Effects of Sitagliptin on Gastric Emptying, Glycaemia and Blood Pressure in Type 2 Diabetes

Diabetes Mellitus Clinical Trial

Official title:

Effects of Sitagliptin on Postprandial Glycaemia, Incretin Hormones and Blood Pressure in Type 2 Diabetes - Relationship to Gastric Emptying

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02324010
• Other study ID #: 140916
• Status: Completed
• Phase: Phase 2
• First received: December 16, 2014
• Last updated: July 5, 2017
• Start date: July 2015
• Est. completion date: January 2017

Study information

• Verified date: July 2017
• Source: Royal Adelaide Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the acute effects of sitagliptin on postprandial glycemia, incretin hormones and blood pressure, and the relationship to gastric emptying, after a mashed potato meal in patients with type 2 diabetes.

Description:

The purpose of this study is to (i) evaluate the acute effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin (100mg once daily for two days), on gastric emptying, postprandial plasma glucose, insulin, glucagon and 'incretin' hormones (ie. glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)), blood pressure and heart rate after a high carbohydrate meal, and (ii) to determine whether the magnitude of the effects of sitagliptin on postprandial glycaemia and blood pressure is related to the rate of gastric emptying, in patients with type 2 diabetes.

The rate of entry of carbohydrate into the small intestine is especially important in patients with diabetes mellitus. Sitagliptin is an orally administered inhibitor of dipeptidyl-peptidase-IV (DPP-IV), the enzyme responsible for the degradation of GLP-1. It is hypothesized that sitagliptin will increase the GLP-1 response to, and thereby slow gastric emptying and diminish the glycaemic and blood pressure response to, a carbohydrate-containing meal.

Twenty healthy subjects (male and female) will be studied. Each subject will be studied on two occasions following treatment for 2 days with sitagliptin (100mg once daily) or matching placebo in a randomized, double blind, crossover design. Measurements of gastric emptying, intragastric meal distribution, blood glucose concentrations, gut hormones, blood pressure, splanchnic flow and appetite will be measured for 4 hours following ingestion of a mashed potato meal.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: January 2017
• Est. primary completion date: January 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria:

• Type 2 diabetes (World Health Organisation (WHO) criteria), managed by diet or metformin alone

• Body mass index (BMI) 20 - 40 kg/m2

• Males and females (females of reproductive potential must be using an appropriate contraceptive method)

• Glycated haemoglobin (HbA1c) = 8.5%

• Haemoglobin above the lower limit of the normal range (i.e. >135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (i.e. >10mcg/L)

Exclusion Criteria:

• Subjects with gastrointestinal disease, significant upper or lower gastrointestinal symptoms, or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy)

• Other significant illness, including epilepsy, cardiovascular or respiratory disease.

• History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy.

• Impaired renal or liver function (as assessed by calculated creatinine clearance < 50 mL/min using the Cockroft-Gault equation (27) or abnormal liver function tests (> 2 times upper limit of normal range)).

• Requirement for medication known to influence blood pressure and/or heart rate and/or gastrointestinal function, drugs with anticholinergic effects

• Alcohol consumption > 20 g per day

• Smoking > 10 cigarettes per day

• Pregnancy or lactation.

• Vegetarian

• Allergy to sitagliptin or any other 'gliptin'.

• Donation of blood within the previous 3 months

• Participation in any other research studies within the previous 3 months

• Exposure to ionising radiation for research purposes in the previous 12 months

• Inability to give informed consent

Related Conditions & MeSH terms

• Diabetes Mellitus
• Gastroparesis

Intervention

Drug:
• Sitagliptin
100mg mane for 2 days
• Placebo
Inactive drug (Placebo)

Locations

Country	Name	City	State
Australia	University of Adelaide, Discipline of Medicine, Royal Adelaide Hospital	Adelaide	South Australia

Sponsors (1)

Lead Sponsor	Collaborator
Royal Adelaide Hospital

Country where clinical trial is conducted

Australia, 

References & Publications (32)

Ahrén B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):517-33. Review. — View Citation

Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007 May;132(6):2131-57. Review. — View Citation

Chaikomin R, Rayner CK, Jones KL, Horowitz M. Upper gastrointestinal function and glycemic control in diabetes mellitus. World J Gastroenterol. 2006 Sep 21;12(35):5611-21. Review. — View Citation

