adverse effects

GI microbiome modulator may improve metformin tolerability

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Combining a gastrointestinal microbiome modulator with metformin may help alleviate intestinal adverse effects commonly related to type 2 diabetes, according to research in the Journal of Diabetes Science and Technology.

The double blind, randomized, crossover study suggests that a gastrointestinal microbiome modulator (GIMM), known to stimulate microbiota that generate short chain fatty acids instead of lactic acid, may help patients with type 2 diabetes better tolerate metformin when the two drugs are taken together. The most common adverse effects related to metformin are diarrhea, heartburn and nausea, followed by abdominal pain, bloating and retching, according to researchers.

“GI side effects prevent many patients from taking metformin and limit dosing in others, and a slow titration schedule is presently the only option to try to reduce metformin-related GI adverse effects,” Mark Heiman, PhD, vice president of research and chief scientific officer at MicroBiome Theraputics, told Endocrine Today. “These issues result in many patients having to turn to more costly anti-diabetic drugs with greater potential safety issues.”

Mark Heiman

Mark Heiman

Jeffrey Burton, PhD, of Pennington Biomedical Research Center in Baton Rouge, Louisiana, Heiman and colleagues from other institutions analyzed data from 10 patients (eight women) aged 29 to 71 years with type 2 diabetes who reported experiencing metformin adverse effects. Participants completed two treatment sequences between June 2013 and June 2014 — one with metformin/GIMM combination; one with metformin and a placebo — lasting 2 weeks each, with a 2-week break between the sequences. Participants were assigned 500 mg metformin along with their assigned GIMM or placebo at breakfast and dinner for the first week, followed by 500 mg metformin (three times a day) with GIMM or a placebo taken with the first and third metformin doses. Researchers used an adapted questionnaire about irritable bowel syndrome to evaluate GI symptoms and measured fasting blood glucose with a glucometer.

Researchers calculated a composite tolerability score using patient ratings of severity of four GI symptoms, which were then combined into a single score for each participant using a weighted sum.

Combining metformin and GIMM resulted in a better tolerance score than metformin combined with a placebo (6.78 vs. 4.45, P = .0006). In addition, mean fasting glucose levels were lower with the metformin/GIMM combination (121.3 mg/dL) than with the metformin/placebo combination (151.9 mg/dL, P < .02).

“Larger trials with a GIMM-metformin combination are needed to replicate and expand these findings,” Heiman said. “These trials might allow the greater use of metformin in type 2 diabetes patients and improve treatment of the disease.”

“The principal limitation for chronic metformin therapy in some patients is presentation of persistent adverse GI symptoms that may cause patients to discontinue metformin use,” the researchers wrote. “The data observed in this pilot clinical trial suggest that a modulator of the GI microbiome could both alleviate metformin-mediated GI symptoms and may improve glucose regulation.” – by Regina Schaffer

Tiagabine add-on for drug-resistant partial epilepsy..

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Epilepsy is a common neurological condition that affects almost 0.5% to 1% of the population. Nearly 30% of people with epilepsy are resistant to currently available drugs. Tiagabine is one of the newer antiepileptic drugs; its effects as an adjunct (add-on) to standard drugs are assessed in this review.

OBJECTIVES: To evaluate the effects of add-on treatment with tiagabine on seizures, adverse effects, cognition and quality of life for people with drug-resistant localisation-related seizures. SEARCH
METHODS: This is an updated version of the original Cochrane review published in 2012 (Issue 5). We searched the Cochrane Epilepsy Group Specialised Register (November 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 10) and MEDLINE (1946 to November 2013). No language restrictions were imposed. We also contacted the manufacturers of tiagabine and experts in the field to seek any ongoing or unpublished studies.
SELECTION CRITERIA: Randomised placebo-controlled add-on trials of people of any age with localisation-related seizures in which an adequate method of concealment of randomisation was used were included. The studies could be double-blind, single-blind or unblinded and of parallel or cross-over design. They had to have a minimum treatment period of eight weeks. Trials using an active drug control group were also included.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Disagreements were resolved by discussion. Outcomes investigated included 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, effects on cognition and quality of life. The primary analyses were performed by intention-to-treat. Worst-case and best-case analyses were calculated for seizure outcomes. Dose response was evaluated in regression models. Risk of bias in each study was assessed by two review authors using the Cochrane `Risk of bias` tool.
MAIN RESULTS: Four parallel-group and two cross-over group trials were included. The overall risk ratio (RR) with 95% confidence intervals (CIs) for a 50% or greater reduction in seizure frequency (tiagabine vs placebo) was 3.16 (95% CI 1.97 to 5.07). Because of differences in response rates among trials, regression models were unable to provide reliable estimates of response to individual doses. The RR for treatment withdrawal was 1.81 (95% CI 1.25 to 2.62). The 99% CIs for the adverse effects of dizziness, fatigue, nervousness and tremor did not include unity, indicating that they are significantly associated with tiagabine. For cognitive and quality of life outcomes, the limited available data suggested no significant effects on cognition and mood and adjustment. Two of the five studies were judged as having low risk of bias, three studies unclear risk of bias and one study high risk of bias. Overall study quality was rated as high using the GRADE approach.
CONCLUSIONS: Tiagabine reduces seizure frequency but is associated with some adverse effects when used as an add-on treatment for people with drug-resistant localisation-related seizures.