Effects of empagliFlozin on myocardIal metabOlic Rate of glucosE Estimated Through 18FDG PET (FIORE Study)
NCT ID: NCT04183868
Last Updated: 2023-01-18
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE4
Total Enrollment
26 participants
Study Classification
INTERVENTIONAL
Study Start Date
2016-04-30
Study Completion Date
2021-10-31
Brief Summary
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Diabetes is an independent risk factor for ischemic heart disease (CAD) and heart failure, and cardiovascular diseases are the main cause of mortality and morbidity in patients with diabetes. Recent studies on cardiovascular outcomes have shown that type 2 sodium glucose co-transporter (SGLT-2i) inhibitors are not only effective in improving glycometabolic control, but are also able to reduce major CV events (MACE) and hospitalization for heart failure. However, it is still unclear whether the beneficial CV effects of treatment with SGLT2i are due to indirect mechanisms such as reduction in blood pressure, improvement of vascular stiffness, reduction in body weight and visceral adiposity, reduction in uricemia or whether they have effects direct on the heart. Recently, it was shown that in nondiabetic porcine model with heart failure, the treatment with empagliflozin was associated with a switch of myocardial fuel utilization from glucose uptake toward uptake of ketone bodies and free fatty acid, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.
It is not known whether empagliflozin treatment is able to modify the heart's energy metabolism even in humans.
In this study we hypothesize that empagliflozin may determine beneficial CV effects reducing myocardial metabolic rate of glucose assessed by hyperinsulinemic euglycemic clamp 18F-FDG PET scans in patients with type 2 diabetes.
This is a single-center, prospective, controlled, randomized, open-label, two parallel group and switch, active-comparator study that evaluates the comparative effects of 26 weeks of treatment with empagliflozin versus glimepiride add on metformin on myocardial metabolic rate of glucose estimated through 18F-FGD-PET scan in patients with type 2 diabetes without a history of coronary heart disease. At the end of 26 weeks of treatment, subjects belonging to the first group will be shifted to glimepiride therapy, while subjects belonging to the second group will be shifted to empagliflozin treatment for 26 weeks. All subjects, then, will control themselves.
It is not known whether empagliflozin treatment is able to modify the heart's energy metabolism even in humans.
In this study we hypothesize that empagliflozin may determine beneficial CV effects reducing myocardial metabolic rate of glucose assessed by hyperinsulinemic euglycemic clamp 18F-FDG PET scans in patients with type 2 diabetes.
This is a single-center, prospective, controlled, randomized, open-label, two parallel group and switch, active-comparator study that evaluates the comparative effects of 26 weeks of treatment with empagliflozin versus glimepiride add on metformin on myocardial metabolic rate of glucose estimated through 18F-FGD-PET scan in patients with type 2 diabetes without a history of coronary heart disease. At the end of 26 weeks of treatment, subjects belonging to the first group will be shifted to glimepiride therapy, while subjects belonging to the second group will be shifted to empagliflozin treatment for 26 weeks. All subjects, then, will control themselves.
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Detailed Description
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Diabetes mellitus type 2 (T2DM) is the most common metabolic disease and its prevalence is rapidly increasing. T2DM is a chronic disease that affects over 451 million people in the world and this number is expected to increase over the years and it is estimated that in 2045 there will be in the world over 693 million patients with T2DM. Diabetes is an independent risk factor for ischemic heart disease (CAD), stroke and peripheral artery disease and cardiovascular diseases are the main cause of mortality and morbidity in patients with diabetes. It is estimated that subjects with T2DM have a risk of cardiovascular events same as those of non-diabetic subjects with a previous cardiovascular event and several epidemiological studies have reported that the incidence of fatal and nonfatal coronary events in patients with T2DM is 1.5 to 3-4 times higher than non-diabetics of the same age.
Many studies showed that, in diabetic subjects, improved plasma glucose is associated with a reduction in microvascular complications. Instead, is not completely shown that a reduction of plasma glucose result in a reduction of cardiovascular events. In fact, although it was noted that, in subjects with T2DM, good control glyco-metabolic is associated with modest cardiovascular benefits in the long term, however, the intensive treatment hypoglycemic agent or the use of antidiabetic drugs is often associated with adverse events cardiovascular.
Recently, it was approved for the treatment of T2DM a new class of drugs, inhibitors of sodium glucose cotransporter type 2 (SGLT-2), that work by blocking the renal glucose reabsorption, causing glycosuria. SGLT-2 inhibitors have a good safety profile, are effective in reducing HbA1c regardless of the duration of diabetes and the degree of beta-cell dysfunction and insulin resistance and exhibit a low risk of hypoglycemia. In addition, the loss of glucose renal induced by SGLT2 inhibitors is associated with modest weight loss and reduction in blood pressure. Pre clinical studies showed that SGLT2 inhibitors, through a reduction in glucose toxicity, determine an improvement in insulin resistance liver and muscle and a restoration of first and second phase insulin secretion. The improvement of β-cell function and insulin sensitivity, assessed by indexes derived from OGTT, was obtained in subjects with T2DM, even after a single dose of empagliflozin, selective SGLT2 inhibitor. There are few data on the changes in insulin sensitivity, assessed by hyperinsulinemic euglycemic clamp, and insulin secretion, estimated by intravenous glucose test tolerance (IVGTT), induced by SGLT2 inhibitor. It was shown that, in subjects with T2DM at high cardiovascular risk, treatment with empagliflozin in addition to standard therapy was associated with a significant reduction of the composite cardiovascular endpoint, consisting of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, compared to placebo. In addition, treatment with empagliflozin in addition to standard therapy determined in a significant reduction in cardiovascular mortality, mortality from all causes and hospitalization for heart failure compared to placebo. It is not completely known the mechanism through which treatment with empagliflozin is associated to an improvement of cardiovascular outcomes. Growing evidences suggest that empagliflozin performs positive cardiovascular effects through a reduction in blood pressure, an improvement in arterial stiffness, a reduction in body weight and visceral adiposity. Recently, it was shown that in nondiabetic porcine model with heart failure, the treatment with empagliflozin was associated with a switch of myocardial fuel utilization from glucose uptake toward uptake of ketone bodies and free fatty acid, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.
Myocardial positron emission tomography (PET) with 18F-Fluorodeoxyglucose (18F-FDG), a widely used glucose analogue, in combination with the euglycemic-hyperinsulinemic clamp is considered the gold standard to measure myocardial metabolic rate of glucose under standardized experimental conditions. In this study we hypothesize that empagliflozin may determine beneficial cardiovascular effects reducing myocardial metabolic rate of glucose assessed by hyperinsulinemic euglycemic clamp 18F-FDG PET scans in patients with type 2 diabetes with no history of coronary heart disease, compared to treatment with glimepiride, both add on metformin.
Study design
13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, will be treated with empagliflozin for 26 weeks and will be compared with a group of 13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, treated with glimepiride (both in addition to metformin) for 26 weeks. At the end of 26 weeks of treatment, subjects belonging to the first group will be shifted to glimepiride therapy, while subjects belonging to the second group will be shifted to empagliflozin treatment for 26 weeks. All subjects, then, will control themselves.
Schematic overview of the study timeline
Visit 1 Screening (week -1): Clinical examination, vital signs (systolic and diastolic blood pressure and pulse), anthropometric measures, HbA1c, FPG, haematology and biochemistry, pro-BNP, high sensitivity C-reactive protein (hsCRP), troponin T, renal function, albumin/creatinine ratio (ACR), evaluation criteria for inclusion and exclusion, electrocardiogram (ECG), echocardiogram, Holter ECG.
Visit 2 Randomization (week 0 baseline): Hyperinsulinemic euglycemic clamp combined with 18F-FDG PET. Assignment two treatment arms randomly with ratio of 1: 1. Beginning of treatment with empagliflozin 10 mg/day in one arm and the other glimepiride.
Visit 3 (week 4): Clinical examination, security monitoring (systolic and diastolic blood pressure), hypoglycemia and adverse events evaluation
Visit 4 (week 8): Clinical examination, security monitoring (ECG (assessment of P Wave, QRS Complex, QT Interval), systolic and diastolic blood pressure), hypoglycemia and adverse events evaluation
Visit 5 (week 12): Clinical examination, security monitoring, hypoglycemia and adverse events evaluation
Visit 6 (week 26): Clinical examination, vital signs (systolic and diastolic blood pressure and pulse), anthropometric measures, haematology and biochemistry, pro-BNP, high sensitivity C-reactive protein (hsCRP), troponin T, renal function, ACR, ECG, echocardiogram, Holter ECG
Visit 7 (week 26+ 1 day): Hyperinsulinemic euglycemic clamp combined with 18F-FDG PET (shift of the treatment groups).
Visit 8 (week 30): Clinical examination, security monitoring (systolic and diastolic blood pressure), hypoglycemia and adverse events evaluation
Visit 9 (week 34): Clinical examination, security monitoring (ECG, blood pressure), hypoglycemia and adverse events evaluation
Visit 10 (week 40): Clinical examination, security monitoring, hypoglycemia and adverse events evaluation
Visit 11 (week 52): Clinical examination, vital signs, anthropometric measures, haematology and biochemistry, pro-BNP, high sensitivity C-reactive protein (hsCRP), troponin T, renal function, ACR, ECG, echocardiogram, Holter ECG.
Visit 12 (week 52 + 1 day): Hyperinsulinemic euglycemic clamp combined with 18F-FDG PET
Hyperinsulinemic euglycemic clamp combined with 18F-FDG-PET scan for assessment of peripheral insulin sensitivity and myocardial glucose uptake.
Myocardial metabolic rate of glucose (Global MRGlu - mmol/min/100mg) will be measured by 18F-FDG-PET acquired in the course of euglycemic hyperinsulinemic clamp as previously described. Subjects will be received a priming dose of insulin (Humulin R 100UI/ml; Eli Lilly) during the initial 10 min to acutely raise the desired levels of plasma insulin, followed by continuous insulin infusion fixed at 40 mU/m2 x min. The blood glucose level will be maintained constant at 90 mg/dl for the next 120 min by infusing 20% glucose at varying rates according to blood glucose measurements performed at 5-min intervals (mean coefficient of variation of blood glucose was \<4%). Glucose metabolized by the whole body (M) will be calculated as the mean rate of glucose infusion measured during the last 60 minutes of the clamp examination (steady state) and was expressed as milligrams per minute per kilogram fat-free mass (MFFM).
The 18F-FDG PET imaging procedure will be performed on a hybrid PET/CT scanner (GE Discovery ST8- 2D PET scanner), starting 60 minutes after the insulin infusion. 60-min dynamic acquisition will be started simultaneously with the intravenous injection of 370 MBq18F-FDG and the insulin-glucose infusion will be continued during entire PET acquisition. The estimation of myocardial MRGlu will be performed using a Patlak compartmental modelling, a widely diffuse technique provided by a graphical tool specific for cardiac images analysis (PCARD) in PMOD Software platform (Version 3.806). PCARD allows to measure the global MRGlu as well as the segmental myocardial glucose uptake by using a segmentation algorithm to divide myocardium into standard 17 segments model according to ASNC (American Society of Nuclear Cardiology) guideline and the American Heart Association (AHA).
Sample size
The "Sample Size" in the study is of 26 subjects (13 subjects per group). The same result has been calculated considering a significant reduction in group Empagliflozin of 40 % in myocardial metabolic rate of glucose estimated through 18F-FGD-PET, compared to a change in the treatment arm glimepiride of 15% and assuming a standard deviation of 5%, a "dropout" of 10%, with a power of 85% and an alpha error of 0.05%, using the power calculation available at the following website https://clincalc.com/Stats/SampleSize.aspx.
