be seen as hypothesis-generating and more confirmation is required.

Guidelines

ADA Standards of Medical Care in Diabetes (2016, adapted)

• Metformin is the preferred initial pharmacological agent for type 2 diabetes if well-tolerated and no contraindications exist. (Level of evidence: A)
• If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target over 3 months, add a second oral agent, a GLP-1 receptor agonist, or basal insulin. (Level of evidence: A)
  • The choice of oral agents include sulfonylurea, thiazolidinedione, DPP-4 inhibitors and SGLT2 inhibitors
• A patient-centered approach should be used to guide choice of pharmacological agents. Considerations include efficacy, cost, potential side effects, weight, comorbidities, hypoglycemia risk, and patient preferences. (Level of evidence: E)

ACCF/AHA Guideline for the Management of Heart Failure (2013, adapted)

• Treatment with thiazolidinediones (eg, rosiglitazone) is associated with fluid retention in patients with heart failure and should be avoided in patients with NYHA class II through IV.
• Drugs known to adversely affect the clinical status of patients with current or prior symptoms of HFrEF are potentially harmful and should be avoided or withdrawn whenever possible (eg, most antiarrhythmic drugs, most calcium channel–blocking drugs [except amlodipine], NSAIDs, or thiazolidinediones). (Level of Evidence: B)

Design

• Prospective, randomized, placebo-controlled trial
• N=5,238
  • Pioglitazone (n=2,605)
  • Placebo (n=2,633)
• Setting: 321 centres in 19 European countries
• Enrollment: 2001 to 2002
• Mean follow-up: 34.5 months
• Analysis: intention-to-treat
• Primary outcome: all-cause mortality, non fatal MI (including silent MI), stroke, ACS, endovascular or surgical intervention in the coronary or leg arteries, and above-ankle amputation

Population

Inclusion Criteria

=Published elsewhere

• T2DM
• Age 35-75 years
• HbA_1c >6.5%
• Macrovascular disease, defined by:
  • MI or stroke at least 6 months prior to the trial
  • PCI or CABG at least 6 months prior to recruitment
  • ACS at least 3 months before recruitment
  • coronary artery disease (CAD), defined by positive exercise test, stenosis of >50% on angiography, or positive scintigraphy
  • peripheral arterial disease (PAD) in the leg, defined as previous major amputation, or intermittent claudication with an ankle or toe brachial pressure index of <0·9

Exclusion Criteria

• T1DM
• Only using insulin therapy
• Planned coronary or peripheral revascularization
• Heart failure of NYHA Class II or above
• ischaemic ulcers, gangrene, or rest pain in the leg
• already had haemodialysis
• ALT >2.5x upper limit of normal

Baseline Characteristics

From the Pioglitazone group

• Demographics: Age 61.9 years, 67% male, 98% white race
• BMI: 30.7±4.7 kg/m²
• T2DM:
  • Time since first diagnosis 8 (4-13) years, HbA_1c 7·8 (7.0-8.9)%
  • Treatment: 1 oral antihyperglycemic agent 30%, 2 oral antihyperglycemic agent 25%, insulin and 1 or 2 oral antihyperglycemic agents 30%
• Macrovascular disease criteria:
  • MI 47%, stroke 19%, PCI or CABG 31%, ACS 14%, CAD 48%, PAD 19%
  • ≥2 macrovascular disease criteria 47%
• BP: systolic 144±18 mm Hg, diastolic 83±10 mm Hg
• LDL-C : 2.9 (2.3-3.5) mmol/L; HDL-C: 1·1 (0.9-1.3) mmol/L; triglyceride: 1.8 (1.3-2.6) mmol/L
• Other medical history: microvascular complications 43%, active smoker 13%, hypertension 75%

Interventions

• Participants were randomized to pioglitazone or placebo in addition to their existing medications
• The therapeutic target was HbA_1c<6.5%, as per the International Diabetes Federation European Region 1999 guidelines
• Pioglitazone regimen was 15 mg in the first month, 30 mg in the 2nd month, and 45 mg thereafter to achieve the maximum tolerated dose

Outcomes

Comparisons are pioglitazone vs plcebo

Primary outcomes

All-cause mortality, non fatal MI (including silent MI), stroke, ACS, endovascular or surgical intervention in the coronary or leg arteries, and above-ankle amputation

514 vs. 572 patients (HR 0·90, 95% CI 0·80-1·02, P=0·095)

Secondary outcomes

All-cause mortality, non-fatal MI, and stroke

301 vs. 358 patients (HR 0.84; 95% CI 0.72-0.98; P=0.027)

All-cause mortality

177 vs. 186 patients (HR 0.96; 95% CI 0.78-1.18; P=NS)

Non-fatal MI

119 vs. 144 first events (HR 0.83; 95% CI 0.65-1.06; P=NS)

Stroke

86 vs. 107 first events (HR 0.81; 95% CI 0.61-1.07; P=NS)

Major leg amputation

26 vs. 26 first events (HR 1.01; 95% CI 0.58-1.73; P=NS)

ACS

56 vs. 72 first events (HR 0.78; 95% CI 0.55-1.11; P=NS)

Coronary revascularization

169 vs. 193 first events (HR 0.88; 95% CI 0.72-1.08; P=NS)

Leg revascularization

80 vs. 65 first events (HR 1.25; 95% CI 0.90-1.73; P=NS)

Other outcomes

Change in HbA_1c

−0·8 vs. −0·3% (P<0.0001)

Change in LDL-C

7.2 vs. 4.9% (P=0.003)

Change in HDL-C

19 vs. 10.1% (P<0.0001)

Change in LDL-C/HDL-C

-9.5 vs. -4.2 (P<0.0001)

Change in triglycerides

-11.4 vs. 1.8% (P<0.0001)

Change in weight

+3.6kg vs. -0.4kg (P<0.0001)

Reduction in systolic blood pressure

3 vs. 0 mm Hg (P=0.03)

Subgroup Analysis

• There were no significant interactions in pre-specified subgroup analyses (demographic characteristics, macrovascular disease, co-morbidities, medication use, lipid levels at entry).

Adverse events

Any serious events: 46% vs 48% of patients (P=0.110)

• Endpoint events: 15% vs 16% of patients (P=0.123)
• Non-endpoint events: 41% vs 44% of patients (P=0.09)

Malignancies: 97 vs. 99 patients (P=NS)

• Bladder: 14 vs 6 patients (P=0.069)
• Colorectal: 16 vs 15 patients (P=0.834)
• Lung: 15 vs 12 patients (P=0.544)
• Hematological: 6 vs 10 patients (P=0.327)
• Breast: 3 vs 11 patients (P=0.034)

Heart failure: 11% vs. 8% of patients (P<0.0001)

• Requiring admission: 6% vs. 4% of patients (P=0.007)
• Fatal: 25 vs. 22 patients (P=0.634)

Angina pectoris: 89 vs. 122 patients (P=0.025)

TIA: 34 vs. 39 patients (P=0.587)

Pneumonia: 53 vs. 35 patients (P=0.047)

Atrial fibrillation: 42 vs. 51 patients (P=0.374)

Criticisms

• Patients with >2.5x ALT elevation were excluded, this might have excluded patients who may respond best to glitazones due to their effect of reducing hepatic insulin resistance.
• The trial closed earlier than anticipated and this might have reduced the possibility of observing a positive effect on the primary endpoint.
• The main secondary endpoint (all-cause mortality, non-fatal MI, and stroke) was not mentioned in the design paper, but the authors emphasized that it was added before trial data were unblinded.

Funding

• Takeda Pharmaceutical Company
• Eli Lilly and Company