pioglitazone

People with type 2 diabetes who took the drug pioglitazone were less likely to develop dementia later in life.

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Source: AAN

People with diabetes are twice as likely to develop dementia as those without the disease. In a new study, people with newly diagnosed type 2 diabetes who took the diabetes drug pioglitazone were less likely to later develop dementia than those who did not take the drug.

The study is published in the February 15, 2023, online issue of Neurology.

The results were strongest among people who also had a history of stroke or ischemic heart disease, a condition caused by narrowed arteries in the heart. The study does not prove that the drug reduces the risk of dementia for people with diabetes. It only shows an association.

“Since dementia develops for years before diagnosis, there may be an opportunity for intervening before it progresses,” said study author Eosu Kim, MD, Ph.D., of Yonsei University in Seoul, Republic of Korea.

“These results may suggest that we could use a personalized approach to preventing dementia in people with diabetes in the case that they have a history of ischemic heart disease or stroke.”

For the study, researchers looked at the national Korean health database for people newly diagnosed with type 2 diabetes who did not have dementia. They were followed for an average of 10 years. Of the 91,218 participants, 3,467 received the drug pioglitazone.

During the study, 8.3% of the people taking pioglitazone developed dementia, compared to 10.0% of those who were not taking the drug. After researchers accounted for other factors that could affect dementia risk, such as high blood pressure, smoking and physical activity, they found that people taking pioglitazone were 16% less likely to develop the disease than those who did not take it. The benefit was stronger among people who had a history of ischemic heart disease or stroke, with reduced risks of 54% and 43%.

The reduced risk also increased as people used the drug for longer periods. People who took the drug for four years were 37% less likely to develop dementia than those who did not take the drug, while those who took it for one to two years were 22% less likely.

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The results were strongest among people who also had a history of stroke or ischemic heart disease, a condition caused by narrowed arteries in the heart.

People taking the drug were also less likely to have a stroke during the study.

Kim noted that side effects of pioglitazone include swelling, weight gain, bone loss and congestive heart failure, and more research is needed on the long-term safety of the drug and whether there is an optimal dose that could minimize side effects while maintaining the benefits.

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Kim said.

“In some previous studies of people with dementia or at risk of cognitive decline who did not have diabetes, pioglitazone did not show any protection against dementia, so it’s likely that a critical factor affecting the effectiveness is the presence of diabetes. More research is needed to confirm these findings.”

A limitation of the study was information on drugs was based on insurance claims, so it’s possible that some people did not take the drugs as prescribed.

Similar efficacy, lower adverse event risk with lower doses of pioglitazone

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Both 15 mg and 30 mg pioglitazone doses have similar efficacy as 45 mg for preventing new-onset diabetes, stroke and myocardial infarction but with lower risk for adverse events, according to study findings.

In post hoc analysis of data from the Insulin Resistance Intervention after Stroke (IRIS) trial published in Diabetes, Obesity and Metabolism, participants taking less than 45 mg pioglitazone had lower risks for edema, weight gain and heart failure than those taking 45 mg, showing the agent may be better utilized at lower doses.

J. David Spence, CM, MD, FRCPC, FAHA
Spence is a professor of neurology and clinical pharmacology at Western University, and director of the Stroke Prevention Atherosclerosis Research Centre at the Robarts Research Institute in London, Ontario, Canada.

“Pioglitazone is the most potent therapy for insulin resistance, but it is underutilized, largely because of adverse effects from the 45 mg dose: leg swelling in 20% and weight gain in 10% of patients,” J. David Spence, CM, MD, FRCPC, FAHA, professor of neurology and clinical pharmacology at Western University, and director of the Stroke Prevention Atherosclerosis Research Centre at the Robarts Research Institute in London, Ontario, Canada, told Healio. “In this study we analyzed outcomes comparing lower doses — combining those who took 15 mg or 30 mg per day — with those taking 45 mg per day. We found that lower doses provided most of the benefit, with no significant increase in leg swelling and weight gain compared to placebo, and less than the 45 mg dose. This means that pioglitazone can be used more widely, as most patients will tolerate the lower doses.”

