Propolis Improves Glycemic Control in Subjects With Type 2 Diabetes and Chronic Periodontitis

June 8, 2016 updated by: Mohamed Anees

Propolis Improves Periodontal Status and Glycemic Control in Subjects With Type 2 Diabetes Mellitus and Chronic Periodontitis: a Randomized Clinical Trial

Background:

Propolis is a natural resin made by bees from various plant sources. Propolis exerts antimicrobial, anti-inflammatory, immunomodulatory, antioxidant, and antidiabetic properties. The purpose of this study was to assess the adjunctive benefit of propolis supplementation in individuals with both chronic periodontitis and type 2 diabetes mellitus (T2DM) receiving scaling and root planing (SRP).

Methods:

A 6-month randomized blinded clinical trial comparing SRP with placebo (placebo+SRP group, n=26) or combined with a 6- month regimen of 400 mg oral propolis once daily (propolis+SRP group, n=26) was performed in patients with long-standing T2DM and chronic periodontitis. Treatment outcomes included hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), serum N€-(carboxymethyl) lysine (CML) and changes in periodontal parameters.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

INTRODUCTION

Diabetes mellitus (DM) is a metabolic disorder characterized by frequent periods of hyperglycemia, which induce certain molecular pathways that seem to be crucial to the initiation of angiopathic complications of DM. Several mechanisms have been suggested to explain the pathogenicity of complications of hyperglycemia such as protein kinase C isoforms, enhanced polyol pathway flux, and increased accumulation of advanced glycosylated end-products. A dysregulated immune response stemming from an inappropriate cytokine production is a possible mechanism underpinning the cross-susceptibility between periodontal disease and DM. DM has been unambiguously determined as one of the major risk factors of periodontitis. It was reported that the risk of periodontitis increases to almost threefold in diabetic patients when compared to healthy individuals. The glycemic control level is believed to be of paramount importance as a determinant of the increased risk for developing complications. Diabetic patients with an HbA1c level more than 9% were found to have an increased prevalence of advanced chronic periodontitis in comparison to healthy people according to the US National Health and Nutrition Examination Survey (NHANES) III.

Two decades ago, periodontitis was added to represent the sixth complication of DM. Individuals suffering from periodontal diseases often have increased serum levels of proinflammatory cytokines, such as IL-1, IL-6 and TNF-α. Diabetic patients with periodontitis possess hyperinflammatory immune cells that lead to enhanced release of proinflammatory cytokines, which eventually lead to insulin resistance resulting in a greater risk of poor glycemic control when compared to diabetic patients without periodontitis. The accumulation of irreversible advanced glycation end-products (AGEs), predominantly N€-(carboxymethyl) lysine (CML) has shown to alter cell function and tissue structure. Due to difficulty in managing diabetes; there is a critical need for new therapeutic modalities for prevention of diabetes-related complications.

Propolis is a natural resin synthesized by honey bees from substances extracted from parts of some plants, buds and sap. Due to its physical characteristics, propolis is utilized by the honey bees to protect the hives against foreign invaders. Propolis has been used for centuries as a homeopathic medicine known for its anti-inflammatory properties, especially in Europe and ancient Egypt. It has traditionally been used for the management of numerous diseases, such as gastrointestinal disorders and mucocutaneous infections of fungal, bacterial and viral etiology.

There are several types of propolis that differ in composition depending on the plant source which varies according to the geographic zone such as Brazil, Peru, China and Europe. Propolis contains more than more than 230 constituents, including flavonoids, cinnamic acids and their esters, caffeic acid and caffeic acid phenethyl ester. It has been found to have a wide array of biological activities, including antibacterial, antiviral, fungicidal, anti-inflammatory, antioxidant, hepatoprotective, free radical scavenging, immunomodulatory and anti-diabetic activity. Recently, investigations revealed that caffeic acid phenethyl ester (CAPE) is an important active molecule found in propolis and is responsible for most of its therapeutic properties.

The actions of Chinese and Brazilian propolis in streptozotocin-induced type 1 diabetes mellitus in Sprague Dawley rats was explored and the results indicated that both types of propolis significantly inhibited more body weight loss and plasma glucose increase in experimental rats. Additionally, rats treated with Chinese propolis exhibited an 8.4% reduction in HbA1c levels in comparison to non-treated diabetic group.

