In Focus
Moving towards a more precise treatment of diabetes Current treatments for type 2 diabetes exhibit large variation in efficacy and some patients even respond adversely to certain treatments. Karl Gruber reports on how a new generation of studies to identify novel genetic loci associated with different pathologies heralds a new era for precision treatment of type 2 diabetes. Precision medicine, the new term for what was widely known as personalised medicine, recognises that individual responses to disease treatments are in most cases not unique, but are common to groups of patients that share a particular underlying biological basis or genetic background, says David Altshuler, Program Director in Medical and Population Genetics at the Broad Institute (Boston, MA, USA). Precision medicine approaches are already in use for some types of diabetes, says Mark McCarthy, professor of Diabetic Medicine and Group Head at the Wellcome Trust Centre for Human Genetics (Oxford, UK). However, they are restricted to monogenic forms of diabetes. A new exploratory triple-agonist drug—which activates the glucagonlike peptide 1, gastric inhibitory polypeptide, and glucagon receptors— opens the possibility of bringing precision medicine to general type 2 diabetes treatment. The drug has shown exceptional results in a rodent model of obesity and diabetes, reducing blood glucose, appetite, and body fat to baseline levels. The study was co-led by Matthias Tschöp, research director of the Helmholtz Diabetes Center and Director of the Institute for Diabetes and Obesity at the German Research Center for Environmental Health (Munich, Germany) and Richard DiMarchi, professor in biomolecular sciences at Indiana University (Bloomington, IN, USA). “The ability to tailor these peptides, increasing or decreasing the magnitude of the effect on each hormone, offers the promise to evolve therapy over time and to tailor it to specific sub-populations”, explains DiMarchi.
But, for such a drug to move into the realm of precision medicine, McCarthy notes that further studies will need to show heterogeneity with respect to diabetes aetiology and therapeutic response that can be mapped onto different drug regimens. Evidence for such heterogeneity in people with type 2 diabetes is lacking, partly due to the difficulties in identifying many of the factors influencing individual predisposition to drug effectiveness and in establishing a convincing link to translational outcomes. “Genetic predisposition to type 2 diabetes is distributed across many genes, most of them individually so weak that they are almost impossible to quantify in an individual”, notes McCarthy. “Plus the impact of lifestyle, environment, maternal factors, and, potentially, of somatic mutation would need to be taken into account to truly individualise treatment”, he adds. “In patients with obesity and type 2 diabetes, we do know that there are a number of subpopulations which show different key symptoms”, says Tschöp. “For example, there are different levels of fatty liver disease, pancreatic function, adiposity, and maybe hypothalamic inflammation, but we are still lacking suitable biomarkers and drug candidates to specifically address such subtypes with novel individualised medicines.” The problem, adds DiMarchi, lies in the need to acknowledge human variability: “animal models of disease, unlike humans, are highly inbred and fail to provide the information we need to understand human disease at a level that allows us to intervene with much enhanced precision”. So, even with detailed genomic data, implementation of precision
www.thelancet.com/diabetes-endocrinology Vol 3 March 2015
medicine is not straightforward. Metformin, for example, exhibits variability in its efficacy and adverse effects, notes Jose Florez, Assistant in Medicine at the Massachusetts General Hospital and Associate Professor at Harvard Medical School (Boston, MA, USA). “The genetic basis of this variation is being explored”, he says, “and candidate loci such as the transporters OCT1, MATE1 and MATE2 may contain variation that influences the bioavailability of metformin”. However, so far no significant clinical outcome has been reliably predicted based on such loci. “Many more samples are needed to establish these associations with sufficient statistical confidence”, he explains. While promising, precision medicine approaches for type 2 diabetes still have a significant road ahead. Further research is needed to elucidate and disentangle the many factors that contribute to clinical outcomes of novel drug formulations. Among these factors, epigenetic modifications are likely to play an important role, says Tschöp, as they affect “everything from feeding behaviour to cell metabolism”. Furthermore, he adds, “some of those epigenetic effects can be programmed in response to environmental influences and inherited to future generations—generating a new dimension of potential sensitivities and resistances to challenges as well as therapeutics”. This means that novel disease subtypes might arise as we develop therapies for current ones, says Tschöp. “Only with the elucidation of the epigenetic mechanisms at play do we hold a chance of getting ahead”, he concludes.