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. — View Citation

Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011 Jan;13(1):7-18. doi: 10.1111/j.1463-1326.2010.01306.x. Review. — View Citation

ELRICK H, STIMMLER L, HLAD CJ Jr, ARAI Y. PLASMA INSULIN RESPONSE TO ORAL AND INTRAVENOUS GLUCOSE ADMINISTRATION. J Clin Endocrinol Metab. 1964 Oct;24:1076-82. — View Citation

Gentilcore D, Bryant B, Wishart JM, Morris HA, Horowitz M, Jones KL. Acarbose attenuates the hypotensive response to sucrose and slows gastric emptying in the elderly. Am J Med. 2005 Nov;118(11):1289. — View Citation

Horowitz M, Edelbroek MA, Wishart JM, Straathof JW. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia. 1993 Sep;36(9):857-62. — View Citation

Horowitz M, Rayner CK, Jones KL. Mechanisms and clinical efficacy of lixisenatide for the management of type 2 diabetes. Adv Ther. 2013 Feb;30(2):81-101. doi: 10.1007/s12325-013-0009-4. Epub 2013 Feb 13. Review. — View Citation

Information JsP: Merck Sharp & Dohme (Australia) Pty Ltd. South Granville, NSW, Australia, 2008.

Jansen RW, Lipsitz LA. Postprandial hypotension: epidemiology, pathophysiology, and clinical management. Ann Intern Med. 1995 Feb 15;122(4):286-95. Review. — View Citation

Jian ZJ, Zhou BY. Efficacy and safety of acarbose in the treatment of elderly patients with postprandial hypotension. Chin Med J (Engl). 2008 Oct 20;121(20):2054-9. — View Citation

Jones KL, Horowitz M, Carney BI, Wishart JM, Guha S, Green L. Gastric emptying in early noninsulin-dependent diabetes mellitus. J Nucl Med. 1996 Oct;37(10):1643-8. — View Citation

Jones KL, Tonkin A, Horowitz M, Wishart JM, Carney BI, Guha S, Green L. Rate of gastric emptying is a determinant of postprandial hypotension in non-insulin-dependent diabetes mellitus. Clin Sci (Lond). 1998 Jan;94(1):65-70. — View Citation

Khoo J, Rayner CK, Jones KL, Horowitz M. Incretin-based therapies: new treatments for type 2 diabetes in the new millennium. Ther Clin Risk Manag. 2009 Jun;5(3):683-98. Epub 2009 Aug 20. — View Citation

Ma J, Pilichiewicz AN, Feinle-Bisset C, Wishart JM, Jones KL, Horowitz M, Rayner CK. Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes. Diabet Med. 2012 May;29(5):604-8. doi: 10.1111/j.1464-5491.2011.03496.x. — View Citation

Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986 Jan;29(1):46-52. — View Citation

Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993 Jan;91(1):301-7. — View Citation

Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, Schmiegel WH. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997 Nov;273(5 Pt 1):E981-8. — View Citation

Parker BA, Sturm K, MacIntosh CG, Feinle C, Horowitz M, Chapman IM. Relation between food intake and visual analogue scale ratings of appetite and other sensations in healthy older and young subjects. Eur J Clin Nutr. 2004 Feb;58(2):212-8. — View Citation

Pilichiewicz AN, Chaikomin R, Brennan IM, Wishart JM, Rayner CK, Jones KL, Smout AJ, Horowitz M, Feinle-Bisset C. Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men. Am J Physiol Endocrinol Metab. 2007 Sep;293(3):E743-53. Epub 2007 Jul 3. — View Citation

Rayner CK, Samsom M, Jones KL, Horowitz M. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care. 2001 Feb;24(2):371-81. Review. — View Citation

Russo A, Stevens JE, Wilson T, Wells F, Tonkin A, Horowitz M, Jones KL. Guar attenuates fall in postprandial blood pressure and slows gastric emptying of oral glucose in type 2 diabetes. Dig Dis Sci. 2003 Jul;48(7):1221-9. — View Citation

Sasaki E, Goda K, Nagata K, Kitaoka H, Ohsawa N, Hanafusa T. Acarbose improved severe postprandial hypotension in a patient with diabetes mellitus. J Diabetes Complications. 2001 May-Jun;15(3):158-61. — View Citation

