The clinical response to sulphonylurea, an oral antidiabetic agent often used in combination with metformin to control blood glucose in type 2 diabetes (T2DM) patients, has been widely associated with a number of gene polymorphisms, particularly those involved in insulin release. We have reviewed the genetic markers of CYP2C9, ABCC8, KCNJ11, TCF7L2 (transcription factor 7-like 2), IRS-1 (insulin receptor substrate-1), CDKAL1, CDKN2A/2B, KCNQ1 and NOS1AP (nitric oxide synthase 1 adaptor protein) genes that predict treatment outcomes of sulphonylurea therapy. A convincing pattern for poor sulphonylurea response was observed in Caucasian T2DM patients with rs7903146 and rs1801278 polymorphisms of the TCF7L2 and IRS-1 genes, respectively. However, limitations in evaluating the available studies including dissimilarities in study design, definitions of clinical end points, sample sizes and types and doses of sulphonylureas used as well as ethnic variability make the clinical applications challenging. Future studies need to address these limitations to develop personalized sulphonylurea medicine for T2DM management.
The global prevalence of diabetes, a major non-communicable disease, continues to be on an increasing trend. According to the International Diabetes Federation, an estimated 381.8 million adults from 219 countries worldwide had diabetes in 2013, and the number is expected to increase to 591.9 million by 2035.1 Current treatment recommendations for type 2 diabetes (T2DM) are consistent with the progressive decline in β-cell function starting with lifestyle changes and oral monotherapy, combination oral therapy and finally insulin.2, 3
Sulphonylureas, the oldest and most commonly used oral agents for the management of T2DM worldwide with an elevated HbA1c (glycosylated haemoglobin) reduction capacity of 1–2% are often added to metformin once the latter fails to control blood glucose.3, 4, 5 Because of the nature of T2DM, patients will eventually reach a state where the sulphonylurea is unable to bring blood glucose to the target range, known as ‘sulphonylurea failure’, as shown in the large-scale United Kingdom Prospective Diabetes Study.6 Although there is currently no universally accepted definition of sulphonylurea failure, researchers have defined it as either primary or secondary sulphonylurea failure. According to Defronzo,7 a patient showing poor glycaemic control following sulphonylurea initiation, which includes a fasting plasma glucose (FPG) reduction of <1.1 mmol l−1, low fasting C-peptide and FPG of >15.0 to 16.6 mmol l−1, is considered to have primary sulphonylurea failure. Secondary sulphonylurea failure is defined as failure to maintain HbA1c below 7% after an initial ability to achieve this target following sulphonylurea therapy.8
Pharmacogenomics, a rapidly advancing field in which the association between inherited genetic variants and drug response is investigated,9 is a key step in personalized medicine that would allow clinicians to select the best drug for the management of a particular disease or condition.10 Single-nucleotide polymorphisms (SNPs) are the most common type of genetic variant occurring in about one of every 300th nucleotide in the entire human genomic DNA.11 Variants of several genes including the TCF7L2 (transcription factor 7-like 2), PPARG, FTO, KCNJ11, NOTCH2, WFS1 and CDKAL1 have been shown to significantly increase the risk of T2DM,12 a highly genetically susceptible disease.13 As some of these genes have a key role in insulin secretion, which is also the primary effect of sulphonylurea, there is growing interest in investigating the effect of these gene mutations on patient response to the drug.14, 15, 16, 17
In this review, we analyse the association between SNPs of nine T2DM genes and sulphonylurea response in T2DM patients from previously reported candidate gene studies and the challenges in implementing these findings in clinical practice. The outcome measure in this review is the clinical response to sulphonylureas instead of the pharmacokinetic parameters, which has already been reported in a previous review.18 We also provide a current update of recent evidence and genes not covered in the earlier review of sulphonylurea pharmacogenomics.19 A systematic search was conducted in PubMed using the MESH terms: genetic AND polymorphism AND sulphonylurea AND response NOT review and we limited the search to English language papers with available full texts between 1 January 2004 and 31 March 2015. To narrow the scope to sulphonylureas, only studies assessing the efficacy of sulphonylureas, combined either with or without metformin, were considered in this review, whereas studies that combined other oral agents or insulin with sulphonylureas20 were excluded.