For more on the triple-agonist drug see Nat Med 2014; 21: 27–36 For more on individual responses to metformin see Diabetes 2014; 63: 2590–9
Karl Gruber 171
Moving towards a more precise treatment of diabetes Current treatments for type 2 diabetes exhibit large variation in efficacy and some patients even respond adversely to certain treatments. Karl Gruber reports on how a new generation of studies to identify novel genetic loci associated with different pathologies heralds a new era for precision treatment of type 2 diabetes. Precision medicine, the new term for what was widely known as personalised medicine, recognises that individual responses to disease treatments are in most cases not unique, but are common to groups of patients that share a particular underlying biological basis or genetic background, says David Altshuler, Program Director in Medical and Population Genetics at the Broad Institute (Boston, MA, USA). Precision medicine approaches are already in use for some types of diabetes, says Mark McCarthy, professor of Diabetic Medicine and Group Head at the Wellcome Trust Centre for Human Genetics (Oxford, UK). However, they are restricted to monogenic forms of diabetes. A new exploratory triple-agonist drug—which activates the glucagonlike peptide 1, gastric inhibitory polypeptide, and glucagon receptors— opens the possibility of bringing precision medicine to general type 2 diabetes treatment. The drug has shown exceptional results in a rodent model of obesity and diabetes, reducing blood glucose, appetite, and body fat to baseline levels. The study was co-led by Matthias Tschöp, research director of the Helmholtz Diabetes Center and Director of the Institute for Diabetes and Obesity at the German Research Center for Environmental Health (Munich, Germany) and Richard DiMarchi, professor in biomolecular sciences at Indiana University (Bloomington, IN, USA). “The ability to tailor these peptides, increasing or decreasing the magnitude of the effect on each hormone, offers the promise to evolve therapy over time and to tailor it to specific sub-populations”, explains DiMarchi.
But, for such a drug to move into the realm of precision medicine, McCarthy notes that further studies will need to show heterogeneity with respect to diabetes aetiology and therapeutic response that can be mapped onto different drug regimens. Evidence for such heterogeneity in people with type 2 diabetes is lacking, partly due to the difficulties in identifying many of the factors influencing individual predisposition to drug effectiveness and in establishing a convincing link to translational outcomes. “Genetic predisposition to type 2 diabetes is distributed across many genes, most of them individually so weak that they are almost impossible to quantify in an individual”, notes McCarthy. “Plus the impact of lifestyle, environment, maternal factors, and, potentially, of somatic mutation would need to be taken into account to truly individualise treatment”, he adds. “In patients with obesity and type 2 diabetes, we do know that there are a number of subpopulations which show different key symptoms”, says Tschöp. “For example, there are different levels of fatty liver disease, pancreatic function, adiposity, and maybe hypothalamic inflammation, but we are still lacking suitable biomarkers and drug candidates to specifically address such subtypes with novel individualised medicines.” The problem, adds DiMarchi, lies in the need to acknowledge human variability: “animal models of disease, unlike humans, are highly inbred and fail to provide the information we need to understand human disease at a level that allows us to intervene with much enhanced precision”. So, even with detailed genomic data, implementation of precision
www.thelancet.com/diabetes-endocrinology Vol 3 March 2015
medicine is not straightforward. Metformin, for example, exhibits variability in its efficacy and adverse effects, notes Jose Florez, Assistant in Medicine at the Massachusetts General Hospital and Associate Professor at Harvard Medical School (Boston, MA, USA). “The genetic basis of this variation is being explored”, he says, “and candidate loci such as the transporters OCT1, MATE1 and MATE2 may contain variation that influences the bioavailability of metformin”. However, so far no significant clinical outcome has been reliably predicted based on such loci. “Many more samples are needed to establish these associations with sufficient statistical confidence”, he explains. While promising, precision medicine approaches for type 2 diabetes still have a significant road ahead. Further research is needed to elucidate and disentangle the many factors that contribute to clinical outcomes of novel drug formulations. Among these factors, epigenetic modifications are likely to play an important role, says Tschöp, as they affect “everything from feeding behaviour to cell metabolism”. Furthermore, he adds, “some of those epigenetic effects can be programmed in response to environmental influences and inherited to future generations—generating a new dimension of potential sensitivities and resistances to challenges as well as therapeutics”. This means that novel disease subtypes might arise as we develop therapies for current ones, says Tschöp. “Only with the elucidation of the epigenetic mechanisms at play do we hold a chance of getting ahead”, he concludes.
For more on the triple-agonist drug see Nat Med 2014; 21: 27–36 For more on individual responses to metformin see Diabetes 2014; 63: 2590–9
Karl Gruber 171
