Clinical trial NCT06005142: Therapeutic Intervention of Eriomin Associated with Metformin in the Control of Hyperglycemia in Pre-Diabetic Patients
Official title: Therapeutic Intervention of Nutraceutical Eriomin Associated with Metformin to Improve the Control of Hyperglycemia in Patients with Prediabetes: a Double-blind, Randomized, Placebo-controlled Crossover Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Pre-diabetes
Keywords: citrus flavonoids
Eriomin
oral antidiabetic biguanide (metformin)
hyperglycemia
microbiota
Lead sponsor: São Paulo State University
Sponsor class: OTHER
Collaborators: name: Ingredients by Nature TM
First posted: 2023-08-22
Enrollment: 80
Sex: ALL
Minimum age (years): 35
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: A crossover, randomized, placebo-controlled, double-blind clinical trial will be conducted for 12 weeks, with a two-week washout interval, followed by another 12 weeks, totaling 26 weeks.

All participants must be under oral biguanide (metformin) (1000 mg/day) regimen by at least two weeks before the intervention, and they will be measure for glycemia, HbA1c and OGTT, and an interview with an MD and Nutritionist in order to confirm eligibility, according to the inclusion/exclusion criteria.

The selected individuals will be randomly distributed into 2 groups, and they will receive alternately Eriomin (or placebo), followed by 2-weeks of washout, and placebo (or Eriomin) for 12 weeks.

At the beginning of the first, 12th, 14th, and 26th weeks, all subjects will be evaluated for the following: Glycemia, OGTT, HbA1c, Insulin, Lipids, TEAC, MDA, GLP-1, inflammatory, hepatic, kidney, and anthropometric parameters, and microbiota composition.
Primary purpose: TREATMENT

Brief summary: Citrus bioflavonoids, such as eriocitrin, hesperidin and naringin, have been shown improved hyperglycemia, insulin resistance and systemic inflammation, related to the development of type 2 diabetes. The nutraceutical Eriomin, a lemon flavonoid extract composed mainly by eriocitrin (70%) and other flavonoids (30%), improved the control of moderate hyperglycemia in pre-diabetic and diabetic patients without drug therapy. However, most patients with pre-diabetes are on oral biguanide (metformin) therapy, despite its limited efficacy (30-40%) on glycemic control and its undesirable gastrointestinal effects.

Therefore, in the current study, Eriomin will be administered at a dose of 250 mg/d to adults diagnosed with pre-diabetes and being treated with metformin (1,000 mg/d). This clinical trial was designed as a placebo-control, double-blind, two-arm, crossover design. Clinical characteristics, body composition, food consumption, metabolic and inflammatory biomarkers and the microbiota of all patients will be evaluated before, during and at the end of the 12-week period (arm). Biochemical and metabolic parameters associated with prediabetes are expected to improve or return to normal with Eriomin in combination with metformin. At the same time, an increase in beneficial intestinal bacteria is expected, reducing pre-diabetic dysbiosis, and perhaps a noticeable improvement in body composition.

Detailed description: Recent evidence shows that bioflavonoids from citrus fruits and herbs can reduce hyperglycemia, dyslipidemia, insulin resistance and the systemic inflammatory process related to type 2 diabetes (T2D). Although they can be found in fruits and herbs, bioflavonoid supplements and nutraceuticals can provide sufficient and safe amounts of bioactive compounds to prevent the development of metabolic disorders, such as metabolic syndrome, diabetes, obesity and others. Eriocitrin flavanone, present in lemons, limes and oranges, has demonstrated anti-inflammatory, anti-hyperglycemic and antioxidant properties and is an integral part of lemon bioflavonoid supplements that have been widely marketed.

Eriocitrin metabolism, similar to hesperidin, is resistant to pancreatic enzymes and are mostly deglycosylated by intestinal bacteria (Bacteroides distasonis or Bacteroides uniformis) to eriodictyol before absorption. A minimal amount can be absorbed as glycosylated in the upper intestine. Eriodictyol, the aglycon of eriocitrin, can be metabolized by intestinal bacteria (with 3,4-dihydroxycinnamic acid formation) to homoeriodictyol and hesperetin through methoxylation. In the liver, eriodictyol is metabolized into glucuronides and conjugated sulfates of eriodictyol, homoeriodictyol, and hesperitin, through sulfation, glucuronidation and methylation, and later released into the circulation to exert biological activity.

