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Power in numbers: Precision medicine aims to revolutionize diabetes research
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AUSTIN, Texas — Precision medicine that carefully phenotypes and genotypes patients in large clinical trials will give researchers the power to better understand new forms of diabetes, leading to the development of novel therapies targeting diabetes, Judith Fradkin, MD, said during a presentation.
Power from large clinical trials offer clinicians and researchers the chance to look at the gene-environment interaction in type 2 diabetes, and a better understanding of the causes of various health disparities in those with the disease, Fradkin said during the plenary session at the American Association of Clinical Endocrinologists Annual Scientific and Clinical Congress.
“A major barrier to precision medicine is the heterogeneity of type 2 diabetes,” Fradkin, director of the division of diabetes, endocrinology and metabolic diseases for the National Institute for Diabetes Digestive and Kidney Diseases, said. “Type 2 diabetes is really a syndrome rather than a disease, where we see very substantial variation in terms of rates of progression, in terms of the characteristics of people at presentation, in terms of the response to treatment and the development of complications.”
Looking forward, Fradkin said the NIDDK aims to study heterogeneity in diabetes two major ways:
- researchers plan to examine rare and extreme phenotypes
- application of ‘omics’ approaches to large clinical studies
“In both cases, we’re going to try to develop better approaches for deep metabolic phenotyping that will enable us to interrogate these populations,” Fradkin said.
A few precision medicine findings have already emerged from diabetes studies, Fradkin said, offering researchers a roadmap in how to proceed.
DPP study
In the landmark Diabetes Prevention Program (DPP) study, 3,234 participants with overweight and prediabetes were randomly assigned to receive 850 mg metformin twice daily, intensive lifestyle intervention (diet, physical activity and behavior modification) or placebo with a goal of 7% weight loss to prevent or delay progression to type 2 diabetes; 45% of participants were from minority groups.
Subgroup analyses have yielded a variety of findings regarding which interventions work best for which subpopulations, Fradkin said. In every racial and ethnic group, intensive lifestyle intervention worked best, reducing the risk for developing type 2 diabetes by approximately 50%. Metformin was also effective across racial subgroups, reducing diabetes risk by an average of 31%.
“However, when you look at subgroups by age, you see a very different picture,” Fradkin said. “In people who are younger than [age] 45 [years], metformin was essentially as effective as lifestyle. In contrast, when you look at people aged 60 [years] or greater, you see that lifestyle was much more effective; metformin was not much better than placebo and, in fact, in this group, we actually saw a 71% reduction in progression to type 2 diabetes with the lifestyle intervention.”
Intervention success in the DPP also varied according to gestational diabetes status in women, Fradkin said. Metformin was a “highly effective” intervention among women with gestational diabetes, whereas in women without gestational diabetes, the effect of metformin was closer to placebo vs. lifestyle modification, although it did still result in a significant risk reduction for type 2 diabetes.
“These kinds of analyses give you some information on which subsets of your patients with prediabetes might do better with particular approaches to prevention,” Fradkin said.
Today, a phase 3 extension of the DPP continues, Fradkin said. In the DPPOS ongoing outcomes study, patients in the metformin group continue to receive the drug, as do patients in the placebo and lifestyle groups if prescribed by their treating physician.
“We now have the largest randomized exposure to metformin of any study,” Fradkin said. “Over the next 10 years, we’re going to have the power to see other outcomes, like CVD and cancer. So we think we’re going to be able to provide really important information on whether metformin does prevent CVD and cancer, and, with regard to the topic of this discussion, which subgroups might be likely to benefit.”
TODAY study
The TODAY study compared metformin monotherapy with two alternative approaches in 699 children with type 2 diabetes: one strategy combining metformin with rosiglitazone and the other strategy combining metformin with intensive lifestyle intervention. The goal, Fradkin said, was to test the hypothesis that combination therapy initiated early in children with type 2 diabetes would maintain glycemic control better than metformin alone.
“The major factor that emerged from this study was the dismal results in all treatment groups in terms of very rapid progression to glycemic failure, defined in this study as an HbA1c of 8%,” she said. “But, again, when we look by racial and ethnic groups, we did see some variation.”
In black participants, Fradkin said both rosiglitazone plus metformin and lifestyle intervention plus metformin were more effective when compared with those interventions in the entire cohort. In addition, when looking at the cohort and the intention-to-treat analysis, researchers observed that, after an initial run-in period of 2 months of metformin therapy, those who progressed more rapidly had a much higher HbA1c at time of randomization, she said.
“This gives us some information with regard to how aggressive we should be based on what HbA1c level is achieved with metformin therapy,” she said.
GRADE study
The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, to evaluate glycemia-lowering effectiveness and patient-centered outcomes. Researchers will compare the effectiveness of a sulfonylurea (glimepiride), a DPP-IV inhibitor (sitagliptin [Januvia, Merck]), a GLP-1 receptor agonist (liraglutide [Victoza, Novo Nordisk]) and insulin glargine over an average follow-up of 4 years. SGLT2 inhibitors had not received FDA approval at the time of study design.
The study is the first comprehensive comparative effectiveness trial of major treatments. The primary outcome is time to failure (an HbA1c 7%). About 45% of participants are minorities, which will facilitate individual analyses, Fradkin said.
‘Omics’ in clinical studies
In GRADE, researchers are collecting genetic samples and stool samples to better understand predictors of response, or lack or response to a drug, and any molecular pathways that might be involved, Fradkin said. Other studies have also yielded findings through “omics” approaches.
“In DPPOS, we’ve learned quite a bit from ‘omics’ approaches,” Fradkin said. “We’ve seen that branch chain amino acids are a biomarker that can predict rate of progression to type 2 diabetes. People who carries risk genes for type 2 progress more rapidly, but, have similar responses to interventions.”
“Another major aspect of this ‘omics’ approach is something NIDDK is partnering with industry on,” Fradkin said. “We call this the accelerating medicines partnership. It is designed to identify novel, therapeutic targets that could be the basis for drug development. We have created a knowledge portal for type 2 diabetes in which both NIH and the pharmaceutical companies have submitted genotype and phenotype information on well-characterized populations. This information is now available to anybody who wants to analyze it.” – by Regina Schaffer
References:
Fradkin J. Precision Medicine for Diabetes: Where Are We? Presented at: AACE Annual Scientific and Clinical Congress; May 3-7, 2017; Austin, Texas.
Diabetes Prevention Program Research Group. N Engl J Med. 2002;doi:10.1056/NEJMoa012512.
TODAY Study Group. N Engl J Med. 2012;doi:10.1056/NEJMoa1109333.
Disclosure: Fradkin reports no relevant financial disclosures.