Polymorphism affecting pharmacokinetics of sulphonylureas
CYP2C9 gene polymorphisms
The cytochrome P450 2C9 (CYP2C9) has a major role in the metabolism of sulphonylureas including tolbutamide, glibenclamide, glimepiride and glipizide in the liver.21 It is encoded by the CYP2C9 gene located at chromosome 10q24 and has two polymorphisms, the CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu),18, 22, 23 besides the wild-type CYP2C9*1.24 Of the four studies reviewed (Table 1), three involved CYP2C9*2 and CYP2C9*3 and were conducted on Caucasians22, 23, 25 who have a relatively higher frequency of these genotypes than Asians.18 Zhou et al.22 reported that Scottish T2DM patients who harboured the CYP2C9*2/*2, *2/3 or *2/3 displayed higher odds of achieving the target HbA1c of <7% after 18 months of sulphonylurea initiation in combination with metformin (Supplementary Table 1) (odds ratio (OR)=3.44; 95% confidence interval (CI): 1.65–7.15; P=0.0009). The odds are even greater in carriers of CYP2C9*2/3 alone (OR=7.54; 95% CI: 2.00–28.45; P=0.003).22
Becker et al.23 used prescribed dose change from the first until the 10th sulphonylurea prescription as outcome and found that Dutch carriers of CYP2C9*1/3, *2/3 or *3/3 needed a significantly lower tolbutamide dose increase (12 mg; 95% CI: −469 to −69; P=0.009) compared with CYP2C9*1/*1, *1/*2 or *2/*2 carriers, but there were no significant differences observed in patients taking glibenclamide and glimepiride. This observation may have been as a result of higher blood concentrations of tolbutamide because of its lower metabolism by the CYP2C9 enzyme in the risk allele carriers.18 However, it may not reflect clinical response as there was no difference seen in FPG across all genotypes (Table 1). By contrast, the study by Surendiran et al.26 on a relatively smaller sample of Asian Indian T2DM patients after 3 months of sulphonylurea–metformin combination therapy showed a significant association (P<0.01) between CYP2C9*1/*3 and *1/*2 with controlled diabetes (FPG <110 mg dl−1) and CYP2C9*1/*3 with uncontrolled diabetes (FPG >110 mg dl−1). In another study on Caucasians, no differences in HbA1c reduction were found among the different genotypes of CYP2C9.25
Only the study by Zhou et al.,22 but not the other two,23, 25 provide strong evidence of improved response to sulphonylureas in Caucasian carriers of CYP2C9*2 and CYP2C9*3 genotypes. More studies on Asians are warranted particularly using HbA1c as outcome measure, which would better reflect clinical response to sulphonylureas.27
Polymorphisms affecting pharmacodynamics of sulphonylureas
ABCC8 gene polymorphisms
Sulphonylureas bind directly to the KATP channel (ATP-sensitive K+ channel) leading to its closure and initiate the process of insulin release from the β-cell as shown in Figure 1.28, 29 The KATP channel is made up of four ATP-binding cassette transporters known as sulphonylurea receptors (SUR-1) and four inward-rectifier potassium ion channels (Kir6.2).30 The ABCC8 gene located at chromosome 11p15.1, consisting of 39 exons, encodes the SUR-1,31 which is the binding site of sulphonylureas (Figure 1). Owing to its direct involvement in drug action, many studies have associated its polymorphisms with clinical response.
