Introduction
Heterogeneity of type 2 diabetes
Pharmacogenetic studies of novel glucose-lowering drugs
Gene | Genetic variant | Study population (n) | Glucose-lowering treatment | Clinical outcome | Reference |
---|---|---|---|---|---|
GLP1R | rs6923761 (G>A, C) | 206 with T2D | Sitagliptin 100 mg/day, vildagliptin 100 mg/day, or linagliptin 5 mg/day added to metformin or to metformin and sulfonylurea for 6 months | Smaller reduction in HbA1c (by 4.4 mmol/mol; p = 0.016) for AA vs AG and GG genotypes | [14] |
GLP1R | rs6923761 (G>A, C) | 140 with T2D | Sitagliptin 100 mg/day or vildagliptin 100 mg/day added to metformin or to metformin and sulfonylurea for 6 months | The A allele was associated with HbA1c reduction (β = −3.6 mmol/mol, p = 0.011) Smaller reduction in HbA1c for AA vs AG and GG genotypes (change: −1.3 mmol/mol vs −8.7 mmol/mol; p = 0.008) | [15] |
GLP1R | rs3765467 (G>A, C, T) | 246 with T2D | Vildagliptin, sitagliptin, linagliptin, saxagliptin, gemigliptin for 24 weeks | Greater reduction in HbA1c for AA and GA vs GG genotypes (14.2 mmol/mol vs 9.8 mmol/mol; p = 0.022); OR for ≥10% HbA1c reduction 2.00 (95% CI 1.03, 3.89) in multivariable logistic regression analysis | [16] |
KCNQ1 | rs163184 (T>C, G) | 137 with T2D | Sitagliptin 100 mg/day or vildagliptin 100 mg/day added to metformin or to metformin and sulfonylurea for 6 months | Smaller reduction in HbA1c for GG and GT vs TT genotypes (β = –3.3 mmol/mol) in multivariate general linear models | [18] |
KCNJ11 | rs2285676 (T>C) | 331 with T2D, 331 control individuals | Sitagliptin 100 mg/day, vildagliptin 50–200 mg/day, linagliptin 5 mg/day for ≥3 months | CC genotype (vs CT and TT genotypes) had a twofold higher chance of attaining HbA1c ≤53 mmol/mol (OR 2.00 [95% CI 1.03, 3.77]) in logistic regression analysis | [20] |
CTRB1/CTRB2 | rs7202877 (T>C, G) | 49 with T2D (Netherlands), 305 with T2D (UK) | Vildagliptin, sitagliptin for ≥3 months | G allele carriers showed a 5.6 mmol/mol smaller HbA1c response compared with the TT genotype (p = 0.0015) | [21] |
PRKD1 | rs57803087 (A>G) | 171 with T2D | Sitagliptin, saxagliptin, vildagliptin or linagliptin | Mean HbA1c change after 3 months was −10.4 mmol/mol; in GWAS rs57803087 was associated with response to DPP-4i (p = 3.2 × 10−6) | [23] |
CDKAL1 | rs7754840 (G>C) rs7756992 (A>G) | 798 with T2D | DPP-4i (n = 512) | HbA1c reduction after 3 months was −1.1 mmol/mol per rs7754840 C risk allele (p = 0.02), maintained after 12 months For rs7756992, HbA1c reduction per risk allele was also significant over 12 months (G risk allele: HbA1c −0.9 to 1.9 mmol/mol) | [24] |
IL-6 | rs1800796 (G>A, C) rs2097677 (G>A) | 331 with T2D | DPP-4i in combination with other glucose-lowering drugs | No relationship between two IL6 SNPs and non-response to DPP-4i (≥2.2 mmol/mol HbA1c decrease at 3 months); OR for both SNPs combined was 0.45, (p = 0.07) Lower odds (OR 0.15) for non-response in moderate/high physical activity group (for both SNPs combined) | [27] |
TCF7L2 | rs7903146 (C>G, T) | 961 with T2D | Linagliptin (5 mg/day) plus metformin or pioglitazone (placebo controlled) | Linagliptin lowered HbA1c in all variant carriers (CC −9.0 mmol/mol, CT −8.4 mmol/mol, TT −6.2 mmol/mol) HbA1c response was reduced in TT compared with CC carriers (2.8 mmol/mol; p = 0.02) | [30] |
DPP4 | rs2909451 (C>A, T) rs759717 (G>C) | 27 with T2D and hypertension and 38 healthy control individuals | Sitagliptin 100 or 200 mg/day or matching placebo (RCT) | Genotypes associated with higher DPP4 activity during sitagliptin (rs2909451 TT and rs759717 CC) Predictors of DPP4 activity (multivariable analysis): sitagliptin dose, history of type 2 diabetes or hypertension, age, baseline systolic BP, rs2909451 genotype (β = 0.19, p = 0.04) | [32] |