Hence, it was hypothesized that periodontal therapy with SRP in conjunction with oral daily supplementation of propolis in patients with chronic periodontitis and T2DM might improve both diabetic and periodontal outcomes. Thus, the aim of the current study is to evaluate whether the adjunctive therapy of oral propolis supplementation to SRP compared to SRP plus placebo, reduces glycated hemoglobin and improves clinical and periodontal parameters after 6 months of therapy in individuals with chronic periodontitis and T2DM.

MATERIALS AND METHODS

Study Population:

The study was approved by the Institutional Review Board of Mansoura University. Subjects were selected during their recall maintenance visits in the Internal Medicine Hospital, Mansoura University, between June and December in 2014. Patients filled out questionnaires gathering information on their dental and oral health care followed by a periodontal screening examination to determine eligible individuals. Patients were considered eligible for the study if they had T2DM with a minimum of five years duration and had been taking stable doses of oral hypoglycemic drugs and/or insulin for at least 6 months. In addition, they should have chronic periodontitis with probing pocket depth and clinical attachment loss ≥ 5 mm with detectable bleeding on probing in at least one site in each sextant. Patients should have a minimum of 20 teeth to be selected. All patients were diagnosed to have moderate to severe chronic periodontitis according to Armitage criteria (24). Exclusion criteria included smokers, recent extended use of antibiotics or non-steroidal anti-inflammatory drugs within the last 3 months, patients who had any periodontal therapy within one year, patients with grade 3 or 4 retinopathy, pregnancy or women using oral contraceptives. Enrolled patients signed written informed consents for study participation.

Study Design:

Fifty two people with T2DM diagnosed with moderate to severe chronic periodontitis were randomly assigned using computer-generated random tables to receive propolis (400 mg capsule orally once daily for six months) as adjuvant to scaling and root planing (Propolis+ SRP group, n = 26), or matching placebo capsules for 6 months in addition to scaling and root planing (Placebo+SRP group, n = 26) in this parallel randomized blinded controlled trial with an allocation ratio = 1:1. The generated allocation sequences were concealed in closed stapled envelopes until interventions were assigned. Investigators were not involved during randomization. Propolis commercially named BioPropolis (Sigma Pharmaceutical Industries for International Business Establishment Co. IBE Pharma, Cairo, Egypt) and matching placebo capsules were used in the study. All participants in both groups were assigned to receive equal number of capsules during the 6- month period. Vials which contain propolis and placebo drugs were labeled with specific codes unknown to patients and investigators. Patients were instructed to take only one capsule daily from the given vial. Patient compliance was calculated by counting the remaining capsules in each returned vial every month. Untoward side effects of both medications were queried and recorded at each visit during the study period.

All individuals received meticulous full mouth scaling and root planing (SRP) with hand curettes and ultrasonic tips under local anesthesia until root surfaces were smooth by clinician (MA) in a single visit. Oral hygiene instructions and motivations for proper tooth brushing and dental flossing were given to the patients. Chlohexidine 0.12% mouthrinse was prescribed for all patients for only two weeks after SRP.

Clinical Periodontal Measurements:

Clinical periodontal parameters including probing pocket depth (PD), clinical attachment level (CAL) (distance from the CEJ to the base of the pocket), Eastman interdental bleeding (EIBI) , gingival (GI) and plaque (PI) indices were assessed at baseline, 3 months and 6 months after therapy by the examiner (HE). Intra-examiner calibration was achieved by examination of 10 patients twice, 24 hours apart before starting the study. Calibration was accepted if measurements of PD and CAL (by using UNC-15 probe) at baseline and 24 hours were similar to 1 mm at the 90% level.

Collection and analysis of Blood:

10 mL of venous blood from the antecubital vein of all participants were collected in heparinized vacutainer tubes at baseline, 3 months and 6 months after treatment. Measurements of HbA1c were carried out via an automated affinity chromatography system (Bio-Rad Micromat II, Hercules, CA). Fasting plasma glucose levels (FPG) were measured by the standard glucose oxidase method. The serum concentration of N€-(carboxymethyl) lysine (CML) was assessed by N€-(carboxymethyl) lysine (CML) ELISA Kit of CML protein adducts (OxiSelect™, Catalog Number STA-316, Cell Biolabs Inc., San Diego, CA, USA). The amount of CML adduct in protein samples was evaluated by comparing the absorbance to a known CML-BSA standard curve as described by the manufacturer.