We included four papers for this review, of which three associated the sulphonylurea response with rs757110 polymorphism14, 25, 32 and one33 on rs1799854 and rs1799859 polymorphisms of the ABCC8 genes (Table 1). The rs757110 missense polymorphism located at exon 33 of the ABCC8 gene results in the change from alanine (Ala) to serine (Ser) at position 1369 of the SUR-1 protein.9 In the study by Zhang et al.,32 the heterozygous and homozygous patients for the risk allele (TG and GG) showed a significantly higher reduction in HbA1c (TG and GG: 1.60% vs TT: 0.76%; P=0.044) compared with the wild-type homozygote (TT), although no differences were seen in the change of FPG levels. The findings by Feng et al.14 that patients who harboured the mutations Ser/Ala (OR=1.4; 95% CI: 1.0–2.1; P=0.006) and Ala/Ala (OR=2.2; 95% CI: 1.4–3.6; P=0.001) had higher odds of responding to gliclazide treatment compared with wild-type carriers seem to agree with this observation.
However, the results of the study by Klen et al.25 on a Caucasian population do not correlate with the findings above. No significant differences in HbA1c was observed among the different genotypes after 3 months of observation (P=0.724) (Table 1), although the exact duration of exposure to medications, which were not reported, may have varied across subjects and influenced the results. This study differs from the earlier studies14, 32 because it was cross-sectional and used sulphonylurea in combination with metformin (Supplementary Table 1).
The rs1799854 polymorphism of ABCC8 gene in the intron 15 splice acceptor site (exon 16-3C/T) did not show any significant association with sulphonylurea response.33 Another silent polymorphism rs1799859 in exon 31 (Arg1273Arg; AGG→AGA; the underlined G and A indicates change of allele G in AGG to A in AGA) was also investigated by Nikolac et al.33 who found that homozygotes of the A risk allele [(AA: 6.3% (5.7–6.8) vs (GA: 7.1% (6.2–8.5) and GG: 7.8% (6.9–8.8)); P <0.0001)] showed significantly lower HbA1c levels compared with heterozygous and wild-type homozygotes33 (Table 1).
The methodological differences between studies make comparison between treatment outcomes among the different polymorphisms of the same ABCC8 gene more complicated. It is too early to conclude that rs757110 has potentially beneficial effects on Asians because of the short 2-month duration of sulphonylurea exposure. In that study, the use of sulphonylurea monotherapy without metformin is also not the usual practice in clinical settings, rather metformin is usually combined with sulphonylurea, as recommended by the current 2015 American Diabetes Association and European Association for the Study of Diabetes treatment guidelines.34
KCNJ11 gene polymorphisms
Possible interindividual variability in clinical markers following sulphonylurea therapy in patients carrying the mutations of the KCNJ11 gene located at 11p15.1 encoding the Kir6.2 receptor of the KATP channel (Figure 1) has long interested researchers.35 The rs5219 (E23K) polymorphism formed by the missense mutation of adenine (A base) for guanine (G base) at the 23rd codon of the 1st exon results in the replacement of glutamine (E) with lysine (K) in the corresponding amino-acid sequence.36
Six papers published between 2006 and 2014 analysed the effect of rs5219, the most widely studied KCNJ11 polymorphism37 to date, on glycaemic response of sulphonylurea-treated T2DM patients (Table 1), of which four were conducted on Caucasians15, 16, 25, 33 and one each on Asians and Arabs.38, 39 The study by Sesti et al.15 on Italian T2DM patients showed that carriers of the risk allele K had a 45% higher risk (OR=1.45; 95% CI: 1.01–2.09; P=0.04) of developing sulphonylurea failure (defined by the need for insulin therapy when sulphonylurea and metformin failed to reduce the FPG to <300 mg/dl−1). This finding is not consistent with another Caucasian study by Javorsky et al.,16 which reported an increased reduction in HbA1c (EK and KK: 1.15% vs EE 0.8%, P=0.036) in patients harbouring the K allele after 2 months of gliclazide initiation following 6-month metformin therapy (Supplementary Table 1). The differences in the duration of sulphonylurea exposure of the patients in these two investigations—Sesti et al.,15 which used maximal doses of glibenclamide and metformin with an average treatment duration of 12 years, compared with Javorsky et al.16 with treatment duration of 6 months16 (Supplementary Table 1)—make comparison and potential clinical inference difficult.