Spence and colleagues analyzed data from IRIS, a randomized, double-blind trial in which researchers compared the efficacy of pioglitazone for preventing new-onset type 2 diabetes, MI or stroke with placebo. Participants randomly assigned pioglitazone started with one 15 mg tablet daily, increased to 30 mg daily at 4 weeks and increased again to 45 mg at 8 weeks. Participants with adverse effects were down titrated to a better tolerated dose. In the ad hoc analysis, participants were categorized based on the most frequent dose taken for each participant from pioglitazone initiation to the end of follow-up. Researchers examined pioglitazone efficacy and adverse outcomes in participants in each dosing group.

Paresh Dandona

“The IRIS study demonstrated that pioglitazone not only reduced the cardiovascular complications, but also reduced the progression of prediabetes to diabetes,” Paresh Dandona, MD, PhD, SUNY distinguished professor and chief of endocrinology in the department of medicine at the University of Buffalo and an Endocrine Today Editorial Board Member, told Healio. “Since most of the patients in the study were treated with the high dose of 45 mg daily, which has a frequent side effects of weight gain and edema, it was important to reanalyze the data to focus on the effects of the two lower doses of the drug.”

Efficacy maintained with lower dose

Of 1,938 participants receiving pioglitazone in IRIS, 28.2% most frequently received less than 15 mg per day, 6.6% received 15 mg, 4.6% received 30 mg and 60.6% received 45 mg. Participants receiving 15 mg or 30 mg per day had a lower HR for MI or stroke compared with placebo (adjusted HR = 0.48; 95% CI, 0.3-0.76; P = .002) than the group receiving 45 mg per day (aHR = 0.74; 95%, 0.59-0.94; P = .01). Compared with placebo, the 15 mg and 30 mg group (aHR = 0.34; 95% CI, 0.15-0.81; P = .01) and the 45 mg group (aHR = 0.31; 95% CI, 0.21-0.46; P < .0001) had similar reduced risks for new-onset diabetes.

Fewer adverse events with lower dose

In an analysis of adverse events, the 15 mg or 30 mg dose group did not have a significantly increased risk for edema, weight gain or heart failure compared with placebo. By contrast, those receiving a 45 mg dose had an increased risk for edema (aHR = 1.81; 95% CI, 1.43-2.3; P < .0001), weight gain (aHR = 2.16; 95% CI, 1.93-2.42; P < .0001) and heart failure (aHR = 1.71; 95% CI, 1.03-2.86; P = .04) compared with placebo.

“While the two lower doses provide CV protection similar to that of the higher dose, the side effects of edema and weight gain are significantly lower,” Dandona said. “This differential between the doses is important since the use of pioglitazone has been hampered by these side effects. I have used the dose of 15 mg daily over the past decade and a half with excellent results in terms of glycemic control without the side effects of weight gain and edema.”

In addition to significant improvements in both glucose level and CV complications for people with diabetes, Dandona said, pioglitazone could give patients a more affordable treatment option.

“Pioglitazone is a generic drug now, it is inexpensive,” Dandona said. “This is relevant in the context of the astronomical prices of insulin. Hence, pioglitazone must be used prior to insulin, especially since subcutaneously injected insulin has no protective effect on cardiovascular complications.”

Spence said the findings reveal a need for a randomized trial examining the effects of lower doses of pioglitazone. He also said more research is needed to explore ways to reduce fractures in people using pioglitazone.

“In our study, fractures were increased on all doses; most occurred in older women,” Spence said. “The number needed to harm, to cause one serious fracture, was 125 vs. a number needed to treat of only 12 to prevent one case of new-onset diabetes and 24 to prevent one stroke or MI. Probably pioglitazone should be avoided in older women with osteoporosis — the group in which most fractures occurred. It would be important to test in human subjects the observation that, in a rat model, fenofibrate prevented bone loss from pioglitazone.”

FDA announces preliminary safety review of pioglitazone

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The FDA is evaluating preliminary results from a long-term, observational study suggesting patients assigned pioglitazone may be at increased risk for bladder cancer. As of press time, the FDA’s review is ongoing and they have not confirmed an association between pioglitazone and bladder cancer risk.

According to the FDA, the preliminary data are based on 5-year results from an ongoing, 10-year study conducted by Takeda Pharmaceuticals. Although preliminary findings indicated no association between exposure to pioglitazone (Actos, Takeda) and risk for bladder cancer, there was an increased risk among patients with the longest duration of exposure to the drug as well as in those assigned the highest cumulative dosage.

