Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients

Mark M Smits, Lennart Tonneijck, Marcel H A Muskiet, Trynke Hoekstra, Mark H H Kramer, Michaela Diamant, Max Nieuwdorp, Albert K Groen, Djuna L Cahen, Daniël H van Raalte, Mark M Smits, Lennart Tonneijck, Marcel H A Muskiet, Trynke Hoekstra, Mark H H Kramer, Michaela Diamant, Max Nieuwdorp, Albert K Groen, Djuna L Cahen, Daniël H van Raalte

Abstract

Aims: Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile.

Materials and methods: A total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m2 ; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12 weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236).

Results: Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027-0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22-68.21), p = 0.005] and in faeces [ratio 1.5 (1.03-2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p = 0.012], cholic acid [ratio 3.32 (1.26-8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p = 0.008].

Conclusions: Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.

Keywords: DPP-4; GLP-1; bile acids; dipeptidyl peptidase 4; gallbladder emptying; gastric emptying; glucagon-like peptide 1.

© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Gallbladder emptying. Gallbladder volume as measured using ultrasonography; A, before intervention and B, after 12‐week treatment with placebo, sitagliptin or liraglutide. Measurements were performed in the fasting state and after a high‐fat mixed meal; C, maximal ejection fraction (EF) at baseline and after 12‐week treatment; D, area under the curve of the gallbladder volume at baseline and after 12‐week treatment. No significant effects were observed.
Figure 2
Figure 2
Bile acids in serum. Area under the curve (AUC) and incremental‐AUC (iAUC) for the postprandial serum bile acids before and after 12‐week treatment with placebo (PCB), sitagliptin (SITA) or liraglutide (LIRA). Data are presented as µmol/l/2 h. A, cholic acid (CA); B, taurocholic acid (TCA); C, glycocholic acid (GCA); D, chenodeoxycholic acid (CDCA); E, tauro chenodeoxycholic acid (TCDCA); F, glycochenodeoxycholic acid (GCDCA); G, deoxycholic acid (DCA); H, taurodeoxycholic acid (TDCA); I, glycodeoxycholic acid (GDCA); J, ursodeoxycholic acid (UDCA); K, glyco‐ursodeoxycholic acid (GUDCA); L, litocholic acid (LCA); and M, glycinelitocholic acid (GLCA). Tauro‐ursodeoxycholic acid (TUDCA) and taurolithocholic acid (TLCA) are not depicted, as most values were below the detection limit. All data are presented as mean with standard error of the mean. Asterisks (*) indicate statistically significant differences (p < .05) between treatment and placebo, corrected for baseline differences.
Figure 3
Figure 3
Bile acids in faeces. Faecal bile acids and neutral sterols after 12‐weeks of treatment with placebo (PCB), sitagliptin (SITA) or liraglutide (LIRA). A, cholic acid (CA); B, chenodeoxycholic acid (CDCA); C, deoxycholic acid (DCA); D, ursodeoxycholic acid (UDCA); E, lithocholic acid (LCA); F, iso‐lithocholic acid (iso‐LCA); G, coprostanol; H, cholesterol; and I, dihydrocholesterol. All data are presented as median with interquartile range (box) and total range (whiskers). A logarithmic scale was chosen for the y‐axis because of the wide range of values. Asterisks (*) indicate statistically significant differences (p < .05) between treatment and placebo, corrected for baseline differences.

