DPP-IV Inhibitors Underlying Mechanism of Cancer in Diabetic Patients

Effect of DPP-IV Inhibitors on Occurence of Cancers and the Mechanism Using AGE and RAGE in Patients With Type 2 Diabetes

Recently, DPP-IV inhibitors are used as a novel way to augment the incretin system and one of the newest classes of medications in the treatment of type 2 diabetes mellitus (T2DM). Since the DPP-IV inhibitor was first used, about 5 years have passed in USA. However, there were no major side effects including occurrence of cancers. The main mechanism for DPP-IV inhibitors is due to suppress the function of DPP-IV activity. As it is known that the suppressed DPP-IV activity is a marker for early diagnosis of cancers, the reason of disassociation is not clear.

Activation of receptor for advanced glycation endproduct (AGE) is related to sideration of cancers. Meanwhile, the DPP-IV inhibitors may be related to inhibit the activation of receptor for AGE (RAGE). Therefore, DPP-IV inhibitors may work as a cancer protective agent in diabetes by blocking the AGE-RAGE axis.

However, it is not demonstrated why DPP-IV inhibitors have no side effect of occurrence of cancer via blocking the activation of AGE-RAGE.

The investigators examined effect of DPP-IV inhibitors on frequency of cancers and the underlying mechanism using AGE and RAGE before and 5 years after administration of DPP-IV inhibitors in Japanese patients with T2DM.

Study Overview

• Status: Unknown
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Sitagliptin; Drug: Alogliptin; Drug: Vildagliptin

Detailed Description

The AGE and RAGE are measured using ELISA method in the laboratory of Department of Pathophysiology and Therapeutics of Diabetes Vascular Complications, Kurume University, School of Medicine, Japan before and for 5 years after administration of DPP-IV inhibitors.

• Study Type: Observational
• Enrollment (Anticipated): 500

Contacts and Locations

• Study Contact: Name: Kyuzi Kamoi, MD; Phone Number: +81-0258-28-3600; Email: kkam-int@echigo.ne.jp

Study Locations

• Japan
  • Fukuoka
    • Kurume, Fukuoka, Japan, 830-0111
      • Kurume University
      • Contact: Sho-ichi Yamagishi, MD; Phone Number: +81-942-31-7873; Email: shoichi@med.kurume-u.ac.jp
      • Sub-Investigator: Sho-ichi Yamagishi, MD
  • Niigata
    • Nagaoka, Niigata, Japan, 940-2085
      • Nagaoka Red Cross Hospital
      • Sub-Investigator: Sho-ichi Yamagishi, MD
      • Contact: Kyuzi Kamoi, MD; Phone Number: +81-0258-28-3600; Email: kkam-int@echogo.ne.jp
      • Principal Investigator: Kyuzi Kamoi, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

500 patients

Description

Inclusion Criteria:

• Type 2 diabetes mellitus patients with or without cancer

  • Patients who have no treatment with DPP-IV inhibitors.
  • Outpatients regularly visiting hospital
  • Patients 20 years old (gender is disregarded)

Exclusion Criteria:

• Patients with a serious complication in the heart, liver or kidney

  • Pregnant or possibly pregnant patients, or lactating patients
  • Patients participating in other clinical study.
  • Other than the above, patients judged inappropriate as the subjects of this study by the investigator

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DPP-IV inhibitors	Drug: Sitagliptin; The dosage, frequency and duration for each sitagliptin are variant.; Other Names: Other names are not known.; Drug: Alogliptin; The dosage, frequency and duration for each alogliptin are variant.; Other Names: Other names are not known.; Drug: Vildagliptin; The dosage, frequency and duration for each vildagliptin are variant.; Other Names: Other name is not known.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Frequency of cancers	Each one year within 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AGE concentration	Serum AGE is measured using ELISA at the laboratory of Department pf Pathophysiology and Therapeutics of Diabetes Vascular Complications, Kurume University, which requre as 0.75 ml of serum in each patient.	Before and each one year within 5 years
Receptor for AGE concentration	Serum receptor for AGE is measured using ELISA at the laboratory of Department pf Pathophysiology and Therapeutics of Diabetes Vascular Complications, Kurume University, which requre as 0.75 ml of serum in each patient	Before and each one year within 5 years

Collaborators and Investigators

• Sponsor: Nagaoka Red Cross Hospital
• Collaborators: Kurume University
• Investigators: Principal Investigator: Kyuzi Kamoi, MD, Nagaoka Red Cross Hospital

Publications and helpful links

General Publications

• 1.Gooβen K, Gräber S. Longer-term safety of DPP-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis. Diabetes Obes Metab 2012 doi:[Epub ahead of print]. 2.Cornell S. Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes. J Clin Pharm Ther 2012; 21:1365-2710. 3.Cordero OJ, Imbernon M, Chiara LD, Martinez-Zorzano VS, Ayude D, de la Cadena MP, Rodriguez-Berrocal FJ.Potential of soluble CD26 as a serum marker for colorectal cancer detection. World J Clin Oncol 2011;2: 245-61. 4.Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y, Lalla E, Fu C, Hofmann MA, Kislinger T, Ingram M, Lu A, Tanaka H, Hori O, Ogawa S, Stern DM, Schmidt AM. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 2000;18;405:354-60.5.Kang R, Loux T, Tang D, Schapiro NE, Vernon P, Livesey KM, Krasinskas A, Lotze MT, Zeh HJ 3rd. The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc Natl Acad Sci U S A 2012 Apr 16. [Epub ahead of print].6.Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Sitagliptin augments protective effects of GLP-1 against advanced glycation end product receptor axis in endothelial cells. Horm Metab Res 2011; 43:731-4.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Anticipated): October 1, 2017
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: April 26, 2012
• First Submitted That Met QC Criteria: April 27, 2012
• First Posted (Estimate): May 1, 2012

Study Record Updates

• Last Update Posted (Estimate): October 19, 2012
• Last Update Submitted That Met QC Criteria: October 17, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate; Vildagliptin; Alogliptin
• Other Study ID Numbers: 7-Kamoi