Stevens JE, Horowitz M, Deacon CF, Nauck M, Rayner CK, Jones KL. The effects of sitagliptin on gastric emptying in healthy humans - a randomised, controlled study. Aliment Pharmacol Ther. 2012 Aug;36(4):379-90. doi: 10.1111/j.1365-2036.2012.05198.x. Epub 2012 Jun 28. — View Citation

Trahair LG, Vanis L, Gentilcore D, Lange K, Rayner CK, Horowitz M, Jones KL. Effects of variations in duodenal glucose load on blood pressure, heart rate, superior mesenteric artery blood flow and plasma noradrenaline in healthy young and older subjects. Clin Sci (Lond). 2012 Mar;122(6):271-9. doi: 10.1042/CS20110270. — View Citation

Vanis L, Gentilcore D, Rayner CK, Wishart JM, Horowitz M, Feinle-Bisset C, Jones KL. Effects of small intestinal glucose load on blood pressure, splanchnic blood flow, glycemia, and GLP-1 release in healthy older subjects. Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1524-31. doi: 10.1152/ajpregu.00378.2010. Epub 2011 Mar 9. — View Citation

Vella A, Bock G, Giesler PD, Burton DB, Serra DB, Saylan ML, Dunning BE, Foley JE, Rizza RA, Camilleri M. Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes. Diabetes. 2007 May;56(5):1475-80. Epub 2007 Feb 15. — View Citation

Woerle H, Lindenberger T, Linke R, Foley JE, Ligueros-Sayalan AA, ZhangY, He Y-L, BelingerC, Goeke B, Schirra J. A single dose of vidagliptin (VILDA) decelerates gastric emptying (GE) in patients with type 2 diabetes (T2DM). American Diabetes Association, 67th Scientific Sessions 500-p (abstract), 2007.

Wu T, Bound MJ, Zhao BR, Standfield SD, Bellon M, Jones KL, Horowitz M, Rayner CK. Effects of a D-xylose preload with or without sitagliptin on gastric emptying, glucagon-like peptide-1, and postprandial glycemia in type 2 diabetes. Diabetes Care. 2013 Jul;36(7):1913-8. doi: 10.2337/dc12-2294. Epub 2013 Jan 28. — View Citation

Wu T, Rayner CK, Young RL, Horowitz M. Gut motility and enteroendocrine secretion. Curr Opin Pharmacol. 2013 Dec;13(6):928-34. doi: 10.1016/j.coph.2013.09.002. Epub 2013 Sep 20. Review. — View Citation

Yonenaga A, Ota H, Honda M, Koshiyama D, Yagi T, Hanaoka Y, Yamamoto H, Yamaguchi Y, Iijima K, Akishita M, Ouchi Y. Marked improvement of elderly postprandial hypotension by dipeptidyl peptidase IV inhibitor. Geriatr Gerontol Int. 2013 Jan;13(1):227-9. doi: 10.1111/j.1447-0594.2012.00903.x. — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Gastric emptying	Gastric retention (percent in the total stomach)	3 hours per gastric emptying study (i.e. 6 hours)
Secondary	Glycaemia	blood glucose (mmol/L) and plasma insulin (mU/L)	4 hours during each gastric empty study (i.e. 8 hours)
Secondary	Gastrointestinal hormone release	GLP-1, GIP, C-peptide, 3-OMG	4 hours during each gastric empty study (i.e. 8 hours)
Secondary	Intragastric meal distribution	percent retention in the proximal and distal stomach	3 hours during each gastric empty study (i.e. 6 hours)
Secondary	Blood pressure	systolic and diastolic blood pressure (mmHg)	4.5 hours during each gastric empty study (i.e. 9 hours)
Secondary	Heart rate	Heart rate (beats per minute)	4.5 hours during each gastric empty study (i.e. 9 hours)
Secondary	Splanchnic blood flow	Doppler ultrasound of superior mesenteric artery flow (ml/min)	4 hours during each gastric empty study (i.e. 8 hours)
Secondary	Cardiac output	Finapres (L)	4 hours during each gastric empty study (i.e. 8 hours)
Secondary	Stroke volume	Finapres (mL)	4 hours during each gastric empty study (i.e. 8 hours)
Secondary	Appetite	visual analogue questionnaire to assess hunger, fullness, desire to eat (mm)	4 hours during each gastric empty study (i.e. 8 hours)