Clinical trial NCT04053621: Co-administration of Thiamine Pyrophosphate and Metformin in Type 2 Diabetes
Official title: Pirofosfato de Tiamina Como Coadyuvante de la Metformina en el Tratamiento de Pacientes Con Diabetes Mellitus Tipo 2
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Keywords: metformin
thiamine pyrophosphate
B1 vitamin
type 2 diabetes mellitus
metabolic pathways
Lead sponsor: Laboratorios Manuell SA
Sponsor class: INDUSTRY
Collaborators: name: Universidad Nacional Autonoma de Mexico
First posted: 2019-08-12
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Chronic non-infectious diseases have a bigger impact and a higher prevalence every day world-wide. Among them, diabetes stands out being the number one cause of death from degenerative chronic illness in Mexico. Diabetes not only affects quality of life, it can also lead to severe complications that have a great economic impact as well as a health impact on the patient and their family. Some of the complications include liver failure and hypertension. This whole problem can be dated back to an initial hyperglycemic state that when left untreated further develops into insulin resistance, chronic inflammation, metabolic syndrome and diabetes. The purpose of this study is to stop this chain reaction that starts with every hyperglycemic patient by adding thiamine pyrophosphate to the treatment plan of patients diagnosed with type 2 diabetes that are poorly managed with metformin monotherapy. Thiamine pyrophosphate is a form of B1 vitamin that plays an important role as a coenzyme in multiple metabolic routes including the link between glycolysis and Krebs cycle, fatty acids metabolism and branched-chain amino acid metabolism. By doing so, these pathways improve their function and efficiency and thereby utilize plasma glucose. This in turn, decreases the formation of advanced glycation end products (AGEs) which prevents the formation of reactive oxygen and nitrogen species, ultimately there is also an anti-oxidative mechanism involved that improves the inflammatory state the patient is living with. Our hypothesis is that by adding thiamine pyrophosphate to the treatment of patients taking metformin, there will be important progress regarding the inflammatory and metabolic control of patients with type 2 diabetes.

The study will have a duration of approximately 4 months after the total sample is recruited. During this time, subjects will first be examined to determine their eligibility according to the pre-established criteria, in case of inclusion in the study they will sign an informed consent after reading it thoroughly and having answered all their questions. Baseline labs will be taken for every subject for future comparison. They will then be randomized into two parallel groups: an experimental group that will receive weekly infusions of saline infused with 1 gram of thiamine pyrophosphate or a placebo group that will also receive weekly infusions of pure saline. The patients as well as the doctors treating them will be blinded to the assignment of either group. This model will be carried out for a duration of 12 weeks total, during which every patient will continue their metformin treatment with their tolerated dose. There will be verification of treatment adherence by counting the metformin pills during every weekly visit. For the assessment of dependent variables there will be a visit every month with a blinded doctor. These visits will be for: physical and clinical evaluation, evaluation of adverse events, evaluation of treatment adherence and a heart rate variability study. The first and third months a questionnaire about lifestyle will be added to the visit schedule. On the third month, final lab tests will be performed. Finally, one month after completing the treatment, a final visit will be scheduled for a clinical and physical evaluation to make sure there are no problems.


Eligibility criteria: Inclusion Criteria:

* signed informed consent
* diagnosed type 2 diabetes mellitus
* HbA1c between 7.5 and 11%
* monotherapy treatment with metformin at tolerated successful dose

Exclusion Criteria:

* glomerular filtration rate \<60 ml/min/1.73m2
* cardiac o respiratory insufficiency
* liver enzymes 3 times higher than normal parameters
* known allergy to metformin or thiamine pyrophosphate
* pregnancy, lactation or fertile age without a contraceptive method
* participation in another study in the last 6 months
* programmed surgery for the next 4 months
* treatment with any other hypoglycemic agents

Primary outcomes:
measure: hemoglobin A1c
timeFrame: Change from baseline at 3 months
Secondary outcomes:
measure: fasting plasma glucose
timeFrame: Change from baseline at 3 months
measure: Lipids profile
timeFrame: Change from baseline at 3 months
measure: inflammation markers
timeFrame: Change from baseline at 3 months
measure: Lifestyle measurement
timeFrame: Change from baseline at 3 months
measure: heart rate variability
timeFrame: Change from baseline at 3 months
measure: arterial elasticity
timeFrame: Change from baseline at 3 months
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: Centro Especializado en Diabetes, Obesidad, Prevención y Enfermedades Cardiovasculares, S.C.
state: Cdmx
Study officials:
affiliation: Centro Especializado en Diabetes, Obesidad, Prevención y Enfermedades Cardiovasculares, S.C.
name: Melchor Alpizar, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Benítez-Rodríguez MT. Actualidades del Pirofosfato de Tiamina o Carboxilasa. 1st ed. México: Litográfica Santander; 2013.
citation: Elksnis A, Martinell M, Eriksson O, Espes D. Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass. Front Physiol. 2019 Feb 13;10:107. doi: 10.3389/fphys.2019.00107. eCollection 2019.
citation: Lopez-Carmona JM, Rodriguez-Moctezuma JR, Ariza-Andraca CR, Martinez-Bermudez M. [Lifestyle and metabolic control in patients with type 2 diabetes mellitus. Construct validation of IMEVID questionnaire]. Aten Primaria. 2004 Jan;33(1):20-7. doi: 10.1016/s0212-6567(04)78873-3. Spanish.
citation: Pacal L, Kuricova K, Kankova K. Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation? World J Diabetes. 2014 Jun 15;5(3):288-95. doi: 10.4239/wjd.v5.i3.288.
citation: Shapoval GS, Babii LV, Kruglyak OS, Vovk AI. Antioxidant activity of thiamine and its structural analogs in reactions with electrochemically generated hydroxyl radicals and hydrogen peroxide. Theor Exp Chem. 2011; 47, 1: 55 - 60.