The Effect of Addition of Metformin to SGLT2 In Diabetic Patients With Heart Failure With Preserved Ejection Fraction

a prospective open-label, randomized controlled study to evaluate the efficacy of the addition of metformin to SGLT2 in diabetic patient with preserved ejection fraction

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction; Diabete Type 2
• Intervention / Treatment: Drug: Metformin

Detailed Description

Regardless of the benefits noted with SGLT2is, metformin is recommended as first-line therapy for glycemic control in individuals with T2DM and HF, including HFpEF, with estimated glomerular filtration rates (eGFRs) ≥30 mL/min/1.73 m2. This is based on the demonstrated experience with long-term use; its safety, low cost, and low side effect profile; as well as observational (not clinical trial) data suggesting a 20% relative risk reduction in mortality in individuals with HF, including HFpEF.

Nevertheless, it is worth mentioning that Metformin is a common anti-diabetic drug with both systemic and cardioprotective benefits in addition to its hypoglycaemic effect. At the cellular level metformin activates adenosine monophosphate-activated protein kinase (AMPK) an important regulator of several metabolic pathways resulting in enhanced glucose utilisation, reduction of protein synthesis and improvement of mitochondrial function. Furthermore, metformin has been shown to reduce collagen accumulation and potentially reduce LV hypertrophy and improve diastolic function in the diabetic myocardium. The cardio protection afforded by metformin treatment seems to result from interference with TGF-beta signaling pathway and activation of the AMP-kinase signaling cascade. A recent systematic review and meta regression analysis have shown that metformin treatment was associated with a reduction in mortality in patients with HFpEF. In addition, treatment with metformin of non-diabetic metabolic syndrome patients with diastolic dysfunction, on top of lifestyle counseling, was associated with improved diastolic function.

Nevertheless, a recent met analysis showed that initial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy.

based on that we our aim is to evaluate the efficacy of the addition of metformin to SGLT2 in diabetic patient with preserved ejection fraction

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: sara M eladawy; Phone Number: 01222124567; Email: smeladway@msa.edu.eg
• Study Contact Backup: Name: hassan abdellatif; Phone Number: 01092990402; Email: hassangamal79@gmail.com

Study Locations

• Egypt
  • Cairo, Egypt
    • clinical research uint- El-sheikh zayed specialized hospital SMC- Egyptian Ministry of health
    • Contact: hassan abdellatif; Phone Number: 01092990402; Email: hassangamal79@gmail.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

Age of 40 years to 74 years. HFpEF (≥ 50%) Written informed consent of the subject to participate in the study. New York Heart Association functional class I-IV. Diabetic patients SGL-2 naive. Newly diagnosed heart failure of preserved ejection fraction

Exclusion Criteria:

Patients with heart failure with reduced ejection fraction (< 40%) Age less than 40 and more than 74 GFR < 30 mL/min A1c > 9 Known allergy to metformin End- stage liver disease Cancer Pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: control(SGLT2i/ARBs/MRA/ +/- diuretics).; Lifestyle counseling plus standard evidence-based therapy for HFpEF (SGLT2i/ARBs/MRA/ +/- diuretics).
Experimental: intervention; Lifestyle counseling plus standard evidence-based therapy for HFpEF (SGLT2i/ARBs/MRA/ +/- diuretics)+ metformin	Drug: Metformin; The intervention will consist in giving metformin starting with 500 mg once daily 1 gm daily (at breakfast) during the first week; if well tolerated, the dose was progressively increased to 500 mg twice daily (at breakfast and dinner) during week 2, to 1000 mg at breakfast and 500 mg at dinner during week 3, in order to reach the target dose of 1000 mg twice daily (at breakfast and dinner) during the rest of the follow-up. Patients will be followed up by telephone call 2 weeks intervals during the study period 5 SGL-2 will be prescribed to group 1 after diagnosis with HFpEF while group 2 will have SGL-2 and Metformin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospitalization rate	Hospitalization rate	baseline, 3 and 6 months
HRQOL using Minnesota Living with Heart Failure Questionnaire for quality-of-life evaluation (MLFHQ)	HRQOL using Minnesota Living with Heart Failure Questionnaire for quality-of-life evaluation (MLFHQ)	baseline, 3 and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in N-terminal pro-BNP (NT-proBNP)	Change in N-terminal pro-BNP (NT-proBNP)	baseline, 3 and 6 months
The change in the mean early diastolic mitral annular velocity (mean e'), at 3 and 6 months	The change in the mean early diastolic mitral annular velocity (mean e'), at 3 and 6 months	baseline, 3 and 6 months
adverse drug effects	adverse drugs effects	baseline, 3 and 6 months
Neutrophil/lymphocyte ratio -AMPK pathway	Neutrophil/lymphocyte ratio -AMPK pathway	baseline, 3 and 6 months
Inflammatory and oxidative stress	Inflammatory and oxidative stress	baseline, 3 and 6 months
Change in body weight	Change in body weight	baseline, 3 , 6 months

Collaborators and Investigators

• Sponsor: October University for Modern Sciences and Arts
• Collaborators: clinical research unit, El-sheikh zayed specialized hospital - Egyptian Ministry of health
• Investigators: Study Director: sara M eladawy, MSA University; Study Chair: Mai abdelhafez, PhD, MSA University

Publications and helpful links

General Publications

• ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA, on behalf of the American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. 2023 Jan 1;46(Suppl 1):S140-S157. doi: 10.2337/dc23-S009.
• Kittleson MM, Panjrath GS, Amancherla K, Davis LL, Deswal A, Dixon DL, Januzzi JL Jr, Yancy CW. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023 May 9;81(18):1835-1878. doi: 10.1016/j.jacc.2023.03.393. Epub 2023 Apr 19. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2023
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: October 8, 2023
• First Submitted That Met QC Criteria: October 8, 2023
• First Posted (Actual): October 12, 2023

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 8, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: metformin; HFpEF; SGLTi
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Heart Failure; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: C1/HEC1/2023PD

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
• product manufactured in and exported from the U.S.: No