Pioglitazone is prescribed to control blood glucose in patients with type 2 diabetes. The only other drug in this class is rosiglitazone (Avandia, GSK). FDA officials have no clinical data suggesting an association between rosiglitazone and bladder cancer. However, following an FDA advisory committee meeting back in July, officials recommended restrictions be placed on the use of rosiglitazone in addition to revised labeling that includes additional warnings about cardiovascular safety.

The FDA recommends for patients to discuss any concerns with their health care professional. Patients should not stop taking pioglitazone unless told to do so by their health care professional.

Bladder cancer risk not increased with pioglitazone therapy

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Through an analysis of nearly 200,000 patients, no statistically significant increased risk for bladder cancer was found with the use of Actos, according to recent study findings published in JAMA.

Assiamira Ferrara, MD, PhD, of Kaiser Permanente Northern California, and colleagues conducted a bladder cancer cohort analysis of 193,099 people aged 40 years or older in 1997 to 2002 until December 2012; evaluated 464 case patients and 464 matched controls for additional confounders; and performed a cohort analysis for 10 additional cancers on 236,507 people aged 40 years or older in 1997 to 2005 until June 2012. All participants were members of Kaiser Permanente Northern California.

Assiamira Ferrera

Assiamira Ferrara

The additional cancers included prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin’s lymphoma, pancreas, kidney/renal pelvis, rectum and melanoma.

Among the bladder cancer cohort, 34,181 participants received Actos (pioglitazone, Takeda) during follow-up. Overall, 0.65% of participants were diagnosed with bladder cancer. No significant association was found between ever use of pioglitazone and bladder cancer (HR = 1.06; 95% CI, 0.89-1.26).

Through the case-control analysis, researchers found similar rates of bladder cancer between ever use (19.6%) and nonusers (17.5%).

In the study analyzing additional cancers, 16% of participants had received pioglitazone by the end of follow-up. The researchers found no association between most of the cancers and pioglitazone use; however, there was an increased risk for prostate cancer (HR = 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR = 1.41; 95% CI, 1.16-1.71).

“There was no statistically significant increased risk of bladder cancer associated with pioglitazone use,” the researchers wrote. “However, a small increased risk, as previously observed, could not be excluded. The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether the observed associations are causal or due to change, residual confounding, or reverse causality.”

In an accompanying editorial, Joshua M. Sharfstein, MD, of Johns Hopkins Bloomberg School of Public Health, andAaron S. Kesselheim, MD, JD, MPH, of Brigham and Women’s Hospital, wrote that the results “shed new light on the safety of pioglitazone reflecting the dynamic nature of many drug safety questions.

“As in this case, caution and further review are the appropriate responses to many safety signals,” they wrote. “But when emerging available data — clinical, laboratory, observational and even population-based studies — create a compelling picture of risk in excess of potential benefit to patients, the FDA should act to protect the public.”

In another editorial, Phil B. Fontanarosa, MD, MBA, executive deputy editor of JAMA, and colleagues wrote that medical journals have a responsibility to review studies evaluating the potential relationship between drugs, devices or vaccines and adverse outcomes.

“Even though no observational study examining the relationship between an exposure and an outcome can definitively establish ‘positive’ cause-and-effect results, and no observational study can definitively prove ‘negative’ results, each study adds to the totality of evidence regarding the safety of drugs, devices and vaccines,” they wrote. “By publishing the results of these studies, JAMA will continue to provide information physicians can use in discussions with patients and regulatory bodies can use in policy decisions about the benefits and risks of various therapies.”

Pioglitazone, rosiglitazone did not increase bladder cancer risk in patients with type 2 diabetes

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The cumulative use of pioglitazone or rosiglitazone to treat type 2 diabetes was not associated with bladder cancer in a pooled analysis of six populations, according to research published in Diabetologia

“These data challenge the idea that pioglitazone causes bladder cancer,”Helen Colhoun, MD, of the University of Dundee, United Kingdom, toldEndocrine Today. “We find no evidence of such an effect, at least in the time span of the study we have conducted, which was longer than many previously published.”

