Monday, February 20, 2012

European Medicines Agency Scientific Studies on Pioglitazone

The European Medicines Agency released a scientific study on the benefits and risks of the drug pioglitazone, also known as Actos, in January of 2007. This drug is currently used as a single treatment for Type 2 diabetes or in a dual combination form with metformin or sulphonylurea. When used alone, pioglitazone is typically used as therapy for the overweight patient whose Type 2 diabetes is not being controlled through diet and exercise and for whom the drug metformin is inappropriate. The combination drug is most often used in those patients who have insufficient glycemic control despite taking metformin alone or for those patients who have shown a level of intolerance to metformin. The results of the study showed that when pioglitazone was prescribed in conjunction with other anti-diabetic therapies such as insulin, the risk of macrovascular disease was greatly reduced. Macrovascular disease is common in those with long-term diabetes and refers to a disease of the large blood vessels in the body.

Clinical Support for Pioglitazone Application
Evidence was submitted which supported the application of pioglitazone, including four clinical trial reports which studied the safety of the drug when used in conjunction with insulin therapy. The studies were conducted according to prevailing ethical standards, and were random, double-blind, placebo controlled.

First Pioglitazone Study—PNFP-014
Pioglitazone was administered both in 15 mg dosages as well as 30 mg dosages in combination with insulin then compared with using insulin therapy alone. Participants in the studies were between the ages of 30 and 75, and had been on a fixed dose of insulin for at least a month prior to beginning the study. The mean baseline age was 57 years, with an average BMI of 33.6. Nearly 3/4ths of the participants in the study were Caucasian, with slightly more than half being female. Although the baseline systolic blood pressure was minimally higher in the group receiving pioglitazone plus insulin as opposed to the group receiving insulin alone, there were no other baseline variables involved. The patients who received both pioglitazone and insulin showed statistical decreases in the HbA1c levels which measure the average amount of sugar in the blood over a period of three months, and is different from glucose measurements. The HbA1c levels essentially give the physician an indication of how well the diabetes is being controlled.

Second Pioglitazone Study—PNFP-343
The second study compared doses of pioglitazone using 30 mg and 45 mg and was tested on subjects whose Type 2 diabetes was poorly controlled with insulin therapy alone. Participants were at least 18 years old, and had HbA1c values greater than 8%--any value over 6% indicates diabetes which is poorly controlled. The variables in this study were the HbA1c levels and the serum lipids which included total cholesterol, triglycerides, HDL, LDL and VLDL cholesterol and free fatty acids. The mean age was 56.5 and the mean BMI was 33.19, with 63% of the participants being Caucasian, and slightly more than half being male. The mean insulin dose was 69.2 units per day, and over one-fourth of the people in the study stated they also used other forms of anti-diabetic therapies in addition to insulin. The results of the study showed significant reduction in the use of insulin among the groups receiving both strengths of the drug, although there was a greater reduction in those using the 45 mg. tablets.

Third Pioglitazone Study—GLAT
The third study tested the safety and efficiency of the 30 mg. tablet of pioglitazone plus insulin as compared to insulin alone. The participants ranged in age from 30-70 years old who had HbA1c levels higher than 7.5% and were had taking insulin therapy for at least three months. The duration of this study was up to one year, and the variables included baseline HbA1c, Fasting serum levels, fasting serum lipids, FFA levels, urinary albumin/creatinine ratios, c-reactive protein levels, insulin dosage and rate of hypoglycemia. The mean age of the participants was 58.9 years, with a mean BMI of 32.1. The vast majority—96.4% were Caucasian, and the mean duration of the diabetes was 13.5 years. The HbA1c levels averaged 8.8%, which suggested the study population had very poorly controlled diabetes overall. After six months in the trial, those taking the pioglitazone had reduced their HbA1c levels by an average of .69%, while the placebo group had only reached an average of .14 %. The group taking pioglitazone was also able to reduce their insulin use by an average of 11.4 units per day.

