GLITAZONES (ACTOS AND AVANDIA)











  • ✝All values are expressed as change from baseline. FBS (fasting blood sugar) expressed as mg/dl.
  • Baseline A1C ranged from 8.8 - 10% depending on the study
  • Reference [1,2]
Effects of Glitazones on blood sugars in trials lasting 16 - 26 weeks✝
Drug A1C
(monotherapy)		 FBS
(monotherapy)		 A1C
(added to metformin)		 FBS
(added to metformin)
Piolgitazone 15 mg daily -0.3% -30 N/A N/A
Piolgitazone 30 mg daily -0.3% -32 -0.8% -43
Piolgitazone 45 mg daily -0.9% -56 N/A N/A
Rosiglitazone 4 mg once daily 0% -25 -0.6% -33
Rosiglitazone 2 mg twice daily -0.1% -35 N/A N/A
Rosiglitazone 8 mg once daily -0.3% -42 -0.8% -48
Rosiglitazone 4 mg twice daily -0.7% -55 N/A N/A

  • ✝All values are expressed as median increase from baseline
  • Reference [1,2]
Weight gain with Glitazones in controlled trials✝
Drug Weight gain
Pioglitazone 15 mg once daily for 16 - 24 weeks 1.98 lbs (0.9 kg)
Pioglitazone 30 mg once daily for 16 - 24 weeks 2.2 lbs (1 kg)
Pioglitazone 45 mg once daily for 16 - 24 weeks 5.72 lbs (2.6 kg)
Rosiglitazone 4 mg/day for 26 weeks 2.2 lbs (1 kg)
Rosiglitazone 8 mg/day for 26 weeks 6.82 lbs (3.1 kg)

  • ✝All values are expressed as average change from baseline
  • Reference [1,2]
Effect of Glitazones on lipids in controlled trials lasting 26 weeks✝
Drug LDL HDL Triglycerides
Pioglitazone 15 mg once daily +7.2% +14.1% -9%
Pioglitazone 30 mg once daily +5.2% +12.2% -9.6%
Pioglitazone 45 mg once daily +6% +19.1% -9.3%
Rosiglitazone 4 mg/day +14.1% +11.4% -7.8%
Rosiglitazone 8 mg/day +18.6% +14.2% -14.7%



PROactive Study - Pioglitazone vs Placebo for CVD Prevention, Lancet (2005) [PubMed abstract]
  • The PROactive study enrolled 5238 diabetics with evidence of macrovascular disease
Main inclusion criteria
  • Type 2 diabetes
  • HgA1C > 6.5%
  • Objective evidence of CVD defined as myocardial infarction, stroke, PCI, or CABG at least 6 months before entry, acute coronary syndrome at least 3 months before entry, or objective evidence of CAD or PAD
Main exclusion criteria
  • Treated with insulin only
  • NYHA class II - IV heart failure
  • Significant liver disease
Baseline characteristics
  • Average age 62 years
  • Median duration of diabetes - 8 years
  • Average BP - 144/83
  • Median HgA1C - 7.85%
Randomized treatment groups
  • Group 1 (2605 patients) - Pioglitazone target dose of 45 mg once daily
  • Group 2 (2633 patients) - Placebo once daily
  • Pioglitazone was started at 15 mg once daily and increased by 15 mg at monthly intervals if tolerated. 93% of patients in Group 1 achieved the 45 mg dose.
  • Patients continued other diabetes medications and were treated to a target HgA1C of < 6.5%
Primary outcome: Composite of all cause mortality, nonfatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle
Results

Duration: Average of 2.87 years
Outcome Pioglitazone Placebo Comparisons
Primary outcome 19.7% 21.7% HR 0.90, 95% CI [0.80 - 1.02], p=0.095
Overall mortality 6.8% 7% HR 0.96, 95% CI [0.78 - 1.18]
Stroke 3.3% 4.1% HR 0.81, 95% CI [0.61 - 1.07]
Nonfatal myocardial infarction 4.6% 5.5% HR 0.83, 95% CI [0.65 - 1.06]
Heart failure 11% 8% p<0.0001
Bladder cancer 1% <1% p=0.069
Decrease in HgA1C 0.8% 0.3% p<0.0001
Drug discontinuation 16% 17% N/A

Findings: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.







PIVENS Trial - Pioglitazone vs Vitamin E vs Placebo for NASH, NEJM (2010) [PubMed abstract]
  • The PIVENS trial enrolled 247 patients with NASH
Main inclusion criteria
  • Adults with NASH confirmed by liver biopsy within 6 months
  • Definite or possible steatohepatitis with an activity score ≥ 5 or definite steatohepatitis with an activity score of 4
  • Score ≥ 1 for hepatocellular ballooning
Main exclusion criteria
  • Diabetes
  • Alcohol consumption > 20 grams/day for women (> 30 grams/day for men)
  • Hepatitis C or other liver diseases
  • NYHA class II - IV heart failure
  • Taking drug known to cause steatohepatitis
Baseline characteristics
  • Average age 46 years
  • Average ALT - 83 U/L
  • Average AST - 56 U/L
  • Average BMI - 34
  • Average NAFLD activity score - 4.9
  • Average fibrosis stage - 1.5
Randomized treatment groups
  • Group 1 (83 patients) - Placebo once daily for 96 weeks
  • Group 2 (84 patients) - Vitamin E 800 IU once daily for 96 weeks
  • Group 3 (80 patients) - Pioglitazone 30 mg once daily for 96 weeks
Primary outcome: Improvement in histologic features of nonalcoholic steatohepatitis as assessed by the NAFLD score (range 0 - 8, higher scores indicate worse disease) which includes steatosis (0 - 3), lobular inflammation (0 - 3), and hepatocellular ballooning (0 - 2). Fibrosis stage (0 - 4, higher scores indicate worse fibrosis) was also assessed.
Results

