Heat Therapy in Patients With Type 2 Diabetes Mellitus (HEATED)

The Effect of HEAT Therapy on patiEnts With Type 2 Diabetes Mellitus (HEATED): Protocol of a Randomized, Two-arm Controlled Trial

Type 2 diabetes mellitus (T2DM) is a significant burden worldwide. In addition to lifestyle intervention, heat therapy has been shown to be effective in improving glycemic control. To date, there are no randomized, controlled trials investigating the efficacy of heat therapy in T2DM. Our aim is to investigate whether heat therapy with natural mineral water can improve blood glucose status in T2DM patients.

The HEATED study is a two-arm, randomized, controlled study. Patients with T2DM were randomly assigned to Group A (bath in 38 ° C natural thermal mineral water) or Group B (bath in thermoneutral water - 30-32 ° C). Both groups participate in up to five interventions per week, representing 50 to 60 heat therapies over the 12-week study. Each intervention lasts 30 minutes, preceded by a medical examination.

Study Overview

• Status: Withdrawn
• Conditions: Diabetes Mellitus, Type 2; Insulin Resistance
• Intervention / Treatment: Procedure: Passive heating; Procedure: Thermoneutral

Detailed Description

Type 2 diabetes mellitus (T2DM) is a significant burden worldwide. In addition to lifestyle intervention, heat therapy has been shown to be effective in improving glycemic control. To date, there are no randomized, controlled trials investigating the efficacy of heat therapy in T2DM. The study aims to investigate whether heat therapy with natural mineral water can improve blood glucose status in T2DM patients.

The HEATED study is a two-arm, randomized, controlled study. Patients with T2DM will be randomly assigned to Group A (bath in 38 ° C natural thermal mineral water) or Group B (bath in thermoneutral water - 30-32 ° C). Both groups will participate in up to five interventions per week, representing 50 to 60 heat therapies over the 12-week study. Each intervention will last 30 minutes, preceded by a medical examination. At baseline, patients' T2DM status will be recorded and possible micro- and macrovascular complications of T2DM are assessed by physical and laboratory tests. In addition, sensory and autonomic neuropathy will be assessed using Neurometer, Neuropad, and 128 Hz tuning fork tests. Quality of life will be assessed using the SF-36 questionnaire. In addition to baseline, patient data will be recorded at 4, 8, and 12 weeks. During routine blood collection, biobank storage will be performed via plus blood samples collection.

The primary endpoint will be the change from baseline in glycated hemoglobin by week 12 in both groups. Based on a preliminary estimate of the number of items, 65 patients per group are planned to be included in the HEATED study.

The results of the study described above may provide information on the utility of heat therapy in type 2 diabetics. Using the samples stored in the biobank, further analyzes will be performed at the end of the study.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Hungary
  • Pécs, Hungary, 7624
    • Institute for Translational Medicine, University of Pécs

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• patient with type 2 diabetes diagnosed according to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) guidelines
• serum glycated hemoglobin (HbA1c) level between 7 and 10% (53-86 mmol/mol)
• signed written informed consent form

Exclusion Criteria:

• other types of diabetes mellitus
• patients with poor glycaemic control or unstable diabetes
• patients with known serious comorbidity and/ or with advanced macrovascular complications
• active bacterial infection or treatment with antibiotics within 3 weeks
• open wounds or skin lesions
• history of skin-related conditions or sensitivity to prolonged water immersion or exposure to pool chemicals
• severe psychiatric pathology or psychosis
• pregnancy or breastfeeding
• judgment by medical provider that heat therapy/ hydrotherapy poses an undue burden or risk
• participating in other ongoing clinical trials
• heat or balneotherapy in the past 3 months
• morbid obesity (body mass index > 40 kg/m2)
• steroid treatment
• active autoimmune diseases
• coronavirus disease 2019 (COVID-19) in the past 3 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Passive heating; Patients will be randomized to receive whole-body passive heating via 38°C natural thermal mineral water baths.	Procedure: Passive heating; Patients will perform baths in 38°C natural thermal mineral water a maximum of five times per week, over a 12-week period. This will result in a maximum of 60 visits. Each visit will take a maximum of 30 minutes with a physical check-up before and after the bath.
Active Comparator: Thermoneutral; Patients randomized to the comparator group will dip in thermoneutral natural thermal mineral water (30-32°C).	Procedure: Thermoneutral; Patients will perform baths in 30-32°C natural thermal mineral water a maximum of five times per week, over a 12-week period. This will result in a maximum of 60 visits. Each visit will take a maximum of 30 minutes with a physical check-up before and after the bath.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hemoglobin A1c level	The absolut changes in the hemoglobin A1c from baseline to 12-weeks between the two groups will be compared.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hemoglobin A1c level	Absolute change from baseline to follow-up in hemoglobin A1c level.	4 and 8 weeks
Change in fasting plasma glucose	Absolute change from baseline to follow-up in fasting plasma glucose.	4,8, and 12-weeks
Change in fasting insulin	Absolute change from baseline to follow-up in fasting insulin.	4,8, and 12-weeks
Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)	Absolute change from baseline to follow-up in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR).	4,8, and 12-weeks
Decrease of daily insulin dose	Absolute change from baseline to follow-up of the daily insulin dose.	4,8, and 12-weeks
Change in body mass index	Absolute change from baseline to follow-up in body mass index. Weight and height will be combined to report BMI in kg/m^2.	4,8, and 12-weeks
Change in mean blood pressure	Absolute change from baseline to follow-up in mean blood pressure.	4,8, and 12-weeks
Change in heart output	Absolute change from baseline to follow-up in heart output.	4,8, and 12-weeks
Change in the prevalence of electrocardiogram events	Change in the prevalence of electrocardiogram events from baseline to follow-up. Electrocardiogram events represent a composite endpoint of any new events detected using a 12 lead electrocardiogram (e.g., myocardial infarction, atrial fibrillation, atrioventricular block, etc.).	4,8, and 12-weeks
Change in the proportion of hypertension	Absolute change from baseline to follow-up in the proportion of hypertension	4,8, and 12-weeks
Change in the proportion of retinopathy	Absolute change from baseline to follow-up in the proportion of retinopathy	4,8, and 12-weeks
Change in the proportion of nephropathy	Absolute change from baseline to follow-up in the proportion of nephropathy	4,8, and 12-weeks
Change in the proportion of neuropathy	Absolute change from baseline to follow-up in the proportion of neuropathy	4,8, and 12-weeks
Change in total cholesterol level	Absolute change from baseline to follow-up in total cholesterol level.	4,8, and 12-weeks
Change in low-density lipoprotein cholesterol level	Absolute change from baseline to follow-up in low-density lipoprotein cholesterol level.	4,8, and 12-weeks
Change in high-density lipoprotein cholesterol level	Absolute change from baseline to follow-up in high-density lipoprotein cholesterol level.	4,8, and 12-weeks
Change in triglyceride level	Absolute change from baseline to follow-up in triglyceride level.	4,8, and 12-weeks
Change in alkaline phosphatase (ALP)	Absolute change from baseline to follow-up in alkaline phosphatase (ALP).	4,8, and 12-weeks
Change in alanine transaminase (ALT)	Absolute change from baseline to follow-up in alanine transaminase (ALT).	4,8, and 12-weeks
Change in aspartate transaminase (AST)	Absolute change from baseline to follow-up in aspartate transaminase (AST).	4,8, and 12-weeks
Change in gamma-glutamyl transferase (GGT).	Absolute change from baseline to follow-up in gamma-glutamyl transferase (GGT).	4,8, and 12-weeks
Change in glomerular filtration rate	Absolute change from baseline to follow-up in glomerular filtration rate.	4,8, and 12-weeks
Change in creatinine level	Absolute change from baseline to follow-up in creatinine.	4,8, and 12-weeks
Change in thrombocyte aggregation	Absolute change from baseline to follow-up in thrombocyte aggregation.	4,8, and 12-weeks
Heat Shock Protein expression	Difference between the two groups in the level of protein expression using flow cytometry.	4,8, and 12-weeks
Insulin signaling in polymorphonuclear cells	Difference between the two groups in the level of protein expression using flow cytometry.	4,8, and 12-weeks
Lipidom of polymorphonuclear cells	High sensitivity shotgun mass spectrometry will be used to characterize the lipidome of plasma, and polymorphonuclear blood cells.	4,8, and 12-weeks
Lipidom of plasma cells	High sensitivity shotgun mass spectrometry will be used to characterize the lipidome of plasma, and polymorphonuclear blood cells.	4,8, and 12-weeks
Change in obstructive sleep apnea proportion	Change in the proportion of obstructive sleep apnea from baseline to follow-up	4,8, and 12-weeks
Change in the proportion of abnormal overnight pulse oximetry	Absolute change from baseline to follow-up in the proportion of abnormal overnight pulse oximetry.	4,8, and 12-weeks
Change in 24-hour blood pressure	Absolute change from baseline to follow-up in 24-hour blood pressure	4,8, and 12-weeks