References

    1. Smits MM, Tonneijck L, Muskiet MHA, et al. Gastrointestinal actions of GLP‐1 based therapies: glycaemic control beyond the pancreas. Diabetes Obes Metab. 2016;18(2):178–185.
    1. Keller J, Trautmann ME, Haber H, et al. Effect of exenatide on cholecystokinin‐induced gallbladder emptying in fasting healthy subjects. Regul Pept. 2012;179(1‐3):77–83.
    1. Ben‐Shlomo S, Shlomo S, Ben, Zvibel I, et al. Dipeptidyl peptidase 4‐deficient rats have improved bile secretory function in high fat diet‐induced steatosis. Dig Dis Sci. 2013;58(1):172–178.
    1. Pi‐Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22.
    1. Korkmaz H, Araz M, Alkan S, Akarsu E. Liraglutide‐related cholelithiasis. Aging Clin Exp Res. 2015;27(5):751–753.
    1. Pizzimenti V, Giandalia A, Cucinotta D, et al. Incretin‐based therapy and acute cholecystitis: a review of case reports and EudraVigilance spontaneous adverse drug reaction reporting database. J Clin Pharm Ther. 2016;41(2):116–118.
    1. Marso SP, Daniels GH, Brown‐Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–322.
    1. Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap‐‐bile acids in metabolic control. Nat Rev Endocrinol. 2014;10(8):488–498.
    1. Smits MM, Tonneijck L, Muskiet MHA, et al. Cardiovascular, renal and gastrointestinal effects of incretin‐based therapies: an acute and 12‐week randomised, double‐blind, placebo‐controlled, mechanistic intervention trial in type 2 diabetes. BMJ Open. 2015;5(11):e009579.
    1. Glerup H, Bluhme H, Villadsen GE, et al. Gastric emptying: a comparison of three methods. Scand J Gastroenterol. 2007;42(10):1182–1186.
    1. Dodds WJ, Groh WJ, Darweesh RM, et al. Sonographic measurement of gallbladder volume. AJR Am J Roentgenol. 1985;145(5):1009–1011.
    1. Sari R, Balci MK, Coban E, Karayalcin U. Sonographic evaluation of gallbladder volume and ejection fraction in obese women without gallstones. J Clin Ultrasound. 2003;31(7):352–357.
    1. Bastouly M, Arasaki CH, Ferreira JB, et al. Early changes in postprandial gallbladder emptying in morbidly obese patients undergoing Roux‐en‐Y gastric bypass: correlation with the occurrence of biliary sludge and gallstones. Obes Surg. 2009;19(1):22–28.
    1. Vrieze A, Out C, Fuentes S, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol. 2014;60(4):824–831.
    1. van Meer H, Boehm G, Stellaard F, et al. Prebiotic oligosaccharides and the enterohepatic circulation of bile salts in rats. Am J Physiol Gastrointest Liver Physiol. 2008;294(2):G540–G547.
    1. Schaap FG, Trauner M, Jansen PLM. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11(1):55–67.
    1. Napolitano A, Miller S, Nicholls AW, et al. Novel gut‐based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014;9(7):e100778.
    1. Stone BG, Gavaler JS, Belle SH, et al. Impairment of gallbladder emptying in diabetes mellitus. Gastroenterology. 1988;95(1):170–176.
    1. Smits MM, van Raalte DH, Tonneijck L, et al. GLP‐1 based therapies: clinical implications for gastroenterologists. Gut. 2016;65(4):702–711.
    1. Nunez DJ, Yao X, Lin J, et al. Glucose and lipid effects of the ileal apical sodium‐dependent bile acid transporter inhibitor GSK2330672: double‐blind randomized trials with type 2 diabetes subjects taking metformin. Diabetes Obes Metab. 2016;18(7):654–662.
    1. Carulli N, Loria P, Bertolotti M, et al. Effects of acute changes of bile acid pool composition on biliary lipid secretion. J Clin Invest. 1984;74(2):614–624.
    1. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99(6A):3C–18C.
    1. Hodge RJ, Lin J, Vasist Johnson LS, et al. Safety, pharmacokinetics, and pharmacodynamic effects of a selective TGR5 agonist, SB‐756050, in type 2 diabetes. Clin Pharmacol Drug Dev. 2013;2(3):213–222.
    1. van Can J, Sloth B, Jensen CB, et al. Effects of the once‐daily GLP‐1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non‐diabetic adults. Int J Obes. 2014;38(6):784–793.
    1. Jinnouchi H, Sugiyama S, Yoshida A, et al. Liraglutide, a glucagon‐like peptide‐1 analog, increased insulin sensitivity assessed by hyperinsulinemic‐euglycemic clamp examination in patients with uncontrolled type 2 diabetes mellitus. J Diabetes Res. 2015;2015:706416.
    1. Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26‐week, randomised, parallel‐group, open‐label trial. Lancet. 2010;375(9724):1447–1456.
    1. Gutzwiller J‐P, Hruz P, Huber AR, et al. Glucagon‐like peptide‐1 is involved in sodium and water homeostasis in humans. Digestion. 2006;73(2‐3):142–150.
    1. Mekjian HS, Phillips SF, Hofmann AF. Colonic secretion of water and electrolytes induced by bile acids: perfusion studies in man. J Clin Invest. 1971;50(8):1569–1577.
    1. Devkota S, Turnbaugh PJ. Cancer: an acidic link. Nature. 2013;499(7456):37–38.
    1. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426–435.

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