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Targeted Drug Treatment for Diabetes Genetic Subset Successful in Small, Early Trial

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NEW YORK (GenomeWeb) — Researchers from Lund University in Sweden have reported the first positive results from a study in which they treated a genetic subset of diabetes patients with a currently available drug that targets the suspected genetic architecture of their disease.

Published today in Science Translational Medicine, the study tested the drug yohimbine, commonly prescribed to treat male impotence, in a small cohort of 50 type 2 diabetes patients recruited on the basis of their ADRA2A genotype.

Patients in the study who were homozygous or heterozygous for a recently discovered ADRA2A risk variant showed a marked change in insulin response after treatment with yohimbine compared to baseline, while those with a wild-type genotype showed no difference between their insulin measurements on and off the drug.

According to the study authors, the ADRA2A variant, at rs553668, has been shown in studies to be associated with over expression of the α2A-adrenergic receptor and results in impaired insulin secretion.

Based on this, the researchers hypothesized that diabetic patients who carry this variant may respond particularly well to treatment with an α2AAR-targeted agent. Fortunately, such a drug already exists in yohimbine, a compound derived from tree bark and approved in the US by prescription only for the treatment of impotence.

Yohimbine has been previously investigated as a diabetes treatment with mixed results, but the Swedish team had hoped the drug would perform better in a genotype-driven trial.

In their study, the Lund University researchers recruited 50 patients in total, of which one left the study after an initial screening visit. Of the remaining 49, 21 were wild-type for the risk allele, 21 were heterozygous, and seven were homozygous carriers.

According to the study's senior author, Anders Rosengren, the prevalence of homozygous carriers of the ADRA2A risk variant in the overall type 2 diabetes population is about 4 percent, making recruitment of a balanced cohort somewhat difficult. A larger number, about 40 percent of type 2 diabetes sufferers, are heterozygous for the marker.

In an email to PGx Reporter, he wrote that the study size, though small, was sufficient to ensure statistical power and typical for a Phase II trial of this type.

In the study, the Lund researchers used a dose-escalation protocol, treating every patient first with a placebo, and then 10 or 20 mg of yohimbine in a randomized double-blind manner, and then testing their oral glucose tolerance at each visit after administering treatment.

The team also measured insulin secretion at 30 minutes during the oral glucose tolerance test, using this as the primary study variable, due to previous evidence that the ADRA2A risk variant is associated with impaired insulin secretion at that time point specifically.

At baseline, the study found that risk allele carriers, either heterozygous or homozygous, had 25 percent lower insulin secretion at 30 minutes compared to wild-type patients.

In the wild-type group, yohimbine treatment had no significant impact on 30-minute insulin secretion, but in risk allele carriers, treatment markedly increased insulin secretion from baseline — about 20 percent after 10 mg and 29 percent after 20 mg — compared to placebo, essentially raising insulin to similar levels as seen in the non-risk allele participants.

Splitting the risk-allele group into heterozygous and homozygous individuals, the researchers found that treatment with 10 mg of yohimbine raised insulin secretion at 30 minutes by 14 percent per risk allele, and 20 mg raised levels by 16 percent per allele: a clear gene-dose relationship, according to the authors.

Rosengren told PGx Reporter in his email that he and his colleagues are now planning to try to modify yohimbine to reduce its side effects. Participants in the trial reported side effects that have been previously well characterized for other uses of the drug, such as anxiety and elevated blood pressure. If they achieve this, they plan to conduct a larger study over a longer time frame.

Rosengren and his coauthors noted in the paper that while the feasibility of genotype-based treatment in a complex polygenic disorder such as diabetes remains a topic of debate, the team's success with the ADRA2A risk variant study serves as a proof of concept that a genetically guided treatment approach is possible in this setting.

Unfortunately, the group's effort with yohimbine represents, in some ways, the best case scenario for such attempts. Most risk markers identified in diabetes, as well as other genetically complex and heterogeneous diseases, have not offered nearly as clear an avenue for targeted treatment, Rosengren added.

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