Comment

If lifestyle changes are not effective for maintaining glycaemic control, metformin is recommended as the first glucose-lowering drug to use in a patient with type 2 diabetes, if the patient has no contraindications— eg, renal impairment or hypoxic disorders.1 However, the glucose-lowering response to metformin can vary greatly between patients, with some people responding poorly to this biguanide. Because of the well known therapeutic inertia with respect to pharmacological treatment of diabetes, insufficient glucose control might persist for a long time before any treatment adjustment is made in people who respond poorly to metformin monotherapy. Intensification of therapy generally consists of a second, and eventually a third, glucose-lowering drug being added to metformin.1 A more logical attitude might be to stop giving metformin to poor responders if they can be clearly identified, instead of increasing the number of drugs prescribed and persisting with metformin treatment. A valuable alternative to prescribing metformin to everybody with type 2 diabetes might be to select the most appropriate patients for this pharmacological approach and to give the drug to these patients only. For a long time, physicians have been prescribing metformin according to simple clinical criteria (eg, bodyweight, age, absence of comorbidities), which might affect both efficacy and safety, although most of the efficacy and safety concerns have been addressed.2 No clear clinical information is available to help physicians decide which patients with type 2 diabetes might benefit most from metformin. Various factors might contribute to the interindividual variability of the metabolic response to metformin therapy. On the one hand, the pharmacological profile of metformin might be affected by pharmacokinetics that might change the exposure to the drug or by pharmacodynamics that might directly affect its glucoselowering action. On the other hand, a patient’s genetic background or environment might also affect metformininduced HbA1c reduction. Although interest in the pharmacogenetics of type 2 diabetes has increased in recent years,3 data are still scarce. By analysing the data of the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study and using a genome-wide complex trait analysis approach, Kaixin Zhou and colleagues4 conclude in The

Lancet Diabetes & Endocrinology that genetic variants contribute to the interpatient variation in response to metformin, in terms of HbA1c reduction within the first 18 months after initiation of treatment. They estimate the heritability of metformin glycaemic response to be up to 34%, a level similar to heritability estimates for schizophrenia and Alzheimer’s disease. The dual effect of a patient’s disease pathophysiology and their individual response to metformin is supported by the fact that heritability affects both pretreatment baseline and ontreatment HbA1c concentrations. Although the genetic variants are likely to have a small-to-moderate effect and be scattered across the genome, Zhou and colleagues’ data4 suggest that, in the future, genetic analysis of individual patients might enable physicians to make predictions about a patient’s glucose-lowering response to metformin. This treatment approach could enable stratified therapy and individualised management, which are of special interest in a heterogeneous and complex disease such as type 2 diabetes.5 However, this study of Zhou and colleagues4 has some limitations. First, the investigators used a rather small sample size; genome-wide association study analyses need to have large samples to find as many genetic variants as possible to enable better predictions to be made for personalised medicine. Second, the HbA1c reduction was simply assessed by the difference between one baseline HbA1c concentration and the lowest HbA1c value within 18 months of metformin initiation. Third, without measurements of plasma concentrations of metformin, it is not known whether the heritability mainly affects the pharmacodynamics or the pharmacokinetics of the drug. The crude approach to assessing HbA1c reduction might have overestimated the efficacy of metformin therapy and might explain why a surprisingly large HbA1c reduction was achieved relative to the mean dose of metformin reported. For metformin monotherapy, HbA1c was reduced from 8·7% (SD 1·3) at baseline to 7·0% (1·0) on treatment, with a mean dose of 1·26 g (0·47) per day; for the addition of metformin to sulfonylureas, HbA1c was reduced from 9·2% (1·3) to 7·4% (1·1), with a mean dose 1·29 g (0·51) per day. By contrast, a systematic review of clinical trials6 reported that metformin monotherapy versus

www.thelancet.com/diabetes-endocrinology Published online March 19, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70064-6

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Personalising metformin therapy: a clinician’s perspective

Lancet Diabetes Endocrinol 2014 Published Online March 19, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70064-6 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70050-6

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placebo lowered HbA1c by 1·12% (95% CI 0·92–1·32), and metformin versus placebo added to other oral antidiabetic drugs lowered HbA1c by 0·95% (0·77–1·13); a significantly greater reduction in HbA1c was achieved with higher doses (≥1·7 g per day) than with lower doses of metformin (≤1·5 g per day). Determining whether genetic background affects pharmacokinetics or pharmacodynamics of metformin with these data is not possible. Data suggest that oral absorption, hepatic uptake, and renal excretion of metformin are largely mediated by organic cation transporters (OCTs).7 An intron variant of OCT1 (single nucleotide polymorphism rs622342) has been associated with a decreased effect of metformin on blood glucose concentration. In a large cohort of patients with type 2 diabetes, an 80-fold variability in steady-state trough metformin plasma concentration was reported;8 OCT1 activity was found to affect metformin steady-state pharmacokinetics, and OCT1 genotype to affect HbA1c response to metformin treatment.8 However, overall, the effect of structural variants of OCTs8 and other cation transporters (such as multidrug and toxin extrusion transporters)9 on the pharmacokinetics of metformin seems to be rather small, and the subsequent effects on HbA1c reduction are also modest.7 In conclusion, variation in glycaemic response to metformin is likely to be multifactorial, making it difficult to identify the effect of individual genetic variants. Despite the demonstration of a rather high heritability of the glucose-lowering response to

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metformin by Zhou and colleagues,4 further genetic studies are needed before a truly stratified approach to metformin treatment in patients with type 2 diabetes can be proposed. André J Scheen Division of Diabetes, Nutrition and Metabolic Disorders and Clinical Pharmacology Unit, Department of Medicine, CHU Sart Tilman, B-4000 Liège, Liège, Belgium [email protected] I have received lecture or advisor fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi-Aventis, and Takeda. 1

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Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577–96. Scheen AJ, Paquot N. Metformin revisited: a critical review of the benefit-risk balance in at-risk patients with type 2 diabetes. Diabetes Metab 2013; 39: 179–90. Maruthur NM, Gribble MO, Bennett WL, et al. The pharmacogenetics of type 2 diabetes: a systematic review. Diabetes Care 2014; 37: 876–86. Zhou K, Donnelly L, Yang J, et al. Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. Lancet Diabetes Endocrinol 2014; published online March 19. http://dx.doi. org/10.1016/S2213-8587(14)70050-6. Scheen AJ, Van Gaal LF. Combatting the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes. Lancet Diabetes Encocrinol 2014; published online Feb 19. http://dx.doi. org/10.1016/S2213-8587(14)70004-X. Hirst JA, Farmer AJ, Ali R, Roberts NW, Stevens RJ. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care 2012; 35: 446–54. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50: 81–98. Christensen MM, Brasch-Andersen C, Green H, et al. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet Genomics 2011; 21: 837–50. Stocker SL, Morrissey KM, Yee SW, et al. The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther 2013; 93: 186–94.

www.thelancet.com/diabetes-endocrinology Published online March 19, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70064-6

Personalising metformin therapy: a clinician's perspective.

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