Prevention of Instent Renarrowing With Aggressive Glucose Lowering With Pioglitazone in Diabetic Patients
Condition: Coronary Artery Disease; Angina Pectoris; Type 2 Diabetes Mellitus; Percutaneous Coronary Intervention
MeSH terms: Coronary Artery Disease; Angina Pectoris; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Patients with diabetes have worse outcomes after percutaneous coronary intervention (PCI)
      procedures, compared to those patients without diabetes. They are at increased risk of death,
      heart attack, or needing further procedures due to renarrowing of their coronary narrowings
      after implantation of a coronary stent. Studies have suggested that poor control of diabetes
      may be partly responsible for these poor outcomes. Thiazolidinedione drugs, such as
      pioglitazone, can improve the diabetes control and make the patient more sensitive to the
      effects of insulin. Preliminary studies suggest that pioglitazone may also help prevent
      renarrowing after PCI.

      This study was a pilot study designed to determine whether more aggressive treatment of the
      diabetes with the routine use of the drug pioglitazone (30mg/day for 6 months), in addition
      to the patient's usual diabetic medications adjusted to optimize their diabetic control (get
      glycated hemoglobin < 7%), could reduce the amount of tissue buildup within the stent after 6
      months, compared to a group less aggressively treated without pioglitazone and their usual
      medications for diabetes.

      An intravascular ultrasound probe was used to assess the extent of tissue buildup within the
      stent and this was performed immediately after the PCI as a baseline and repeated after 6
      months of therapy.

      The investigators hypothesize that the more aggressive diabetic treatment with pioglitazone
      would reduce the extent of tissue growth within the stent after 6 months of therapy.
    

Detailed description: 
      Background: Despite drug-eluting stents (DES), diabetic patients remain at high risk of
      restenosis and poor clinical outcomes after percutaneous coronary intervention (PCI). Studies
      have suggested poor glycemic control and insulin resistance may be predictors of poor
      outcomes after PCI. There are conflicting studies as to whether strategies to improve
      glycemic control can improve outcomes after PCI. Thiazolidinediones, such as pioglitazone
      (PIO), may have anti-restenotic benefits, independent of glycemic control.

      Study design: This study was a single centre prospective, randomized, open-label,
      blinded-endpoint (PROBE) parallel design trial. Type 2 diabetic patients, treated with diet
      or oral antidiabetic medication (sulfonylurea vs. metformin or combination; but no
      thiazolidinedione or insulin), who are undergoing elective or urgent PCI with stenting were
      eligible. Fifty type 2 diabetic patients were randomly assigned to either: intensive glycemic
      control: pioglitazone (PIO; 30 mg/d x 6 months) in addition to titration of oral hypoglycemic
      agents (OHA) to get HbA1c<6% (PIO: n=25) vs. conservative glycemic control: titration of OHA
      to get HbA1c<7% (CONTROL: n=25). Intravascular ultrasound (IVUS) was performed immediately
      after PCI and repeated at 6 months to determine the effect on instent neointimal plaque
      volume and area. Coronary stenting was carried out in a standard fashion, with routine use of
      a glycoprotein 2b/3a inhibitor during the procedure. From August 2002 until June 2005, DES
      were not permitted in the protocol. After June 2005, we amended the protocol to allow DES, as
      they had become routinely used in diabetic patients in our institution, especially for vessel
      size <3mm and/or lesion length>15mm. DES were used in 7 PIO and 11 CONTROL subjects, and bare
      metal stents (BMS) in the rest. Patients were then followed with clinic visits at 1, 3 and 6
      months. OHA, other than pioglitazone, were adjusted in a stepwise manner in order to attain
      the HbA1c targets. Other concomitant medications, including anti-anginals, lipid-lowering
      therapy, and antihypertensive medication were adjusted according to their clinical need and
      current Canadian guidelines. After 6 months treatment, or before if clinically indicated, all
      subjects were to return for repeat cardiac catheterization, including repeat coronary
      angiography and IVUS of the intervened vessel to assess the serial change in luminal
      dimensions. Fasting blood was collected for plasma glucose, HbA1c, insulin, lipid profile,
      hs-CRP, adiponectin, leptin, matrix metalloproteinase-9, and interleukin-6 at the time of PCI
      and at the follow-up IVUS. If the patient developed recurrent ischemic symptoms before 6
      months, the final IVUS could be performed earlier, if they were found to have
      clinically-significant restenosis (diameter stenosis > 50%). Otherwise, patients were still
      encouraged to have their protocol 6 month IVUS follow-up. 41 patients (n=20 PIO, n=21
      CONTROL) had analyzable pairs of IVUS.

      Study hypothesis: We hypothesized that there would be significantly less instent neointimal
      proliferation on IVUS at 6 months in the group receiving aggressive glycemic control plus the
      thiazolidinedione pioglitazone. We also hypothesized that the reduction in neointimal
      hyperplasia will likely relate to improvements in glycemic control (HbA1c) and insulin
      resistance. Additionally, we wanted to explore the biochemical predictors (glucose
      parameters, lipids, inflammatory markers, adipokines) for neointimal proliferation.
    

Intervention name(s): pioglitazone; oral hypoglycemic agents
Intervention type(s): Drug; Drug
Intervention description(s): pioglitazone 30mg p.o. once a day for 6 months; sulfonylurea or metformin
Intervention MeSH terms: Pioglitazone; Hypoglycemic Agents
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: diabetes; stents; restenosis; thiazolidinediones; coronary atherosclerosis