Low-quality trials behind popular diabetes combo pills in India

None of the five most commonly prescribed diabetes pills in India that combine metformin with other medicines have gone through rigorous testing that meets standards laid out by the World Health Organization, a study suggests.

Metformin has long been considered an initial treatment for diabetes, and in recent years drug makers have increasingly been blending fixed doses of this medicine with fixed doses of other diabetes drugs that attack the disease differently. In India, the five top-selling fixed dose combination pills account for 500 different brands, researchers note in BMJ Global Health.

For the current study, researchers examined data from both published and unpublished clinical trial results for the five top-selling combination pills in India, which account for 80 percent of the market for these blended medicines in that country.

None of the trials provided robust evidence that these pills are safe or effective for treating diabetes, the study found. Just one trial compared giving a fixed dose pill to giving each medicine separately, and it was too small and too low quality to definitively show which option might be safer or better for patients.

“Our concern is that sales of fixed dose combinations are (rising for) diabetes and overtaking sales of metformin,” senior study author Allyson Pollock of Newcastle University in the U.K. said by email.

While all five combination pills in the study have been approved for sale in India, only two have been cleared in the U.S. and just one has been allowed in Australia.

The authors go on to say that India’s Central Drugs Standard Control Organization (CDSCO) should go public on the data it used to approve these drugs, given the ostensible lack of evidence on their safety and effectiveness.

Worldwide, nearly one in 10 adults had diabetes in 2014, and the disease will be the seventh leading cause of death by 2030, according to the World Health Organization.

Most of these people have type 2 diabetes, which is associated with obesity and aging and happens when the body can’t properly use or make enough of the hormone insulin to convert blood sugar into energy. Left untreated, diabetes can lead to nerve damage, amputations, blindness, heart disease and strokes.

More than 60 million people in India have been diagnosed with type 2 diabetes, researchers note.

For the current study, researchers focused on minimum standards set by the WHO more than a decade ago for clinical trials of fixed dose combination pills. Among other things, trials needed to have several hundred to several thousand patients, last at least six months, and test the safety and effectiveness of fixed dose combination pills against individual pills taken separately.

In the current analysis, just two trials had more than 500 participants and only 10 lasted at least six months, for example.

Only one trial was designed to show whether the combination worked better than individual drugs alone, and no study assessed the relative risks and benefits of taking two separate pills instead of a single combination pill.

The lack of high quality clinical trials suggests that these fixed dose combination pills should be banned in India, the study authors conclude.

Patients shouldn’t make any changes without first seeing doctor, said IHPI member Dr. Mark Fendrick, a researcher at the University of Michigan in Ann Arbor.

“The concerning findings of this study - that clinical trials demonstrating safety and efficacy of these fixed dose combinations were neither publicly available or of low quality, suggest that Indian patients taking these combinations should discuss with their clinicians whether it is prudent to switch to a different agent,” Fendrick said by email.

For some patients, fixed-dose pills may make it easier to stick to a drug regimen than taking two separate tablets, and that convenience might make it easier for them to keep diabetes in check, Fendrick said.

“Individuals with type 2 diabetes frequently require multiple medications to control blood sugar, blood pressure and cholesterol,” Fendrick added. “Thus, fixed dose combinations - including those using metformin - have been a mainstay of treatment to simplify medication regimens and improve adherence.”