Fourth Pioglitazone Study—PROactive
This study was aimed at those with Type 2 diabetes as well as pre-existing macrovascular disease. The participants were between the ages of 35 and 75, with a mean age of 62 years. Over 2/3 of the participants were male, and were required to have one or more of the six qualifying criteria to take part in the study. These qualifiers included a) myocardial infarction, b) stroke, c) percutaneous coronary intervention or coronary artery bypass graft, d) acute coronary syndrome, e) evidence of coronary artery disease or f) peripheral arterial disease. Almost twenty percent of the participants had suffered a stroke, and nearly half of them fulfilled two or more of the qualifying criteria.

The patients either received pioglitazone or a placebo along with their existing diabetes therapies which included diet, exercise, insulin, anti-hypertensives, drugs to lower cholesterol or anti-thrombotic agents over a period of 2.5 to 4 years. All patients who were receiving pioglitazone began at a dosage of 15 mg, increased their dosage at month 2 to 30 mg and to 45 mg at the start of month 3. The primary outcome of this study was to determine whether pioglitazone offered any benefit in reducing total mortality or macrovascular morbidity in high-risk patients with Type 2 diabetes. Other outcomes which were also of interest included the time to the first occurrence of cardiovascular death, non-fatal MI, the treatment differences according to prior stroke history, or the time to the first occurrence of a stroke. The patients in the study were also analyzed according to number of hospitalizations, total number of days in the hospital, lipid serum control, time to beginning permanent insulin use, use of hypertensive medications, and glycemic controls.

Criteria for Inclusion in the PROactive Study
Participants in the study were between the age of 35 and 75, had at least one of the additional qualifying criteria other than Type 2 diabetes and objective evidence of coronary artery disease based on medical testing or a positive exercise test. Over 99% of the participants were Caucasian, the average length of the diabetes was 9.5 years, and had a BMI of 30.9. Over 95% of the study participants had a history of cardiovascular disease and 59% were current or past smokers.

Results of PROactive Study
The results of the PROactive study showed a 10% risk reduction in the different qualifying criteria areas in those taking pioglitazone. Fewer endpoint diseases such as non-fatal MI, stroke and ACS were observed among those taking pioglitazone, and the only event occurring more frequently in those taking pioglitazone was leg revascularization. Those patients who had suffered prior MI or stroke showed a benefit when taking pioglitazone in the incidence of cardiovascular death. The group taking pioglitazone also showed fewer hospitalizations than the placebo group. While the levels of insulin therapy increased significantly for the placebo group, those taking pioglitazone saw only a very slight increase. Pioglitazone also significantly reduced triglycerides and increased HDL while decreasing levels of LDL.

Adverse Effects Among Participants Taking Pioglitazone—All Four Studies Included
While the combination of pioglitazone and insulin appeared to be well tolerated, there were some side effects including edema or water retention and an increase in weight. The GLAT study showed an increase in hypoglycemia (32.4% as compared to 21.8% among the placebo group), however this was not considered to be medically significant as hypoglycemia can be treated and is not fatal. Few deaths occurred in the first three studies, and none were considered to be a direct result of pioglitazone. In the PROactive study, a total of 77 patients in the pioglitazone group died, while 79 patients in the placebo group died with no apparent tie to the drug. There was no apparent increase in liver toxicity when pioglitazone was added to insulin as well as no negative effects on renal function regarding the first three studies. In the PROactive study, there were also no negative effects on liver or renal functions.

Marketing Authorization for Pioglitazone
The Marketing Authorization for the drug pioglitazone was granted with a defined use in the treatment of Type 2 diabetes, although there were certain contraindications included for those also taking insulin. The safety profile which resulted from the studies raises no new concerns about pioglitazone, and the primary adverse effects appeared to be weight gain and edema. Since insulin is also known to cause these same side effects, it was unclear whether they relate directly to pioglitazone. The final recommendations for the drug pioglitazone included the fact that it should be a second-line option as compared to metformin and insulin, that it should exclude those patients with heart failure, that treatment should start at the lowest dose and increase gradually, that patients taking the drug should be monitored regularly and that further studies should take place regarding metformin plus insulin vs. pioglitazone plus insulin prior to approval of wider use.

Author: Sullo & Sullo Attorneys

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