There are two other recent studies on Caucasians, one by Nikolac et al.33 and the other by Klen et al.,25 which did not show significant differences in HbA1c levels among the different genotypes of E23K polymorphism (Table 1). Unlike the earlier studies,15, 16 which used a prospective design, these two were cross-sectional in nature with no clear mention of the duration of sulphonylurea treatment.
Other studies, one on Japanese T2DM patients38 and another on Egyptians,39 reported a similar pattern suggesting a possible role for the E23K variant with a poor outcome using sulphonylurea therapy. Carriers of the increased risk allele, K, in the Japanese subjects deteriorated faster requiring insulin therapy earlier (7.7±4.6 years) compared with wild-type homozygotes (11.1±6.1 years) and heterozygous subjects (11.2±6.3 years, P=0.015). El-sisi et al.39 showed an increase in the relative risk of sulphonylurea failure (OR=1.65; 95% CI: 1.04–2.60; P=0.04) using HbA1c >8% after sulphonylurea therapy as indicator, although the duration of treatment and the possibility of metformin combination were not stated.39 This finding is consistent with the earlier report by Sesti et al.15
Although rs5219 has been strongly linked to increased T2DM risk in Caucasians,40 currently, there is little conclusive evidence that the polymorphism confers an added risk of failure with sulphonylurea therapy in this population. However, it may be too early to infer that this polymorphism is associated with a significantly poor response to sulphonylureas in Asians and Arabs owing to the dissimilarities in study designs of the papers discussed above.
Polymorphism affecting insulin release mechanisms
TCF7L2 gene polymorphisms
The TCF7L2 gene spanning 215.9 kb at chromosome 10q25.3 (ref. 41) has the strongest association with T2DM to date, confirmed by multiple studies across different ethnicities.42, 43 Its role in the WNT signalling pathway, acting as nuclear receptor for β-catenin, is of paramount importance in pancreas and islet proliferation.44, 45 Although several mechanisms have been proposed including decreased β-cell mass, impaired β-cell GLP-1 signalling and decreased glucagon secretion resulting in reduced insulin secretion, the exact mechanism of how TCF7L2 predisposes the T2DM to risk is far from clear.46 One possible role of TCF7L2 is that it is needed in the release of insulin secretory granules from the β-cell (Figure 1). The presence of this gene ensures that the readily releasable granules containing insulin remain in close proximity to violated-dependent Ca2+ channels, allowing insulin release during membrane depolarization due to the influx of Ca2+.43
We evaluated three papers that elucidated the association between rs7903146 (refs. 17, 47, 48) and one on rs12255372 variants17 with that of glycaemic response to sulphonylurea (Table 2). Evidence from the three papers clearly suggests poor sulphonylurea response in carriers of the T allele of the rs7901346 polymorphism in Caucasians. Using a distinctively large sample size of Scottish T2DM patients from the GoDARTS study, Pearson et al.17 discovered that carriers of the T allele had increased odds of failure with sulphonylurea therapy (OR 1.27, P=0.017). Holstein et al.47 reinforce this finding in their study of German T2DM patients in which they found that the T allele carriers had 57% more risk of sulphonylurea failure (OR 1.57, 95% (1.01–2.45); P=0.046). Another study of Europeans reported significantly lower HbA1c reductions (CT and TT 0.86% vs CC 1.16%, P=0.003) in heterozygous and homozygous T allele carriers after 6 months of sulphonylurea therapy.48 Similarities in methodologies in all three papers, which included use of metformin in combination with sulphonylurea, assessment of outcome after 6 months of therapy and use of similar outcome measures (sulphonylurea failure defined by HbA1c >7%17, 47) lend strong evidence that there is decreased efficacy of sulphonylurea in Caucasian T2DM patients with rs7903146 polymorphism.