Duration: 96 weeks
Outcome Placebo Vit E Pioglitazone Comparisons
Primary outcome (% with improvement) 19% 43% 34% 1 vs 2 p=0.001 | 1 vs 3 p=0.04
Decrease in NAFLD score 0.5 1.9 1.9 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Decrease in fibrosis stage 0.1 0.3 0.4 1 vs 2 p=0.19 | 1 vs 3 p=0.10
Resolution of NASH (% of patients) 21% 36% 47% 1 vs 2 p=0.05 | 1 vs 3 p=0.001
Weight gain (lbs) 1.54 0.88 10.3 1 vs 2 p=0.65 | 1 vs 3 p<0.001
Decrease in ALT (U/L) 20 37 41 1 vs 2 p=0.001 | 1 vs 3 p<0.001
Decrease in AST (U/L) 3.8 21 20 1 vs 2 p<0.001 | 1 vs 3 p<0.001
Drug discontinuation 14.5% 7.1% 17.5% N/A

Findings: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes.





IRIS trial - Pioglitazone vs Placebo for the Secondary Prevention of CVD, NEJM (2016) [PubMed abstract]
  • The IRIS trial enrolled 3876 patients with recent TIA or ischemic stroke who had insulin resistance
Main inclusion criteria
  • ≥ 40 years old
  • TIA or stroke within previous 6 months
  • Insulin resistance (defined as score > 3 on the HOMA-IR index)
Main exclusion criteria
  • History of diabetes
  • NYHA class III or IV heart failure or class II with reduced EF
  • Active liver disease
  • Moderate to severe edema
Baseline characteristics
  • Average age 63 years
  • Stroke at trial entry - 88%
  • History of CAD - 12%
  • Average HgA1C - 5.8%
  • Average BMI - 30
  • Average SBP - 133, DBP - 79
Randomized treatment groups
  • Group 1 (1939 patients) Pioglitazone target dose of 45 mg once daily (median dose at end of study was 29 mg)
  • Group 2 (1937 patients) Placebo
  • Pioglitazone was started at a dose of 15 mg once daily and increased by 15 mg at monthly intervals
Primary outcome: First fatal or nonfatal stroke or fatal or nonfatal myocardial infarction
Results

Duration: Median of 4.8 years
Outcome Pioglitazone Placebo Comparisons
Primary outcome 9% 11.8% HR 0.76, 95%CI [0.62 - 0.93], p=0.007
Stroke 6.5% 8% HR 0.82, 95%CI [0.61 - 1.10], p=0.19
MI or unstable angina 5% 6.6% HR 0.75, 95%CI [0.52 - 1.07], p=0.11
Overall mortality 7% 7.5% HR 0.93, 95%CI [0.73 - 1.17], p=0.52
Development of diabetes 3.8% 7.7% HR 0.48, 95%CI [0.33 - 0.69], p<0.001
Bone fractures 6.9% 4.9% p=0.008
Weight gain (> 4.5 kg) 52% 34% p<0.001
Weight gain (> 13.6 kg) 11.4% 4.5% p<0.001
Edema 36% 25% p<0.001
Bladder cancer 0.6% 0.4% p=0.37
Drug discontinuation 40% 33% N/A

Findings: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture.






























RECORD trial - Rosiglitazone + Metformin or Sulfonylurea vs Metformin + Sulfonylurea for CVD, Lancet (2009) [PubMed abstract]
  • The RECORD trial enrolled 4458 diabetics who were on monotherapy with either metformin or a sulfonylurea and were taking maximum doses of the drugs
Main inclusion criteria
  • Age 40 - 75 years
  • Type 2 diabetes
  • Taking monotherapy with either metformin or sulfonylurea
  • HgA1C of 7.1 - 9%
  • BMI > 25
Main exclusion criteria
  • Hospitalization for cardiovascular event within 3 months
  • History of heart failure
Baseline characteristics
  • Average age - 58 years
  • History of CAD - 17%
  • Average BMI - 31
  • Average HgA1C - 7.9%
  • Average BP 139/83
Randomized treatment groups
  • Group 1 (2220 patients) - Rosiglitazone 4 - 8 mg once daily added to current therapy
  • Group 1 (2227 patients) - Whichever medication (metformin or sulfonylurea) they were not taking was added to their therapy
  • Patients were treated to a target HgA1C of ≤ 7%
  • Rosiglitazone was started at a dose of 4 mg once daily and increased to 8 mg after 8 weeks
  • If HgA1C was > 8.5% during trial, another oral medication was added to the rosiglitazone group and the metformin/sulfonylurea group was switched to insulin
Primary outcome: Composite of cardiovascular hospitalization or cardiovascular death
Results

Duration: Average of 5.5 years
Outcome Rosiglitazone Met or SU Comparisons
Primary outcome 14.5% 14.5% HR 0.99, 95%CI [0.85 - 1.16], p=0.93
Overall mortality 6.1% 7% HR 0.86, 95%CI [0.68 - 1.08], p=0.19
Myocardial infarction 2.9% 2.5% HR 1.14, 95%CI [0.80 - 1.63], p=0.47
Cardiovascular death 2.7% 3.1% HR 0.84, 95%CI [0.59 - 1.18], p=0.32
Heart failure 2.7% 1.3% HR 2.10, 95%CI [1.35 - 3.27], p=0.001
Weight change (lbs) +8.7 -1.7 p<0.0001
Taking statin by end of study 55% 46% p<0.05
  • The HgA1C decreased by about 0.27% more in Group 1 than in Group 2 by the end of the study (p<0.0001)

Findings: Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures, mainly in women. Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs.