SGLT-2i, Heart, Improvement of Cardiovascular Autonomic Neuropathy

Start 14 Nov 2025 · Status Ongoing, recruiting · 1 EU/EEA countries · 2 sites · Protocol SHICAN

Overview

Sponsor-declared trial summary

Phase Therapeutic use (Phase IV)

Status Ongoing, recruiting

Participants planned 80

Countries 1

Sites 2

type 2 diabetes

Primary Objective #1: to evaluate whether the cardiovascular effects of SGLT-2is are, at least in part, mediated by autonomic innervation in patients with type 2 diabetes mellitus; Primary Objective #2: to explore the effects of SGLT2is on the progression of CAN in patients affected by type 2 diabetes mellitus;

Key facts

Sponsor: Universita Cattolica Del Sacro Cuore
Participant type: Patients
Age range: 18-64 years, 65+ years
Gender: Male and Female
Therapeutic area: Phenomena and Processes [G] - Metabolism [G03], Diseases [C] - Nutritional and Metabolic Diseases [C18]
Trial duration: 14 Nov 2025 → ongoing
Decision date (initial): 2025-07-21
Transition trial: No
Low-intervention: Yes
Rare-disease indication: No
Vulnerable population: No
Funding sources: Ministero dell’Università e della Ricerca (Project Code: PRIN 2O22TJWNLL)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Primary Objective #1: to evaluate whether the cardiovascular effects of SGLT-2is are, at least in part, mediated by autonomic innervation in patients with type 2 diabetes mellitus;
Primary Objective #2: to explore the effects of SGLT2is on the progression of CAN in patients affected by type 2 diabetes mellitus;

Secondary objectives 1

to evaluate whether the beneficial effects on glucose metabolism observed with SGLT2i treatment could also be mediated by a regulation of autonomic innervation

Conditions and MedDRA coding

type 2 diabetes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

Informed consent obtained before any study-specific procedures. Patients must be able to understand and be willing to sign a written informed consent
Men and women with type 2 diabetes mellitus
age > 45 years old
patients with stable medical therapy including other anti-hyperglycemic agents alone or in combination with a basal insulin analogue for at least 3 months prior to the screening visit (including stable insulin dose defined as no variation over 30% in daily insulin dose in the preceding 3 months, as evaluated by the Investigator)
HbA1c above or equal to 7.0% but less than 8.5% at screening
Women of childbearing potential must have a negative blood or urine pregnancy test at the baseline visit
Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.9 of the protocol
Ability to take oral medications
Will and ability to comply with the protocol
Patients who are intolerant to metformin, or in metformin failure, or present clinical indications for initiating SGLT2 inhibitor therapy (e.g., heart failure, diabetic kidney disease), in accordance with current clinical guidelines

Exclusion criteria 16

Type 1 diabetes mellitus
Patients on dialysis or with estimated glomerular filtration rate (eGFR) below the following thresholds, depending on the assigned treatment: - eGFR <45 mL/min/1.73 m² for patients planned to receive ertugliflozin - eGFR <30 mL/min/1.73 m² for patients planned to receive empagliflozin, canagliflozin, or dapagliflozin;
diagnosis of chronic obstructive pulmonary disease or respiratory failure
inability to provide informed consent
patients with history of breast, bladder and prostate cancer
previous diagnosis of Latent Autoimmune Diabetes of Adults (LADA)
use of SGLT-2is in the 90 days prior to screening, acute decompensation of glycemic control requiring immediate intensification of treatment to prevent acute complications (e.g. diabetic ketoacidosis) in 90 days prior to screening
acute coronary or cerebro-vascular event in the 90 days prior to randomization, currently planned coronary, carotid or peripheral artery revascularization, NYHA class III or IV, unstable angina
sick sinus syndrome, second or third degree atrio-ventricular block (except in patients with a functioning artificial pacemaker)
chronic obstructive lung disease with evidence of bronchospasm (e.g. asthma)
long QT syndrome
severe hypotension
decompensated heart failure
History of diabetic ketoacidosis (DKA), unless a clear and modifiable precipitating factor (e.g., ketogenic diet, excessive alcohol consumption) has been identified and eliminated
Female during pregnancy and breastfeeding
Certified or suspected hypersensitivity to SGLT2 inhibitors

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

Endpoint related to Objective #1: to verify the effect of SGLT-2is on HRV as shown by the difference in LF:HF ratio (a frequency domain measured as improvement of 20% in LF:HF ratio from baseline to end of treatment (6 months).
Endpoint related to Objective #2: to verify the effect of SGLT-2 on CAN progression as shown by the improvement in at least one of the three CART parameter AND an improvement in glucose variability from baseline to end of treatment (6 months)

Secondary endpoints 3

to assess the results of SGLT2i treatment on pancreatic beta cell function (i.e., glucose sensitivity and insulin secretion parameters including those derived from the Mixed Meal Test (MMT)) in patients with and without CAN after 6 months intervention with SGLT2i.
to assess the difference in glycemic variability expressed as mean amplitude of glycemic excursions (MAGE) measured for 2 weeks flash glucose monitoring at baseline and after 6 months of treatment with SGLT-2i.
to explore difference in CAN progression expressed as changes in cardiovascular autonomic reﬂex tests (CARTs) as defined by: a) expiration/inspiration (E/I) ratio, b) 30:15 ratio and c) Valsalva ratio.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 17

Sitagliptin

SUB25227 · Substance

Active substance: Sitagliptin
Pharmaceutical form: FILM COATED TABLETS
Route of administration: ORAL
Max daily dose: 100 mg milligram(s)
Max total dose: 100 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pioglitazone

SUB09857MIG · Substance

Active substance: Pioglitazone
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 30 mg milligram(s)
Max total dose: 30 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Pioglitazone

SUB09857MIG · Substance

Active substance: Pioglitazone
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 15 mg milligram(s)
Max total dose: 15 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Insulin Aspart

SUB08195MIG · Substance

Active substance: Insulin Aspart
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 100 IU international unit(s)
Max total dose: 100 IU international unit(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Insulin Degludec

SUB96394 · Substance

Active substance: Insulin Degludec
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 100 IU international unit(s)
Max total dose: 100 IU international unit(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Empagliflozin

SUB35915 · Substance

Active substance: Empagliflozin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 25 mg milligram(s)
Max total dose: 25 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Empagliflozin

SUB35915 · Substance

Active substance: Empagliflozin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 10 mg milligram(s)
Max total dose: 10 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Semaglutide

SUB32188 · Substance

Active substance: Semaglutide
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 0.5 mg milligram(s)
Max total dose: 0.5 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Semaglutide

SUB32188 · Substance

Active substance: Semaglutide
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 1 mg milligram(s)
Max total dose: 1 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Insulin Lispro

SUB08198MIG · Substance

Active substance: Insulin Lispro
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 100 IU international unit(s)
Max total dose: 100 IU international unit(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Canagliflozin

SUB33463 · Substance

Active substance: Canagliflozin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 300 mg milligram(s)
Max total dose: 300 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Dapagliflozin

SUB31650 · Substance

Active substance: Dapagliflozin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 10 mg milligram(s)
Max total dose: 10 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Insulin Glargine

SUB08196MIG · Substance

Active substance: Insulin Glargine
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 100 IU international unit(s)
Max total dose: 100 IU international unit(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Ertugliflozin

SUB182716 · Substance

Active substance: Ertugliflozin
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL
Max daily dose: 15 mg milligram(s)
Max total dose: 15 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Linagliptin

SUB31340 · Substance

Active substance: Linagliptin
Pharmaceutical form: FILM COATED TABLET
Route of administration: ORAL
Max daily dose: 5 mg milligram(s)
Max total dose: 5 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Semaglutide

SUB32188 · Substance

Active substance: Semaglutide
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 14 mg milligram(s)
Max total dose: 14 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Semaglutide

SUB32188 · Substance

Active substance: Semaglutide
Pharmaceutical form: TABLET
Route of administration: ORAL
Max daily dose: 7 mg milligram(s)
Max total dose: 7 mg milligram(s)
Max treatment duration: 6 Month(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Auxiliary 1

Insulin Glargine

SUB08196MIG · Substance

Active substance: Insulin Glargine
Pharmaceutical form: SOLUTION FOR INJECTION
Route of administration: SUBCUTANEOUS INJECTION
Max daily dose: 8 U unit(s)
Max total dose: 100 U unit(s)
Max treatment duration: 24 Week(s)
Authorisation status: Authorised
ATC code: - — -
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universita Cattolica Del Sacro Cuore

Sponsor organisation: Universita Cattolica Del Sacro Cuore
Address: Largo Francesco Vito 1
City: Rome
Postcode: 00168
Country: Italy

