Therapeutic Intervention of Eriomin Associated With Metformin in the Control of Hyperglycemia in Pre-Diabetic Patients (Eriomin+Met)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pre-diabetes
• Intervention / Treatment: Dietary supplement: Eriomin; Dietary supplement: Washout; Dietary supplement: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Botucatú, SP, Brazil, 18618-689
      • Centro de Estudos e Praticas em Nutrição (CEPRAN)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Eriomin/Placebo; Group A will receive Eriomin (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then placebo (250 mg/day) for 12 weeks.	Dietary supplement: Eriomin; Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day capsule of Eriomin for 12 weeks.; Dietary supplement: Washout; After 12 weeks of treatment with the active component (Eriomin) or placebo, the participants will follow a washout for 2 weeks.; Dietary supplement: Placebo; Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day placebo capsule for 12 weeks.
Placebo Comparator: Placebo/Eriomin; Group B will receive placebo (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then Eriomin (250 mg/day) for 12 weeks.	Dietary supplement: Eriomin; Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day capsule of Eriomin for 12 weeks.; Dietary supplement: Washout; After 12 weeks of treatment with the active component (Eriomin) or placebo, the participants will follow a washout for 2 weeks.; Dietary supplement: Placebo; Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day placebo capsule for 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting Glycemia	Dosages of glycemia concentration (mg/dL) before and after intervention with Eriomin/placebo	0-12-18-26 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oral Glucose Tolerance Test (OGTT)	Changes in blood glucose 2 hours after the oral glucose tolerance test (mg/dL) before and after intervention with Eriomin/placebo	0-12-18-26 week
HbA1c	Dosages of glycated hemoglobin (%) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Insulin	Dosages of Insulin (µU/mL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Blood Lipids profile	Dosages of cholesterol (mg/dL), HDL-cholesterol (mg/dL) and triglycerides (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Antioxidant Capacity	Dosages of Trolox equivalent antioxidant capacity (TEAC) (μM) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Lipid Peroxidation	Dosages of Malondialdehyde (MDA) (mM) the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Glucagon-like peptide-1 (GLP-1)	Dosages of GLP-1 (pmol/L) the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Inflammatory parameters	Dosages of C Reactive Protein (CRP) (mg/dL), TNF-alpha (mg/dL), IL-6 (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Hepatic Enzymes	dosages of alkaline phosphatase (U/L), gamma glutamyl transferase (U/L), aspartate aminotransferase (U/L), and alanine aminotransferase (U/L) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Kidney Blood Parameters	Dosages of urea (mg/dL) and creatinine (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo	0-12-18-26 week
Anthropometric Parameters	Measurements of body weight (kg), muscle mass (kg), fat mass (kg) before and after intervention with Eriomin/placebo	0-12-18-26 week
Microbiota composition by 16S rRNA gene sequencing	Dosages of the main bacteria groups by Operational Taxonomic Units (OTU) and % of relative abundance by group	0-12-18-26 week

Collaborators and Investigators

• Sponsor: Thais Cesar
• Collaborators: Ingredients by Nature TM
• Investigators: Principal Investigator: Thais B Cesar, PhD, Sao Paulo State University; Study Director: Maria Rita M De Oliveira, PhD, Sao Paulo State University; Study Chair: Valeria Cristina Samdrim, PhD, Sao Paulo State University; Study Chair: Katia Sivieri, PhD, Sao Paulo State University; Study Chair: Adriana Lucia Mendes, PhD, Sao Paulo State University; Study Chair: Gabriela A Meira, Nutrition, Sao Paulo State University

Publications and helpful links

General Publications

• Flory J, Lipska K. Metformin in 2019. JAMA. 2019 May 21;321(19):1926-1927. doi: 10.1001/jama.2019.3805.
• Testa R, Bonfigli AR, Genovese S, De Nigris V, Ceriello A. The Possible Role of Flavonoids in the Prevention of Diabetic Complications. Nutrients. 2016 May 20;8(5):310. doi: 10.3390/nu8050310.
• Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond). 2015 Dec 23;12:60. doi: 10.1186/s12986-015-0057-7. eCollection 2015.
• Minato K, Miyake Y, Fukumoto S, Yamamoto K, Kato Y, Shimomura Y, Osawa T. Lemon flavonoid, eriocitrin, suppresses exercise-induced oxidative damage in rat liver. Life Sci. 2003 Feb 21;72(14):1609-16. doi: 10.1016/s0024-3205(02)02443-8.
• Hiramitsu M, Shimada Y, Kuroyanagi J, Inoue T, Katagiri T, Zang L, Nishimura Y, Nishimura N, Tanaka T. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep. 2014 Jan 15;4:3708. doi: 10.1038/srep03708.
• Miyake Y, Shimoi K, Kumazawa S, Yamamoto K, Kinae N, Osawa T. Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem. 2000 Aug;48(8):3217-24. doi: 10.1021/jf990994g.
• Ferreira PS, Spolidorio LC, Manthey JA, Cesar TB. Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high-fat diet. Food Funct. 2016 Jun 15;7(6):2675-81. doi: 10.1039/c5fo01541c. Epub 2016 May 16.
• Ribeiro CB, Ramos FM, Manthey JA, Cesar TB. Effectiveness of Eriomin(R) in managing hyperglycemia and reversal of prediabetes condition: A double-blind, randomized, controlled study. Phytother Res. 2019 Jul;33(7):1921-1933. doi: 10.1002/ptr.6386. Epub 2019 Jun 11.
• Cesar TB, Ramos FMM, Ribeiro CB. Nutraceutical Eriocitrin (Eriomin) Reduces Hyperglycemia by Increasing Glucagon-Like Peptide 1 and Downregulates Systemic Inflammation: A Crossover-Randomized Clinical Trial. J Med Food. 2022 Nov;25(11):1050-1058. doi: 10.1089/jmf.2021.0181. Epub 2022 Jul 7.

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2023
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: March 27, 2023
• First Submitted That Met QC Criteria: August 21, 2023
• First Posted (Actual): August 22, 2023

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: hyperglycemia; microbiota; citrus flavonoids; Eriomin; oral antidiabetic biguanide (metformin)
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Prediabetic State
• Other Study ID Numbers: SaoPSU23

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No