Effect of Linagliptin + Metformin vs Metformin Alone in Patients With Prediabetes

Insulin Resistance Clinical Trial

— PRELLIM  

Official title:

Effect of Linagliptin + Metformin vs Metformin Alone on the Role of Pancreatic Islet Function, Insulin Resistance and Markers of Cardiovascular Risk in Patients With Prediabetes: Randomized Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03004612
• Other study ID #: CEI-22-16
• Status: Completed
• Phase: Phase 4
• Start date: January 2016
• Est. completion date: June 2019

Study information

• Verified date: July 2019
• Source: Universidad de Guanajuato
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Type 2 diabetes is a worldwide epidemic disease, and preventive strategies are needed to face this health problem. The goal of this clinical trial is to evaluate the effect of linagliptin + metformin vs metformin alone on physiopathological parameters, such as glucose metabolism, insulin resistance, insulin secretion and pancreatic beta cell function in patients with impaired fasting glucose plus impaired glucose tolerance, during 24 months.

Description:

The main goal of this clinical trial is to compare the effect of two different treatments during 24 months:

1. Lifestyle modification program + metformin 850mg twice daily

2. Lifestyle modification program + linagliptin (2.5mg) and metformin (850mg) twice daily

on the following parameters, after 24 months of treatment:

1. Glucose metabolism, evaluated by the oral glucose tolerance

2. Insulin resistance, evaluated by the oral glucose tolerance in 100% of the patients and by hyperglycemic clamp in 10 % of the patients

3. Insulin secretion, evaluated by the oral glucose tolerance in 100% of the patients and by hyperglycemic clamp in 10 % of the patients

4. Pancreatic beta cell function, evaluated by the oral glucose tolerance in 100% of the patients and by hyperglycemic clamp in 10 % of the patients

5. Systemic inflammation and cardiovascular risk factors, evaluated by cytokines interlelukin-6 (IL6), C-reactive protein (PCR), and measurement of the intima media thickness by ultrasound.

All the patients will have a basal evaluation with an oral glucose tolerance test, lipid profile, body composition, and IMT measurement by ultrasonography; and 10 % will be invited for the hyperglycemic clamp. After the basal evaluation, if the patients result with IMPAIRED GLUCOSE TOLERANCE and have at least 2 risk factors, they will be invited to the intervention phase where they will be randomized to one of the two treatment groups.

Patients will have a follow-up visit every month to review the adherence to the lifestyle modification program and to the medication. Every 6 months OGTT will be performed on all the patients, and in a subset of patients hyperglycemic clamp will be performed at 0, 6 and 12 months. After 18 and 24 months, patients will repeat the same evaluation performed as the basal evaluation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 144
• Est. completion date: June 2019
• Est. primary completion date: May 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Patients with prediabetes, defined for the existence impaired glucose tolerance (Glucose between 140 and 199 mg/dL at the 2 hours of the Oral Glucose Tolerance test (OGTT) ) with or without impaired fasting glucose (Fasting glucose between 100 and 125 mg/dL)

• Patients who accept to participate in the study and sign the informed consent letter.

Exclusion Criteria:

• Patients with diagnosed Type 2 Diabetes Mellitus previously or detected during the OGTT

• Patients in actual treatment or during the last 3 months with metformin, pioglitazone or another antidiabetic drug, including insulin.

• Serum creatinine > 1.6 mg/dL

• Hypertriglyceridemia very high (>500 mg/dL)

• Pregnant women

• Altered arterial hypertension (Systolic > 180 mmHg or Diastolic >105 mmHg)

• Excessive alcohol intake, acute or chronic

• Medications or medical conditions that affect glucose homeostasis (thiazides, beta blockers, glucocorticoids for systemic use, weight-reducing drugs or anorexigenics, Cushing's syndrome, Thyrotoxicosis.