Helen Colhoun

Helen Colhoun

Colhoun, with Daniel Levin, MD, also of the University of Dundee, and colleagues examined drug effects on bladder cancer risk using data from British Columbia, Finland, Manchester, Rotterdam, Scotland and UK Clinical Practice Research Datalink.

The investigators gathered prescription, cancer and mortality data from patients with type 2 diabetes. Data collected from six centers included 1.01 million patients during 5.9 million person-years; the mean age of the patients at entry into the centers was 60 to 64 years.

To model the effect of cumulative exposure on cancer incidence, a discrete time failure analysis was applied separately to data from each center with Poisson regression; time-dependent adjustments were made for ever use of pioglitazone; results were pooled using fixed and random effects meta-regression.

During a median follow-up of 4 to 7.4 years, there were 3,248 cases of incident bladder cancer, with 117 exposed cases.

No evidence was demonstrated for any association between cumulative exposure to pioglitazone and bladder cancer in men (RR per 100 days of cumulative exposure=1.01; 95% CI, 0.97-1.06) or women (RR=1.04; 95% CI, 0.97-1.11) with adjustments for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone.

Further, no association seen between rosiglitazone and bladder cancer in men (RR=1.01; 95% CI, 0.98-1.03) or women (RR=1; 95% CI, 0.94-1.07).

“The decision to use any drug needs to weigh the risks and benefits associated with that drug,” Colhoun said. “We do not find evidence of bladder cancer being a concern with pioglitazone, but the decision to use the drug should be taken in the context of other known side effects, including fracture risk.”

Calhoun underscored that these data should provide reassurance for patients who have already used the drug and were worried by previous reports about bladder cancer.

The strengths of this particular research, according to investigators, were that “most observational pharmacoepidemiological studies are limited by allocation bias” and that they also “considered exposure to other glucose-lowering drugs in the models.”

Limitations to the study included short-term follow-up duration and absence of data on ethnicities other than white Europeans, BMI and smoking, the researchers conceded.

“Longer-term studies observational of real world exposure to diabetes drugs remain important, not just for this class of drugs, but other diabetes drugs too,” Colhoun said. “Such studies need to be careful to use methods that minimize biases.” – by Allegra Tiver

Pioglitazone and bladder cancer risk: Examining the evidence

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In 2011, accumulating evidence on a possible link between pioglitazone and bladder cancer led to an FDA warning.

Around the same time, several European countries withdrew pioglitazone (Actos, Takeda Pharmaceuticals) from the market. The US package insert now states that data suggest an increased risk for bladder cancer in pioglitazone users. Data also suggest that the risk increases with duration of use. Other warnings state: Do not use pioglitazone in patients with active bladder cancer; use caution when using in patients with a prior history of bladder cancer; and tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency, as these may be due to bladder cancer.

Concern about bladder cancer from pioglitazone first appeared in the PROactive study. In this study, bladder cancer developed more frequently in the pioglitazone group as compared with placebo (11 vs. six cases; P=.069). Eleven of the 20 patients developed bladder cancer within 1 year of beginning the study. After excluding these patients and those with known risk factors, researchers determined that pioglitazone did not increase the risk for bladder cancer.

Taylor_James
James R. Taylor

A retrospective study of US pharmacy claims by Oliveria and colleagues did not find any association between thiazolidinediones and colorectal, liver, bladder or pancreas cancers. The estimated RR for bladder cancer in this study was 1.05 (95% CI, 0.71-1.54). However, there were several limitations of the study because it was retrospective, could not discriminate between different thiazolidinediones, the number of documented bladder cancer cases was relatively small and other risk factors were unaccounted for.

A review of the FDA Adverse Event Reporting System (AERS) showed a high risk for bladder cancer in pioglitazone users (OR=4.3; 95% CI, 2.82-6.52). However, because there are potential biases associated with reporting, these data can be misleading.

Kaiser Permanente Northern California is conducting an observational study on pioglitazone and bladder cancer rates. An interim analysis showed an increased risk for bladder cancer with pioglitazone, with an HR of 1.2 (95% CI, 0.9-1.5). However, when looking at only those receiving pioglitazone for more than 24 months, the risk was increased by 40% with pioglitazone use (HR=1.4; 95% CI, 1.03-2.0). Concern over the time-dependent use design of this and the Oliveria study has been raised, as this may introduce a bias and thus make the results unreliable.