The other polymorphism of the TCF7L2 gene, rs12255372, was also associated with reduced response to sulphonylureas in Caucasians. The result of the GoDARTS study17 showed that T2DM patients harbouring the risk allele T of this polymorphism had 28% increased odds for sulphonylurea failure (OR 1.28, P=0.014). While the association between decreased efficacy of sulphonylureas and rs7903146 seems to be clear in Caucasians, the need for studies associating this TCF7L2 polymorphism with sulphonylurea response in Asians is evident because the currently available data in Asians are mostly for T2DM disease susceptibility.22, 49, 50
Polymorphism affecting glucose transport mechanisms
IRS-1 gene polymorphisms
IRS-1 (insulin receptor substrate-1), a signalling adapter protein involved in the insulin signalling pathway51, 52 encoded by the IRS-1 gene located at 2q36-37,53 has a pivotal role in facilitating glucose transport,54 as shown in Figure 2. The Arg972 polymorphism (rs1801278) of the IRS-1 gene resulting from substitution of glycine to arginine at codon 972 (ref. 55) found near the C terminus of IRS-1 flanked by binding sites for the p85 regulatory subunit of phosphatidylinositol 3-kinase56 causes insulin resistance.57
Of all the IRS-1 gene polymorphisms studied so far, the rs1801278 is the most extensively studied and has proved to be strongly associated with insulin resistance.53 In this review of sulphonylurea response (Table 3), we excluded one out of three papers20 because the sulphonylureas had been analysed together with other classes of oral antidiabetic and insulinotropic agents. Both of the other reviewed papers reported similar findings in which the presence of IRS-1 gene Arg972 polymorphism conferred added risk of sulphonylurea failure39, 58 in T2DM patients. The odds of sulphonylurea failure was higher in Italian patients (OR 2.1; 95% CI: 1.18–3.70; P=0.01), as presented by Sesti et al.,58 compared with that in Egyptian patients (OR 1.75; 95% CI: 1.08–12.4; P=0.041).39 Similar outcome measures and follow-up durations allow for a head-to-head comparison of these two studies despite limitations such as the unclear duration of sulphonylurea and whether metformin was used in the study by El-Sisi et al.39 More studies, however, are needed to obtain a stronger association of this variant and sulphonylurea outcomes.
Other T2DM gene polymorphisms
CDKAL1, CDKN2A/2B, KCNQ1 and NOS1AP gene polymorphisms
Besides polymorphisms of the T2DM genes discussed earlier, several others have been associated with sulphonylurea response (Table 1). The CDKAL1 gene located on chromosome 6p22.3 encodes the cyclin-dependent kinase 5, an enzyme which by phosphorylating the α1C subunit of the L-type voltage-dependent Ca2+ channel, inhibits the Ca2+ efflux from β-cell and facilitates insulin secretion.59 The study of rs7756992 polymorphism of this gene in Caucasians60 reported a significantly higher change in HbA1c at 6 months in heterozygotes and homozygotes of the risk allele A carriers (P<0.05), whereas no significant association between genotypes and sulphonylurea response was reported in a study of Asians.38 Significant reductions in FPG were observed in Asian CC risk allele homozygotes of rs10811661 polymorphisms of the CDKN2A/2B gene, which also inhibit cyclin-dependent kinase 5, although the follow-up duration of 4 weeks was short (Supplementary. Table 1).61 The rs163184 variant of the KCNQ1 gene encoding the KATP channel of pancreatic β-cell62 showed a significantly lower reduction in FPG levels (P<0.05) in carriers of the homozygote GG risk allele.63 It is difficult to associate clinical responses with the findings of the study on rs10494366 variant of NOS1AP (nitric oxide synthase 1 adaptor protein) gene encoding nitric oxide synthase, which allows Ca2+ influx through the Ca2+ channel, because the study used a number of prescriptions for glibenclamide as outcome.64
Challenges in translating current evidence into personalized sulphonylurea medicine
