The influence of age and metformin treatment status on reported gastrointestinal side effects with liraglutide treatment in type 2 diabetes.

AIM: Treatment of type 2 diabetes with glucagon-like peptide-1 (GLP-1) receptor agonists may be limited by gastrointestinal side effects (GISE) in some patients. Risk factors for developing GISE are not known. We analysed patient characteristics that were associated with GISE among patients treated with the GLP-1 receptor agonist liraglutide. METHODS: Data was obtained from an audit database of liraglutide use based in clinical practice in the UK. Patients were grouped into those who did not report GISE, those who reported GISE but continued liraglutide and those who discontinued liraglutide due to GISE within 26 weeks of treatment. Baseline variables of age, diabetes duration, HbA1c, weight, BMI, blood pressure, lipids, gender, ethnicity, alanine transaminotransferase, estimated glomerular filtration rate (eGFR) and diabetes treatment types were tested for possible associations with GISE outcome. Significant variables in univariate analyses were entered into ordinal logistic regression analyses. RESULTS: A total of 4442 patients were suitable for analysis. A total of 3905 (87.9%) did not report GISE, 297 (6.7%) and 240 (5.4%) had GISE and continued and discontinued treatment, respectively. Age, weight, eGFR, metformin status and insulin status were associated with GISE outcome in univariate analyses (P all <0.05). In the final regression model, age (adjusted OR 1.15 [95%CI 1.05,1.26], P=0.002) and non-metformin use (adjusted OR 0.76 [95%CI 0.60,0.96], P=0.020) were associated with worse GISE outcome. CONCLUSION: Older age and non-metformin use were associated with more significant GISE leading to discontinuation of liraglutide treatment. The reasons for these findings are unclear and warrant further investigation.

The association between postprandial urinary C-peptide creatinine ratio and the treatment response to liraglutide: a multi-centre observational study.

AIMS: The response to glucagon-like peptide 1 receptor agonist treatment may be influenced by endogenous ß-cell function. We investigated whether urinary C-peptide creatinine ratio assessed before or during liraglutide treatment was associated with treatment response. METHODS: A single, outpatient urine sample for urinary C-peptide creatinine ratio was collected 2 h after the largest meal of the day among two separate groups: (1) subjects initiating liraglutide (0.6 â†’ 1.2 mg daily) or (2) subjects already treated with liraglutide for 20-32 weeks. The associations between pretreatment and on-treatment urinary C-peptide creatinine ratio and HbA1c change at 32 weeks were assessed using univariate and multivariate analyses (the ratio was logarithm transformed for multivariate analyses). Changes in HbA1c according to pretreatment urinary C-peptide creatinine ratio quartiles are shown. RESULTS: One hundred and sixteen subjects (70 pretreatment, 46 on treatment) with Type 2 diabetes from 10 diabetes centres were studied. In univariate analyses, neither pretreatment nor on-treatment urinary C-peptide creatinine ratio correlated with HbA1c change (Spearman rank correlation coefficient, r = -0.17, P = 0.17 and r = -0.20, P = 0.19, respectively). In multi-linear regression analyses, entering baseline HbA1c and log urinary C-peptide creatinine ratio, pretreatment and on-treatment log urinary C-peptide creatinine ratio became significantly associated with HbA1c change (P = 0.048 and P = 0.040, respectively). Mean (sd) HbA1c changes from baseline in quartiles 1 to 4 of pretreatment urinary C-peptide creatinine ratio were -3 ± 17 mmol/mol (-0.3 ± 1.6%) (P = 0.52), -12 ± 15 mmol/mol (-1.1 ± 1.4%) (P = 0.003), -11 ± 13 mmol/mol (-1.0 ± 1.2%) (P = 0.002) and -12±17 mmol/mol (-1.1±1.6%) (P=0.016), respectively. CONCLUSIONS: Postprandial urinary C-peptide creatinine ratios before and during liraglutide treatment were weakly associated with the glycaemic response to treatment. Low pretreatment urinary C-peptide creatinine ratio may be more useful than higher values by predicting poorer glycaemic response.

Response at 3 months to insulin dose decisions made at exenatide initiation in the Association of British Clinical Diabetologists (ABCD) nationwide exenatide audit.

It is uncertain what should be done with insulin dose if starting exenatide. In the ABCD nationwide exenatide audit, many patients with type 2 diabetes had worsened glycaemia when insulin was stopped. If starting exenatide, insulin should not be stopped but weaned off only if there is significant glycaemic response.

Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit*.

AIM: To assess the extent, safety, efficacy and tolerability of reported off-licence exenatide use through a nationwide audit. METHODS: The Association of British Clinical Diabetologists hosted a password-protected, online collection of anonymized data of exenatide use in real clinical practice. Three hundred and fifteen contributors from 126 centres across UK provided data on 6717 patients. HbA1c and weight changes, exenatide discontinuation, adverse events and treatment satisfaction were compared between non-insulin and insulin-treated patients. RESULTS: Four thousand eight hundred and fifty-seven patients had baseline and follow-up treatment status with mean (±s.d.) baseline HbA1c 9.45 ± 1.69% and BMI 40.0 ± 8.2 kg/m(2) . Of the 4857 patients, 1921 (39.6%) used exenatide with insulin. Comparing patients who continued insulin with exenatide with non-insulin-treated patients, mean (±s.e.) latest HbA1c and weight reduction (median 26 weeks) were 0.51 ± 0.06 versus 0.94 ± 0.04% (p < 0.001) and 5.8 ± 0.2 versus 5.5 ± 0.1 kg (p = 0.278). Insulin-treated patients had higher rates of exenatide discontinuation (31.0 vs. 13.9%, p < 0.001), hypoglycaemia (8.9 vs. 6.1%, p < 0.001), gastrointestinal side effects (28.4 vs. 25.0%, p = 0.008) and treatment dissatisfaction (20.8 vs. 5.7%, p < 0.001). However, 34.2% of the patients continuing insulin still achieved HbA1c reduction ≥1%. There was significant insulin discontinuation, dose reduction and greater sulphonylurea discontinuation among insulin-treated patients. CONCLUSIONS: Addition of exenatide to obese, insulin-treated patients can improve glycaemia and weight. Adverse events were statistically but probably not clinically significantly higher, but combination treatment was less well tolerated. Overall, exenatide was less effective in lowering HbA1c among insulin-treated patients, although significant number of insulin-treated patients still achieved significant HbA1c, weight and insulin reductions. Further research into identifying obese, insulin-treated patients who will tolerate and benefit from exenatide treatment is urgently needed.