Introduction
Diabetes is a fast-growing global epidemic with an increasing prevalence worldwide [
1]. Several genes have been associated with type 2 diabetes susceptibility or manifestation, including genes encoding receptors, transcription factors, cell cycle-associated proteins, modifiers of signal transduction, ion channels and others [
2‐
4]. Recently, single-nucleotide polymorphisms (SNPs) of a gene encoding transcription factor 7-like 2 were shown to have the strongest known genetic risk factor for type 2 diabetes among all diabetes-associated gene SNPs [
5,
6]. The risk of developing diabetes is twice as high in homozygous
TCF7L2 risk variant (rs7903146) carriers (TT) compared with non-risk carriers (CC) [
7,
8]. The initial findings have been replicated in independent studies in multiple ethnic populations and were summarised in a large global meta-analysis [
5]. Pharmacogenetic studies reported a significant association between
TCF7L2 risk variants and efficacy of sulfonylurea treatment, with a twofold greater likelihood of sulfonylurea treatment failure in
TCF7L2 risk carriers [
9]. The mechanisms by which
TCF7L2 polymorphisms increase diabetes risk and affect the treatment response to insulin secretagogues were thought to be related to impaired incretin-induced insulin secretion, impaired suppression of glucagon or impaired glucagon-like peptide-1 secretion [
10‐
13]. Depending on the underlying mechanism, the response to other insulin secretagogues, such as the novel class of dipeptidylpeptidase-4 (DPP-4) inhibitors, also may be affected.
Incretin hormones amplify the first phase of insulin secretion [
14]. The advantage of incretin-based therapies, like orally active DPP-4 inhibitors, is that they have a glucose-dependent insulinotropic action with no intrinsic risk for causing hypoglycaemia. Linagliptin, a potent and selective inhibitor of DPP-4, improves glucose homeostasis in patients with diabetes by blocking the degradation of incretins and thus improving insulin secretion in a glucose-dependent manner [
15,
16]. Linagliptin has been approved for the treatment of patients with type 2 diabetes [
16,
17]. Since linagliptin and the high-risk polymorphisms of
TCF7L2 both affect the same process responsible for the first phase of insulin secretion, it can be hypothesised that the response to linagliptin therapy may differ in patients depending on their allele status. Therefore, we wanted to explore whether the efficacy response to linagliptin (i.e. change from baseline in HbA
1c or change from baseline in 2 h postprandial plasma glucose [PPG] after 24 weeks of treatment) is dependent on the
TCF7L2 genotype in a retrospective analysis of clinical data.
Discussion
The present studies have been undertaken to assess the impact of
TCF7L2 genotypes on the response to incretin-based therapy, for the first time in a longitudinal setting. This is important because genetic polymorphism has been suggested to contribute to the susceptibility of individuals to environmental stimuli, resulting in increased prevalence of diabetes. Of the many genes investigated,
TCF7L2, a β-catenin bipartite transcription factor, integral to the upregulation of incretin secretion from intestinal endocrine L cells and the proliferation of pancreatic beta cells [
25‐
27], has the strongest known association with diabetes [
5,
6]. The high-risk genotypes of
TCF7L2 SNPs rs7903146 and rs12255372 are strongly associated with reduced insulin secretion, possibly owing to impaired response to incretins [
10,
11] and impaired beta cell function [
10,
12,
13]. Accordingly, we tested the hypothesis that the efficacy response to linagliptin therapy, which acts via inhibition of incretin degradation, may be reduced in patients with type 2 diabetes who have high-risk
TCF7L2 genotypes. It is possible that these individuals may be genetically predisposed to produce and secrete less incretin or have an impaired incretin response compared with those with wild-type genotype.
As expected, in the pooled analyses, the HbA1c levels of patients showed no change from baseline when administered placebo. In response to treatment with linagliptin, wild-type homozygous patients exhibited a robust −0.82% (−9.0 mmol/mol) reduction from baseline in HbA1c levels (p < 0.0001). In contrast, the response to treatment with linagliptin in patients who were homozygous for the risk allele was reduced (−0.57% [−6.2 mmol/mol] decrease from baseline in HbA1c on average; p < 0.0006), but still clinically meaningful (>0.5% [>5.5 mmol/mol] decrease).
Similar to the observations for HbA1c, homozygous wild-type patients treated with linagliptin showed a decrease in 2 h PPG levels compared with patients receiving placebo. Heterozygous patients exhibited a response similar to that observed for homozygous wild-type patients and homozygous risk carriers (TT) showed the least decrease from baseline in 2 h PPG levels. However, the number of patients in each of these groups was small and probably not sufficient to allow meaningful conclusions to be made.
The observed differences in linagliptin efficacy response of ~25% between
TCF7L2 homozygous risk carriers (12% of whites) and non-risk carriers are in line with previous data of an association of
TCF7L2 and sulfonylurea response [
9]. This would support the recent postulation by Schäfer et al [
28] that
TCF7L2 variants are associated with a functional defect in the beta cells. Considering that the efficacy response to linagliptin in the TT carriers was clinically relevant, it is intriguing to speculate that a stronger loss of efficacy than that observed in this investigation would have been expected in homozygous carriers if a specific incretin-related defect was present. Based on present data, this cannot be ruled out. Another possibility for the lack of a more pronounced effect may be that polymorphisms in a single gene may not be sufficient to produce a significant change in a patient’s response to a DPP-4 inhibitor. Variants in additional genes could potentially contribute to inter-individual variability in response, and combined analyses of several risk genes for type 2 diabetes implicated in the regulation of beta cell function may further help explain the variability of efficacy response to insulin secretagogues.
The study has some limitations, mainly related to the relatively small sample size. This was addressed by combining the data from four clinical trials. However, we cannot completely rule out the influence of co-medication. The fact that we did observe the same trend for the differences in response to linagliptin treatment between CC wild-type and TT risk carriers by analysing each trial with different background therapies separately, supports our hypothesis. In addition, a disease–genetic process in TCF7L2 carriers could contribute to the effect, but the change in HbA1c level from baseline in the placebo groups did not reveal differences between CC and TT risk allele carriers, indicating a pharmacogenetic effect.
Nevertheless, results must be interpreted with some caution and should ideally be confirmed in a second cohort. Since linagliptin was the only DPP-4 inhibitor evaluated, it is unknown whether or not these observations are specific to linagliptin or whether they can be regarded as a class effect.
In conclusion, to our knowledge, these are the first studies testing the impact of TCF7L2 genotype on the response to incretin therapy (DPP-4 inhibitor) in a longitudinal cohort. Our analyses demonstrate for the first time that although the clinical response to the DPP-4 inhibitor linagliptin was somewhat attenuated in homozygous TCF7L2 risk carriers, this treatment results in a clinically meaningful glucose-lowering potency, even in homozygous high-risk allele carrier patients.