A study by Tseng and colleagues, published in Diabetes Care, reviewed insurance database information in Taiwan and found no significant increase in bladder cancer associated with the use of pioglitazone. There were, however, a relatively small number of cases.

Tseng also discussed some other confounding issues that must be considered. For example, diabetes itself may increase the risk for cancer. Also, pioglitazone is often used as a second- or third-line agent, and thus, the patient has likely had diabetes for a longer time, continues to have hypoglycemia and has been on other medications, all of which may increase the risk for bladder cancer.

Given the information to date, it is difficult to determine whether there is an association between pioglitazone use and bladder cancer. If such an association exists, further clarification on factors such as duration of use, ethnicity and concomitant bladder cancer risk factors must be clarified. Of course, when taking this information into consideration before prescribing pioglitazone, one should also consider the potential benefits of this agent such as reduced cardiovascular disease and improved glucose and lipids. Until better data are available, the FDA’s current precaution seems appropriate.

Pioglitazone may improve NASH, halt disease progression in type 2 diabetes

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Adults with type 2 diabetes randomly assigned Actos therapy were more likely to experience a reduction in nonalcoholic steatohepatitis activity vs. those assigned a placebo, according to study findings published in Annals of Internal Medicine.

In a single-center, parallel-group study, Kenneth Cusi, MD, FACP, FACE,chief of the division of endocrinology, diabetes and metabolism at the University of Florida in Gainesville and Endocrine Today Editorial Board member, and colleagues analyzed data from 101 patients with prediabetes or type 2 diabetes (confirmed via oral glucose tolerance test) and histologically confirmed nonalcoholic steatohepatitis activity (NASH). After baseline measurements (OGTT, euglycemic insulin clamp, DXA scan and liver biopsy), researchers assigned patients to a 500-kcal deficit diet and then randomly assigned them to 30 mg daily Actos (pioglitazone, Takeda Pharmaceuticals), titrated at 2 months to 45 mg daily (n = 50; mean age, 52 years; 72% men; 28% white; 48% with type 2 diabetes), or placebo (n = 51; mean age, 49 years; 69% men; 22% white; 55% with type 2 diabetes) for 18 months. At 18 months, patients again underwent metabolic measurements and a liver biopsy; those on pioglitazone were asked to continue therapy for another 18 months while participants in the placebo group whose NASH resolved were asked to discontinue use; those with persistent disease were invited to initiate pioglitazone therapy for 18 months.

Kenneth Cusi

Kenneth Cusi

The primary outcome was a reduction of at least two points in the nonalcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis at 18 months.

Within the cohort, 18 patients (nine in each group) withdrew from the study before 18 months after being informed in 2011 about a potential risk for bladder cancer with pioglitazone. An additional four patients in each group withdrew during the open-label phase (months 18 to 36) for similar reasons.

Researchers found that more patients assigned to pioglitazone achieved the primary outcome vs. those assigned placebo (58% vs. 17%; P < .001); more patients in the pioglitazone group also had resolution of NASH vs. placebo (51% vs. 19%; P < .001). Pioglitazone therapy also was associated with improvement in individual histologic scores, including fibrosis score, with progression of any fibrosis during 18 months occurring in 12% of pioglitazone patients vs. 28% of placebo patients (P = .039).

Pioglitazone also reduced hepatic triglyceride content from 19% to 7% vs. 15% to 11% in the placebo group, and improved adipose tissue, hepatic and muscle insulin sensitivity (P < .001 for all). All 18-month metabolic and histologic improvements persisted during 36 months of therapy.

There were no between-group differences for adverse events; weight gain was greater with pioglitazone (2.5 kg).

“This histologic benefit, combined with improvement in the mean fibrosis score, suggests that pioglitazone may alter the natural history of the disease,” the researchers wrote. “Evidence of this was the reduction in fibrosis progression over 18 months in patients treated with pioglitazone compared with those receiving placebo.”

The study results are likely to change management of patients with type 2 diabetes and fatty liver, Cusi told Endocrine Today. Pioglitazone, he said, could potentially become for NASH what metformin is to the treatment of type 2 diabetes.