Study outcomes:

The primary outcome of the present clinical trial was the change in HbA1c levels after 6 months of therapy. Secondary outcomes included the change in HbA1c levels after 3 months in addition to the amount of CAL gain, PD reduction and changes in FPG and serum CML levels after 3 and 6 months of therapy.

Statistical Analysis:

A power analysis was performed before commencement of the trial with type I error α = 0.05, β = 0.14 and (1-β) = 0.86. The power was calculated as p = 0.8641 and the estimated minimum sample size required was found to be 20 per each group to achieve a power of 80% based on achievement of 6-month reduction of HbA1c of the test group over the control by 0.8%. All data were explored by using Kolmogrov-Smirnov test of normality. Parametric data were presented as mean ± SD. Baseline comparisons were made using Student's t-test. One-way analyses of variance (ANOVA) with Holm-Sidak post hoc correction for multiple comparisons were used to determine significant changes at different time intervals. Wilcoxon signed rank test and Mann-Whitney test were used to detect differences per group and between groups over time. The α-level for significance was set at 0.05.Statistical analyses were calculated by a statistical software program (Statistical Package for the Social Sciences version 19.0, SPSS, Chicago, IL).

Study Type

Interventional

Enrollment (Actual)

52

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
    • Dakahlia
      • Mansoura, Dakahlia, Egypt
        • Faculty of Dentistry

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

38 years to 63 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients had type 2 diabetes mellitus with a minimum of five years duration and had been taking stable doses of oral hypoglycemic drugs and/or insulin for at least 6 months.
  • Patients should have chronic periodontitis with probing pocket depth and clinical attachment loss ≥ 5 mm with detectable bleeding on probing in at least one site in each sextant.
  • Patients should have a minimum of 20 teeth to be selected.
  • All patients were diagnosed to have moderate to severe chronic periodontitis according to Armitage criteria.

Exclusion Criteria:

  • Smokers.
  • Recent extended use of antibiotics or non-steroidal anti-inflammatory drugs within the last 3 months.
  • Patients who had any periodontal therapy within one year.
  • Patients with grade 3 or 4 retinopathy.
  • Pregnancy.
  • Women using oral contraceptives.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Propolis
400 mg oral proplois (capsule) was given to participants once daily for 6 months after performing scaling and root planing.
Drug: Propolis
Propolis capsules was taken by the experimental group for 6 months after receiving scaling and root planing (SRP).
Other Names:
  • BioPropolis
Placebo Comparator: Placebo
Placebo capsule was given to participants once daily for 6 months after performing scaling and root planing.
Drug: Placebo
Placebo capsules was taken by the control group for 6 months after receiving scaling and root planing (SRP).
Other Names:
  • Starch capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change of glycosylated hemoglobin (HbA1c)
Time Frame: Baseline, 3 and 6 months
HbA1c was evaluated at baseline,3 and 6 months
Baseline, 3 and 6 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Change of pocket depth
Time Frame: From baseline and 6 months
From baseline and 6 months
Change of clinical attachment level
Time Frame: From baseline and 6 months
From baseline and 6 months
Change of fasting plasma glucose level
Time Frame: From baseline and 6 months
From baseline and 6 months
Change of serum N- epsilon (carboxymethyl) lysine level
Time Frame: From baseline and 6 months
From baseline and 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mohamed Anees

Collaborators

Mansoura University

Investigators

  • Study Director: Hesham M. El-Sharkawy, Ass.Prof., Mansoura University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2014

Primary Completion (Actual)

December 1, 2014

Study Completion (Actual)

March 1, 2015

Study Registration Dates

First Submitted

May 29, 2016

First Submitted That Met QC Criteria

June 8, 2016

First Posted (Estimate)

June 9, 2016

Study Record Updates

Last Update Posted (Estimate)

June 9, 2016

Last Update Submitted That Met QC Criteria

June 8, 2016

Last Verified

May 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DENT-1971

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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