Eriocitrin can increase the total antioxidant capacity, leading to a decrease in inflammatory markers (IL-6, MCP-1 and us-CRP) in the blood and organs of mice supplemented with the flavonoid. Eriocitrin also increased catalase and glutathione enzymes in the liver of diabetic rats, and decreased lipid peroxidation in blood, liver and kidney. Furthermore, oral administration of eriodictyol to diabetic rats improved glucose metabolism in the blood, liver and kidney, and suppressed diabetes by upregulating PPARγ29 mRNA expression.

Based on this experimental evidence, the nutraceutical Eriomin, composed of lemon bioflavonoids, was tested as a dietary supplement to control mild to moderate hyperglycemia in pre-diabetic and diabetic patients. After three months of therapy, there was a decrease in hyperglycemia, improvement in insulin resistance and a decrease in HbA1c.

Thus, the hypothesis of the current study is to use the nutraceutical Eriomin as a co-adjuvant to oral biguanide (metformin) therapy, improving control of hyperglycemia and insulin resistance, while increasing efficacy with a low dosage (250 mg/d) of the nutraceutical. It is expected to improve the quality of the microbiota, the glucose metabolism and body composition, in addition to reducing the side effects associated with the continuous use of metformin.

Therefore, the main objective of this study is to evaluate the effects of Eriomin (250mg/day) associated with metformin on glycemic control, insulin resistance and other metabolic, inflammatory and clinical parameters. Furthermore, it will evaluate changes in the microbiota of pre-diabetic patients.

Eligibility criteria: Inclusion Criteria:

* Glycemia of 6.1 to 7.0 mmol / L
* Glycated hemoglobin with values between 5.7 and 6.4%

Exclusion Criteria:

* use of drugs, vitamins and dietary supplements, alcohol consumption (\> 20 g alcohol/d), and intense physical activity (\> 5 hours/week).
* History of cardiovascular disease, diabetes mellitus, liver, kidney or pancreatic disease

Primary outcomes:
measure: Fasting Glycemia
timeFrame: 0-12-18-26 week
Secondary outcomes:
measure: Oral Glucose Tolerance Test (OGTT)
timeFrame: 0-12-18-26 week
measure: HbA1c
timeFrame: 0-12-18-26 week
measure: Insulin
timeFrame: 0-12-18-26 week
measure: Blood Lipids profile
timeFrame: 0-12-18-26 week
measure: Antioxidant Capacity
timeFrame: 0-12-18-26 week
measure: Lipid Peroxidation
timeFrame: 0-12-18-26 week
measure: Glucagon-like peptide-1 (GLP-1)
timeFrame: 0-12-18-26 week
measure: Inflammatory parameters
timeFrame: 0-12-18-26 week
measure: Hepatic Enzymes
timeFrame: 0-12-18-26 week
measure: Kidney Blood Parameters
timeFrame: 0-12-18-26 week
measure: Anthropometric Parameters
timeFrame: 0-12-18-26 week
measure: Microbiota composition by 16S rRNA gene sequencing
timeFrame: 0-12-18-26 week
Other outcomes:
Locations:
city: Botucatú
country: Brazil
facility: Centro de Estudos e Praticas em Nutrição (CEPRAN)
state: SP
Study officials:
affiliation: São Paulo State University
name: Thais B Cesar, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: São Paulo State University
name: Maria Rita M De Oliveira, PhD
role: STUDY_DIRECTOR
affiliation: São Paulo State University
name: Valeria Cristina Samdrim, PhD
role: STUDY_CHAIR
affiliation: São Paulo State University
name: Katia Sivieri, PhD
role: STUDY_CHAIR
affiliation: São Paulo State University
name: Adriana Lucia Mendes, PhD
role: STUDY_CHAIR
affiliation: São Paulo State University
name: Gabriela A Meira, Nutrition
role: STUDY_CHAIR
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