Sitagliptin and Brown Adipose Tissue

NCT02294084 | Completed Phase 4 DMC

• 1 other identifier: P14.242
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

The obesity epidemic has resulted in an exponential increase in obesity-related disorders including type 2 diabetes, dyslipidemia and cardiovascular disease. The associated morbidity and mortality have major consequences both at an individual as well as on the socioeconomical level. Thus, the development of novel therapies aimed at reducing the development of obesity is highly warranted. Brown adipose tissue (BAT) recently emerged as a novel player in energy expenditure in humans as it combusts fatty acids towards heat. Interestingly, obese subjects have less BAT as compared to lean subjects and activation of BAT by means of intermittent cold exposure reduces fat mass. Therefore, BAT is considered a promising novel target to reduce obesity and associated disorders. As cold exposure is not the most desired therapeutic strategy for humans, current pre-clinical research focuses on pharmacological activation of BAT. Interestingly, the investigators have recently shown that central agonism of the receptor for the incretin hormone glucacon-like peptide-1 (GLP-1) results in activation of BAT in mice. One of the currently used anti-diabetic drugs that enhances GLP-1 availability is Sitagliptin (STG). Interestingly, STG also reduces body weight and plasma triglyceride (TG) levels in type 2 diabetes mellitus (T2DM) patients. The mechanism underlying these beneficial metabolic effects is currently unknown. The investigators hypothesize that STG enhances BAT activation, thereby increasing energy expenditure and combustion of TG-derived fatty acids, resulting in lowering of plasma TG levels and body weight. To this end, the investigators will perform a randomized double-blinded placebo-controlled study in which 30 male Dutch Caucasian adults aged 35-50 years with moderate obesity and pre-diabetes are included. Subjects will be treated for 12 weeks with STG or placebo. Before and after treatment, the investigators will determine BAT volume and total BAT activity via cold-induced 18F-FDG PET-CT scans, resting energy expenditure via indirect calorimetry using ventilated hoods, body weight, and body composition via DEXA scan. Furthermore, before and after treatment, blood samples will be taken to measure plasma lipids, glucose and insulin levels. This study will offer valuable novel insight in the effects of pharmacological activation of BAT in human obese subjects.

Conditions

Neoplasms, Adipose Tissue

Outcome Measures

Primary Outcomes (1)

• The effect of sitagliptin treatment on BAT activity in overweight, pre-diabetic subjects BAT volume and activity will be measured by means of cold-induced 18F-FDG PET-CT scans

  BAT volume and activity will be measured by means of cold-induced 18F-FDG PET-CT scans

  after 12 weeks of treatment

Secondary Outcomes (5)

• The effect of sitagliptin treatment on energy expenditure in overweight, pre-diabetic subjects indirect calorimetrie

  after 12 weeks of treatment

• The effect of sitagliptin treatment on muscle glucose metabolism in overweight, pre-diabetic subjects Expression and/or activation of biomarkers for insulin signaling and glucose and lipid metabolism in skeletal muscle biopsies

  after 12 weeks of treatment

• The effect of sitagliptin treatment on fat mass in overweight, pre-diabetic subjects Fat mass will be measured via DEXA scan

  after 12 weeks of treatment

• The effect of sitagliptin treatment on glucose metabolism in overweight, pre-diabetic subjects serum glucose, insulin, and HbA1c. Furthermore, insulin secretion will be determined by OGTT together with C-peptine, glucose and insulin area under the curve

  after 12 weeks of treatment

• The effect of sitagliptin treatment on plasma lipid levels in overweight, pre-diabetic subjects total cholesterol, HDL-C LDL-C triglycerides, and free fatty acids in plasma

  after 12 weeks of treatment

Study Arms (2)

Sitagliptin

EXPERIMENTAL

Subjects will receive Sitagliptin in a dosage of 100 mg/day p.o. for 12 weeks. The dosage corresponds to 1 gift/day.

Drug: Sitagliptin

Placebo

PLACEBO COMPARATOR

Subjects will receive placebo for 12 weeks. Placebo will be given in 1 gift/day

Drug: placebo

Interventions

Sitagliptin DRUG

Each subject in this arm will receive Sitagliptin (100mg/day) for a duration of 12 weeks.

Also known as: Januvia

Sitagliptin

placebo DRUG

Each subject will receive a placebo (once a day) for 12 weeks.

Placebo

Eligibility Criteria

• Age: 35 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Male volunteers, Caucasians, born in the Netherlands
• Age: 35-55 years
• BMI \> 25 and \< 32 kg/m2
• plasma glucose levels 2 h after OGTT between 7.8 and 11 mM (e.g. impaired glucose tolerance)

You may not qualify if:

• Diabetes mellitus (determined on basis of oral glucose tolerance test (OGTT)) defined by ADA criteria
• BMI \> 30 kg/m2 or \< 25 kg/m2
• plasma glucose levels 2 h after OGTT \< 7.8 or \> 11.1 mM
• use of medication known to influence glucose and/or lipid metabolism or BAT activity (e.g. beta blockers)
• any significant chronic disease
• renal, hepatic or endocrine disease
• smoking
• participation in an intensive weight-loss program or vigorous exercise program during the last year before start of the study
• difficulties to insert an intravenous catheter
• recent participation in other research projects (within the last 3 months)

Sponsors & Collaborators

• Ingrid Jazet: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Leiden University Medical Center

Leiden, South Holland, 2333 ZA, Netherlands

Location

Related Publications (1)

• Nahon KJ, Doornink F, Straat ME, Botani K, Martinez-Tellez B, Abreu-Vieira G, van Klinken JB, Voortman GJ, Friesema ECH, Ruiz JR, van Velden FHP, de Geus-Oei LF, Smit F, Pereira Arias-Bouda LM, Berbee JFP, Jazet IM, Boon MR, Rensen PCN. Effect of sitagliptin on energy metabolism and brown adipose tissue in overweight individuals with prediabetes: a randomised placebo-controlled trial. Diabetologia. 2018 Nov;61(11):2386-2397. doi: 10.1007/s00125-018-4716-x. Epub 2018 Aug 25.

  PMID: 30145664 DERIVED

MeSH Terms

Conditions

Neoplasms, Adipose Tissue

Interventions

Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Study Officials

• Patrick Rensen, PhD

  Head of department

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: November 17, 2014
• First Posted: November 19, 2014
• Study Start: March 1, 2014
• Primary Completion: October 1, 2016
• Study Completion: December 1, 2016
• Last Updated: July 16, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)