PNPLA3 | rs738409 (C>G, T) | 41 with T2D and NAFLD | Alogliptin 25 mg/day | G allele carriers showed a stronger positive correlation between change in HbA1c and changes in liver aminotransferases In the weight-loss group, improvements in total cholesterol and triacylglycerols were greater in CG and GG carriers than in CC carriers | [34] |
Gene | Genetic variant | Study population (n) | Glucose-lowering treatment | Clinical outcome | Reference |
---|---|---|---|---|---|
GLP1R | rs3765467 (G>A, C, T) rs761386 (C>G, T) | 36 with T2D | CSII for 6 days followed by combination with exenatide (5 μg twice daily) for 3 days | rs761386 CT/TT genotypes: higher glucose levels at 120 min (75 g OGTT; p = 0.032) Insulin and C-peptide (OGTT) were not significantly different between the genotypes after exenatide treatment | [35] |
GLP1R | rs6923761 (G>A, C) | 90 with T2D and obesity | Liraglutide (1.8 mg/day s.c.) added to metformin for 14 weeks | Variant A allele carriers showed greater decreases in BMI (−0.59 vs −1.69 kg/m2) and fat mass (−0.59 vs −1.69 kg) Weight reduction after liraglutide was greater in A allele carriers by 2.9 kg (95%CI 0.27, 5.64) in multiple regression analysis | [36] |
GLP1R | rs10305420 (C>T) rs3765467 (G>A, C, T) | 289 with T2D and obesity | Exenatide 5 μg twice daily for 6 months | T allele (rs10305420) was associated with smaller reductions in HbA1c (−4.4 mmol/mol) and body weight (−1.27 kg) after exenatide (6 months) | [37] |
CNR1 | rs1049353 (G>A) | 86 with T2D and obesity | Liraglutide (1.8 mg/day s.c.) added to metformin or sulfonylurea for 14 weeks | Before and after treatment, BMI, body weight, fat mass and waist circumference were higher in G vs A allele carriers The decrease in basal glucose and HbA1c was similar in both genotypes. In A allele carriers, HOMA-IR decreased (7.6 ± 8.8 at baseline; 5.8 ± 7.4 at 14 weeks) | [39] |
TCF7L2 | rs7903146 (C>G, T) | 162 with T2D | Exenatide for 8 weeks (n = 56) | Plasma glucose values were similar in CC and CT/TT genotypes (meal tests) before and after exenatide treatment After exenatide, CT and TT (vs CC) carriers demonstrated insulin reduction at 30–180 min during meal test (p < 0.05) | [40] |
SORCS1 | rs1416406 (A>G, T) | 101 with newly diagnosed T2D | Exenatide 5 μg twice daily (weeks 1–4) then 10 μg twice daily (weeks 5–48) | rs1416406 was significantly associated with PIR change (p < 0.05) after adjustment for age, sex and baseline BMI HbA1c and PIR in linear regression: greater reduction in PIR in GG genotype | [43] |
Gene | Genetic variant | Study population (n) | Glucose-lowering treatment | Clinical outcome | Reference |
---|---|---|---|---|---|
SLC5A2 | rs3116149 (G>A) rs9934336 (G>A) rs3813008 (G>A) rs11646054 (G>A) rs3116650 (G>A) | 908 with T2D | Empagliflozin 10 mg (n = 603) vs placebo (n = 305) | No association between SNPs and response to treatment with empagliflozin (HbA1c, fasting glucose, body weight, systolic BP) | [44] |
PNPLA3 | rs738409 (C>G, T) | 80 with T2D and NAFLD | Dapagliflozin 10 mg, n-3 carboxylic acid 4 g, combination of both, or placebo (RCT) | Combination treatment: reduction in liver fat (PDFF) was greater for CG and GG genotypes (relative change −25.4%) than for the CC genotype (−16.1%) | [46] |
UGT1A9 | rs72551330 (T>A, C) | 764 with T2D, 397 healthy control individuals | Canagliflozin 25–400 mg/day (in T2D group) | Higher median dose-normalised canagliflozin AUC in UGT1A9*3 allele carriers (ratio 1.26 [95% CI 1.08, 1.44]) | [47] |
UGT1A9 | rs72551330 (T>A, C) | 65 with T2D, 69 healthy control individuals | Canagliflozin 50–300 mg/day | Dose-normalised AUC for canagliflozin was higher (by 45%) in UGT1A9*3 allele carriers (n = 4) | [48] |