“Until this study, we lacked definitive long-term treatment evidence of safety and benefit for such patients,” Cusi said in an interview. “This study shows now that if you have type 2 diabetes, or even prediabetes, and you take pioglitazone, more than half [of patients] have resolution of NASH. What this means is that endocrinologists will have to think about whether the patient has a fatty liver or not as they consider their second-line therapy after metformin.

“This really is a big game changer,” Cusi said. “NASH may lead to end-stage liver disease, and is currently the second cause of liver transplantation in the United States. We have a drug that may change the natural history of liver disease, prevent the onset of type 2 diabetes as shown in ACT NOW, and ameliorate the risk for coronary artery disease or that of stroke, as recently shown by Kernan et al this year in the New England Journal of Medicine. The cost of pioglitazone will decrease over time, as it currently has a generic formulation, and its safety profile has been tested for over 15 years with issues such as bladder cancer having been cleared from the study published by Lewis et al in JAMA last year. Now endocrinologists will think about and diagnose NASH more often in daily practice, having a safe and effective treatment option at hand.– by Regina Schaffer

Combination methotrexate, pioglitazone therapy offers no added quality-of-life benefits

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In patients with chronic plaque-type psoriasis, pioglitazone therapy taken with methotrexate caused greater reductions in psoriasis area and severity index scores than methotrexate alone but did not significantly improve quality of life, according to study findings.

For the controlled, assessor-blinded, parallel-group study, patients with plaque-type psoriasis were randomly assigned to treatment with methotrexate only (group A) or methotrexate plus 30 mg/daily of oral pioglitazone (group B).Methotrexate (MTX) dosage commenced at 7.5 mg weekly and was adjusted, if necessary, for body mass index.

At week 16, the difference in reduction of mean psoriasis area and severity index (PASI) scores between the groups was statistically significant, according to the researchers, with group B at a 70.3% reduction and group A at a 60.2% reduction.

Fourteen patients in group B achieved PASI 75 by week 16 compared with only two in group A, which was also considered statistically significant.

At week 16, complete clearance of the disease (PASI 100) was achieved by four patients in group B compared with one patient from group A.

Differences between the groups in terms of dermatology life quality index were not significant, however, according to the researchers. In group B, a 63.6% decrease was seen at week 16, and a 56.9% decrease was seen for group A.

Pioglitazone benefits decrease after discontinuing therapy

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The protective effect of pioglitazone on type 2 diabetes prevention observed in adults with impaired glucose tolerance diminishes in the months after discontinuing therapy, with participants randomly assigned the drug progressing to diabetes at a rate similar to those assigned placebo, according to an analysis of the ACT NOW study.

However, researchers also found that the cumulative incidence of diabetes from randomization to end of follow-up remained lower in the pioglitazone group, and more participants in the pioglitazone group reverted to normal glucose tolerance.

“These findings demonstrate that following discontinuation of pioglitazone, disease progression in high-risk IGT individuals can be slowed, although ultimately, the rate of development of diabetes in the pioglitazone-treated group becomes similar to that in the placebo-treated group,” Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at University of Texas Health Science Center, and colleagues wrote.

Researchers analyzed data from 290 adults with IGT at baseline participating in the Actos Now for the Prevention of Diabetes (ACT NOW) study, a randomized, double blind, placebo-controlled trial designed to determine whether pioglitazone therapy (n = 152; 74 men; mean age, 54 years) can prevent or delay progression to diabetes vs. placebo (n = 138; 59 men; mean age, 52 years). Researchers followed the cohort for a mean of 11.4 months after study medication was discontinued and measured incidence of diabetes and IGT.

In both the pioglitazone and placebo groups, 17 participants each developed diabetes during follow-up; however, the cumulative incidence of diabetes from randomization to the end of follow-up remained lower in the pioglitazone group (10.7%) vs. placebo (22.3%; HR = 0.436; 95% CI, 0.285-0.668).

At the end of follow-up, 35 participants in the pioglitazone group remained at normal glucose tolerance (23%) vs. 19 in the placebo group (13.8%; P = .04); cumulative incidence of normal glucose tolerance (at least once during follow-up) was higher in the pioglitazone group vs. placebo (P < .05).