The diversity of the studies from which the available current evidence on sulphonylurea pharmacogenomics is discussed in this review pose challenges to performing pooled or meta-analyses, which would bring us a step closer to personalized medicine. This includes dissimilarities in study designs, definitions of clinical end points (phenotypes), sample sizes, sulphonylurea types and dosage regimens used, as well as ethnic variability. Although prospective studies with a longer follow-up period may increase the accuracy of the findings, some of the studies presented here were cross-sectional25, 33, 39 in design. There are also inconsistencies in clinical end points where some have assessed the sulphonylurea response at a very early stage (primary failure) within a few weeks14 and months,26, 32 whereas others have made the assessment after long-term sulphonylurea therapy (secondary failure).17, 22, 38, 58, 61 The duration of sulphonylurea exposure would certainly have had an impact on the clinical end points. In addition, several studies used sulphonylurea monotherapy14, 32 when in actual clinical settings sulphonylureas are most often coprescribed with metformin.34 The use of metformin in combination with sulphonylureas in the other studies15, 16, 39, 48, 58 may have also influenced the glycaemic response. Several papers, however, did not clearly state if the subjects were also receiving metformin as well as sulphonylureas.33, 39, 48
Although some papers have used a single type of sulphonylurea14, 15, 26, 32, 61 as the intervention, some22, 23, 25, 38, 64 used multiple types of sulphonylureas and some others did not clearly state the type of sulphonylurea used.17, 39 Besides the differences in sulphonylurea types, the doses used also varied and some did not use the maximum sulphonylurea dose14, 17, 32, 63 compared with others which did,15, 58 and this may have had a direct effect in determining sulphonylurea failure. On another note, the sample size of the studies varies greatly with distinctly larger numbers of subjects exceeding a thousand in several studies14, 22 compared with less than a hundred in some,63 which again has a bearing on the conclusion for the genotype associations with glycaemic outcome. Generalizing the available findings to a larger group of patients is also difficult given the fact that most of the studies only represented a particular ethnic group, such as Asian Chinese of Han origin,14, 32 Asians of South Indian descent,26 Asian Japanese38 or Italians.15, 58
Our review observes a strong pattern of poor sulphonylurea response in Caucasian T2DM patients with rs7903146 and rs1801278 polymorphisms of the TCF7L2 and IRS-1 genes, respectively. However, replications of these findings are needed to improve the strength of the current evidence. More multicentred, multiethnic and larger sample studies that are prospective in design with clinically relevant outcome measures of sulphonylurea response and with longer follow-up durations would provide stronger evidence, which may have better clinical applications. The interventions given need to reflect those in actual clinical settings, especially the use of maximum dose of a particular sulphonylurea drug, before deciding on sulphonylurea failure. The low cost65 makes sulphonylureas still a very affordable option in T2DM treatment. Hence, stronger pharmacogenomic evidence may allow genetic testing for these polymorphisms to predict clinical outcomes of sulphonylureas in future. Clinicians will then be able to determine if a particular patient may or may not benefit from sulphonylurea therapy, thus allowing the use of other drug options much earlier in the course of treatment. This personalized sulphonylurea medicine would certainly benefit patients by increasing the chance of them attaining target glucose levels and slowing the progression of diabetes-related complications.
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This study received funding from the University of Malaya, Malaysia (University of Malaya Research Grant RP024-14HTM and Postgraduate Research Grant PG056-2014A) and also Doctor of Philosophy scholarship award from the Ministry of Health, Malaysia.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
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Loganadan, N., Huri, H., Vethakkan, S. et al. Genetic markers predicting sulphonylurea treatment outcomes in type 2 diabetes patients: current evidence and challenges for clinical implementation. Pharmacogenomics J 16, 209–219 (2016). https://doi.org/10.1038/tpj.2015.95
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