Scientific contact point

Organisation: Universita Cattolica Del Sacro Cuore
Contact name: Andrea Giaccari

Public contact point

Organisation: Universita Cattolica Del Sacro Cuore
Contact name: Andrea Giaccari

Locations

1 EU/EEA country · 2 investigational sites

By country

Country	MS status	Planned subjects	Sites
Italy	Ongoing, recruiting	80	2
Rest of world	—	0	—

Investigational sites

Italy

2 sites · Ongoing, recruiting

Ospedale Isola Tiberina Gemelli Isola

UOS Endrocrinologia e Diabetologia, Via Di Ponte Quattro Capi 39, 00186, Rome

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

UOS Centro Malattie Endocrine e Metaboliche, Largo Francesco Vito 1, 00168, Rome

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country	Trial start	Trial end	Recruitment start	Recruitment end	Early termination
Italy	2025-11-14		2025-11-14

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 32 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Type	Title	Version
Protocol (for publication)	D1_Protocol_2025-521748-39-00	1.0
Protocol (for publication)	D1_Protocol_2025-521748-39-00_clean	4.0
Protocol (for publication)	D1_Protocol_2025-521748-39-00_tc	4.0
Recruitment arrangements (for publication)	K1_Recruitment arrangments	1
Subject information and informed consent form (for publication)	L1_SIS and ICF adult	1.0
Subject information and informed consent form (for publication)	L1_SIS and ICF adult_clean	3.0
Subject information and informed consent form (for publication)	L1_SIS and ICF adult_tc	3.0
Subject information and informed consent form (for publication)	L2_Other subject information material_Consenso trattamento dati	1.0
Subject information and informed consent form (for publication)	L2_Other subject information material_Consenso trattamento dati_clean	2.0
Subject information and informed consent form (for publication)	L2_Other subject information material_Consenso trattamento dati_tc	2.0
Subject information and informed consent form (for publication)	L2_Other subject information material_Lettera al Medico Curante	1.0
Subject information and informed consent form (for publication)	L2_Other subject information material_Lettera al Medico Curante_clean	2.0
Subject information and informed consent form (for publication)	L2_Other subject information material_Lettera al Medico Curante_tc	2.0
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Canagliflozin	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Dapagliflozin	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Empagliflozin	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Ertugliflozin	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Insulin aspart	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Insulin degludec	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Insulin Glargine	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Insulin Lispro	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Linagliptin	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Oral Semaglutide	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Pioglitazone	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Sitagliptin	1
Summary of Product Characteristics (SmPC) (for publication)	E2_SmPC_Subcutaneous Semaglutide	1
Synopsis of the protocol (for publication)	D1_Protocol Synopsis EN_2025-521748-39-00	1.0
Synopsis of the protocol (for publication)	D1_Protocol Synopsis EN_2025-521748-39-00_clean	4.0
Synopsis of the protocol (for publication)	D1_Protocol Synopsis EN_2025-521748-39-00_tc	4.0
Synopsis of the protocol (for publication)	D1_Protocol Synopsis IT_2025-521748-39-00	1.0
Synopsis of the protocol (for publication)	D1_Protocol Synopsis IT_2025-521748-39-00_clean	4.0
Synopsis of the protocol (for publication)	D1_Protocol Synopsis IT_2025-521748-39-00_tc	4.0

Application history

2 submissions — initial application plus substantial / non-substantial modifications

#	Type	Code	Submitted	Reference MS	Conclusion	Decision date
1	INITIAL	IN	2025-04-16	Italy	Acceptable 2025-07-21	2025-07-21
2	SUBSTANTIAL MODIFICATION	SM-1	2025-09-04	Italy	Acceptable 2025-10-16	2025-12-09

SGLT-2i, Heart, Improvement of Cardiovascular Autonomic Neuropathy

Overview

Key facts

Trial design

Main objective

Secondary objectives 1

Conditions and MedDRA coding

Eligibility criteria

Inclusion criteria 10

Exclusion criteria 16

Endpoints

Primary endpoints 2

Secondary endpoints 3

Investigational products

Test 17

Auxiliary 1

Sponsors and contacts

Universita Cattolica Del Sacro Cuore

Scientific contact point

Public contact point

Locations

By country

Investigational sites

Country notifications

Results and documents

Documents 32 files

Application history

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