Related Conditions & MeSH terms

• Glucose Intolerance
• Insulin Resistance
• Prediabetic State

Intervention

Combination Product:
• Linagliptin + metformin
Linagliptin-Metformin 2.5/850mg twice daily plus a lifestyle modification program based on nutritional assesment, physical activity prescription and general counseling

Drug:
• Metformin
Metformin 850mg twice daily plus a lifestyle modification program based on nutritional assesment, physical activity prescription and general counseling

Locations

Country	Name	City	State
Mexico	Universidad de Guanajuato	León	Guanajuato

Sponsors (2)

Lead Sponsor	Collaborator
Universidad de Guanajuato	Hospital Regional de Alta Especialidad del Bajio

Country where clinical trial is conducted

Mexico, 

References & Publications (14)

Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trail Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002 Jun 15;359(9323):2072-7. — View Citation

Craddy P, Palin HJ, Johnson KI. Comparative effectiveness of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systematic review and mixed treatment comparison. Diabetes Ther. 2014 Jun;5(1):1-41. doi: 10.1007/s13300-014-0061-3. Epub 2014 Mar 25. — View Citation

Del Prato S, Taskinen MR, Owens DR, von Eynatten M, Emser A, Gong Y, Chiavetta S, Patel S, Woerle HJ. Efficacy and safety of linagliptin in subjects with type 2 diabetes mellitus and poor glycemic control: pooled analysis of data from three placebo-controlled phase III trials. J Diabetes Complications. 2013 May-Jun;27(3):274-9. doi: 10.1016/j.jdiacomp.2012.11.008. Epub 2013 Feb 9. — View Citation

Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 2010 Feb;33(2):428-33. doi: 10.2337/dc09-1499. — View Citation

Faerch K, Borch-Johnsen K, Holst JJ, Vaag A. Pathophysiology and aetiology of impaired fasting glycaemia and impaired glucose tolerance: does it matter for prevention and treatment of type 2 diabetes? Diabetologia. 2009 Sep;52(9):1714-23. doi: 10.1007/s00125-009-1443-3. Epub 2009 Jul 10. — View Citation

Faerch K, Vaag A, Holst JJ, Glümer C, Pedersen O, Borch-Johnsen K. Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action. Diabetologia. 2008 May;51(5):853-61. doi: 10.1007/s00125-008-0951-x. Epub 2008 Mar 4. — View Citation

Faerch K, Vaag A, Holst JJ, Hansen T, Jørgensen T, Borch-Johnsen K. Natural history of insulin sensitivity and insulin secretion in the progression from normal glucose tolerance to impaired fasting glycemia and impaired glucose tolerance: the Inter99 study. Diabetes Care. 2009 Mar;32(3):439-44. doi: 10.2337/dc08-1195. Epub 2008 Dec 3. — View Citation

Heise T, Graefe-Mody EU, Hüttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab. 2009 Aug;11(8):786-94. doi: 10.1111/j.1463-1326.2009.01046.x. Epub 2009 May 19. — View Citation

Kim SH, Liu A, Ariel D, Abbasi F, Lamendola C, Grove K, Tomasso V, Reaven G. Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised, placebo-controlled study. Diabetologia. 2014 Mar;57(3):455-62. doi: 10.1007/s00125-013-3134-3. Epub 2013 Dec 11. — View Citation

King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998 Sep;21(9):1414-31. — View Citation

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403. — View Citation

Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997 Apr;20(4):537-44. — View Citation

Rosenstock J, Klaff LJ, Schwartz S, Northrup J, Holcombe JH, Wilhelm K, Trautmann M. Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care. 2010 Jun;33(6):1173-5. doi: 10.2337/dc09-1203. Epub 2010 Mar 23. — View Citation

Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001 May 3;344(18):1343-50. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from basal fasting and post2h OGTT glucose levels at 12 and 24 months	Fasting and post-2h OGTT glucose values (mg/dl)	12 and 24 months
Secondary	Change from basal pancreatic beta cell function at 12 and 24 months	Evaluated with the measurements of glucose and insulin during the oral glucose tolerance test; as well as with the glucose and insulin measurements from the hyperglycemic clamp, as the Disposition index.	12 and 24 months
Secondary	Change from basal insulin sensitivity at 12 and 24 months	Insulin sensitivity evaluated during the oral glucose tolerance test by the Matsuda index, and reported as an arbitrary units.	12 and 24 months
Secondary	Change from basal Weight at 12 and 24 months	Weight measurement during the study, in kg	12 and 24 months
Secondary	Incidence of type 2 diabetes	New reported cases with T2D according the the ADA diagnostic criteria	24 months