Participants with IGT who progressed to type 2 diabetes during follow-up had a significantly lower insulin secretion/insulin sensitivity index vs. participants who remained at either IGT or normal glucose tolerance. The decline in beta-cell function (IS/IR index) was similar in IGT participants who developed diabetes in both groups, according to researchers.

“In the ACT NOW study, pioglitazone decreased the conversion of IGT (prediabetes) to diabetes by an impressive 72%,” DeFronzo told Endocrine Today. “Not surprisingly, since diabetes has a strong genetic etiology and one cannot choose their parents again, the beneficial effects of pioglitazone on insulin sensitivity and beta-cell function gradually waned over the 12 months following cessation of therapy, and, at the end of 1 year off medications, individuals with IGT were converting to diabetes at the same rate as the placebo-treated group. The good news is that low-dose pioglitazone, which has few side effects, works to prevent the development of diabetes and in the PROactive and IRIS studies was shown to lower risk for [myocardial infarction] and nonfatal stroke. Since pioglitazone has gone generic, it also has become affordable by most patients with type 2 diabetes.” – by Regina Schaffer

Pioglitazone reduces diabetes risk in nondiabetic, insulin resistant patients

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Pioglitazone reduces the risk of diabetes in nondiabetic, insulin resistant individuals with cerebrovascular disease particularly those with prediabetes, according to a study presented at the 76thScientific Sessions of the American Diabetes Association held in New Orleans, Louisiana, US.

The Insulin Resistance Intervention after Stroke (IRIS) trial recently demonstrated a lower risk of stroke, myocardial infarction, and progression to diabetes among nondiabetic, insulin resistant patients who were on the thiazolidinedione drug pioglitazone compared to those on placebo (hazard ratio [HR] 0.76, 95 percent confidence interval [CI], 0.62-0.93; p=0.007). [N Engl J Med 2016;374:1321-1331]

Using the IRIS data, researchers performed a secondary analysis to identify the effect of pioglitazone on diabetes prevention in nondiabetic, insulin resistant patients with a recent stroke.

By 4.8 years follow-up, 3.8 percent of patients in the pioglitazone group (n=73) and 7.7 percent of patients in the placebo group (n=149) developed diabetes (HR, 0.48, 95 percent CI, 0.33-0.69; p<0.0001). [ADA 2016, abstract 380-OR]

The greatest absolute risk reduction (ARR) occurred in patients with a fasting plasma glucose ≥100 mg/dl vs <100 mg/dl (ARR 8.5 vs 0.8 percent), HbA1c ≥5.7 percent vs <5.7 percent (ARR 5.6 vs 1 percent), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) ≥4.6 percent vs <4.6 percent (ARR 6.3 vs 1.4 percent).

“In almost 4,000 nondiabetic patients with stroke or transient ischaemic attack and insulin resistance [not diabetes], pioglitazone reduced the risk of their developing type 2 diabetes by 52 percent, and this was driven mainly by patients who had the most deranged metabolism ie, prediabetes, highest HOMA-IR levels, as well as metabolic syndrome,” said study author Professor Silvio Inzucchi from the Yale School of Medicine, New Haven, Connecticut, US who presented the results.

While the adverse event profile was consistent with previous studies, Inzucchi attributed the lack of increased risk of heart failure to the exclusion of patients with heart failure as well as decrease of study drug dose in patients who developed oedema or weight gain.

“Pioglitazone is now the only oral glucose lowering drug to reduce atherosclerotic events. Pioglitazone is the only glucose lowering drug to prevent diabetes as well as improve cardiovascular outcomes in the same trial,” said Inzucchi, who cautioned that these two findings may not necessarily be linked.

Participants in the IRIS trial were 3,876 nondiabetic patients with no prior history of diabetes, fasting plasma glucose <126 mg/dl, and insulin resistance determined by HOMA-IR >3.0, who had a recent ischaemic stroke or transient ischaemic attack. The participants were randomly assigned to pioglitazone 45 mg QD (n=1,939) or placebo (n=1,937). Mean baseline readings were 98.2 mg/dl (fasting plasma glucose), 5.8 percent (HbA1c), 22.4 uIU/ml (insulin), and 5.4 (HOMA-IR).