Collaborators and Investigators

• Sponsor: University of Pecs

Publications and helpful links

General Publications

• Brunt VE, Howard MJ, Francisco MA, Ely BR, Minson CT. Passive heat therapy improves endothelial function, arterial stiffness and blood pressure in sedentary humans. J Physiol. 2016 Sep 15;594(18):5329-42. doi: 10.1113/JP272453. Epub 2016 Jun 30.
• Salas-Salvado J, Diaz-Lopez A, Ruiz-Canela M, Basora J, Fito M, Corella D, Serra-Majem L, Warnberg J, Romaguera D, Estruch R, Vidal J, Martinez JA, Aros F, Vazquez C, Ros E, Vioque J, Lopez-Miranda J, Bueno-Cavanillas A, Tur JA, Tinahones FJ, Martin V, Lapetra J, Pinto X, Daimiel L, Delgado-Rodriguez M, Matia P, Gomez-Gracia E, Diez-Espino J, Babio N, Castaner O, Sorli JV, Fiol M, Zulet MA, Bullo M, Goday A, Martinez-Gonzalez MA; PREDIMED-Plus investigators. Effect of a Lifestyle Intervention Program With Energy-Restricted Mediterranean Diet and Exercise on Weight Loss and Cardiovascular Risk Factors: One-Year Results of the PREDIMED-Plus Trial. Diabetes Care. 2019 May;42(5):777-788. doi: 10.2337/dc18-0836. Epub 2018 Nov 2.
• Sebok J, Edel Z, Vancsa S, Farkas N, Kiss S, Eross B, Torok Z, Balogh G, Balogi Z, Nagy R, Hooper PL, Geiger PC, Wittmann I, Vigh L, Dembrovszky F, Hegyi P. Heat therapy shows benefit in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Int J Hyperthermia. 2021;38(1):1650-1659. doi: 10.1080/02656736.2021.2003445.
• Romeo GR, Lee J, Shoelson SE. Metabolic syndrome, insulin resistance, and roles of inflammation--mechanisms and therapeutic targets. Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1771-6. doi: 10.1161/ATVBAHA.111.241869.
• Hoekstra SP, Bishop NC, Faulkner SH, Bailey SJ, Leicht CA. Acute and chronic effects of hot water immersion on inflammation and metabolism in sedentary, overweight adults. J Appl Physiol (1985). 2018 Dec 1;125(6):2008-2018. doi: 10.1152/japplphysiol.00407.2018. Epub 2018 Oct 18.
• Hooper PL, Balogh G, Rivas E, Kavanagh K, Vigh L. The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes. Cell Stress Chaperones. 2014 Jul;19(4):447-64. doi: 10.1007/s12192-014-0493-8. Epub 2014 Feb 13.
• Hooper PL. Hot-tub therapy for type 2 diabetes mellitus. N Engl J Med. 1999 Sep 16;341(12):924-5. doi: 10.1056/NEJM199909163411216. No abstract available.
• Sebok J, Edel Z, Dembrovszky F, Farkas N, Torok Z, Balogh G, Peter M, Papp I, Balogi Z, Nusser N, Peter I, Hooper P, Geiger P, Eross B, Wittmann I, Vancsa S, Vigh L, Hegyi P. Effect of HEAT therapy in patiEnts with type 2 Diabetes mellitus (HEATED): protocol for a randomised controlled trial. BMJ Open. 2022 Jul 12;12(7):e062122. doi: 10.1136/bmjopen-2022-062122.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2022
• Primary Completion (Anticipated): January 1, 2024
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: January 5, 2022
• First Submitted That Met QC Criteria: February 8, 2022
• First Posted (Actual): February 14, 2022

Study Record Updates

• Last Update Posted (Actual): April 20, 2023
• Last Update Submitted That Met QC Criteria: April 18, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: insulin resistance; balneotherapy; alternative therapy; heat shock proteins; additional therapy
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance
• Other Study ID Numbers: 818-2/2022/EÜIG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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