The randomization of the subjects will be done using the program "Research Randomizer (www.randomizer.org). The subjects will be allocated to one of two arms of the study (1 = Treatment Empagliflozin; 2 = Treatment Glimepriride;) according to the outline generated by the program indicated above and attached to the protocol.
Safety assessment
During the course of the present study all adverse events (including hypoglycemic episodes), both those suspected to be study drug-related and those not suspected to be related to study medications, will be collected.
Many studies showed that, in diabetic subjects, improved plasma glucose is associated with a reduction in microvascular complications. Instead, is not completely shown that a reduction of plasma glucose result in a reduction of cardiovascular events. In fact, although it was noted that, in subjects with T2DM, good control glyco-metabolic is associated with modest cardiovascular benefits in the long term, however, the intensive treatment hypoglycemic agent or the use of antidiabetic drugs is often associated with adverse events cardiovascular.
Recently, it was approved for the treatment of T2DM a new class of drugs, inhibitors of sodium glucose cotransporter type 2 (SGLT-2), that work by blocking the renal glucose reabsorption, causing glycosuria. SGLT-2 inhibitors have a good safety profile, are effective in reducing HbA1c regardless of the duration of diabetes and the degree of beta-cell dysfunction and insulin resistance and exhibit a low risk of hypoglycemia. In addition, the loss of glucose renal induced by SGLT2 inhibitors is associated with modest weight loss and reduction in blood pressure. Pre clinical studies showed that SGLT2 inhibitors, through a reduction in glucose toxicity, determine an improvement in insulin resistance liver and muscle and a restoration of first and second phase insulin secretion. The improvement of β-cell function and insulin sensitivity, assessed by indexes derived from OGTT, was obtained in subjects with T2DM, even after a single dose of empagliflozin, selective SGLT2 inhibitor. There are few data on the changes in insulin sensitivity, assessed by hyperinsulinemic euglycemic clamp, and insulin secretion, estimated by intravenous glucose test tolerance (IVGTT), induced by SGLT2 inhibitor. It was shown that, in subjects with T2DM at high cardiovascular risk, treatment with empagliflozin in addition to standard therapy was associated with a significant reduction of the composite cardiovascular endpoint, consisting of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, compared to placebo. In addition, treatment with empagliflozin in addition to standard therapy determined in a significant reduction in cardiovascular mortality, mortality from all causes and hospitalization for heart failure compared to placebo. It is not completely known the mechanism through which treatment with empagliflozin is associated to an improvement of cardiovascular outcomes. Growing evidences suggest that empagliflozin performs positive cardiovascular effects through a reduction in blood pressure, an improvement in arterial stiffness, a reduction in body weight and visceral adiposity. Recently, it was shown that in nondiabetic porcine model with heart failure, the treatment with empagliflozin was associated with a switch of myocardial fuel utilization from glucose uptake toward uptake of ketone bodies and free fatty acid, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.
Myocardial positron emission tomography (PET) with 18F-Fluorodeoxyglucose (18F-FDG), a widely used glucose analogue, in combination with the euglycemic-hyperinsulinemic clamp is considered the gold standard to measure myocardial metabolic rate of glucose under standardized experimental conditions. In this study we hypothesize that empagliflozin may determine beneficial cardiovascular effects reducing myocardial metabolic rate of glucose assessed by hyperinsulinemic euglycemic clamp 18F-FDG PET scans in patients with type 2 diabetes with no history of coronary heart disease, compared to treatment with glimepiride, both add on metformin.
Study design
13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, will be treated with empagliflozin for 26 weeks and will be compared with a group of 13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, treated with glimepiride (both in addition to metformin) for 26 weeks. At the end of 26 weeks of treatment, subjects belonging to the first group will be shifted to glimepiride therapy, while subjects belonging to the second group will be shifted to empagliflozin treatment for 26 weeks. All subjects, then, will control themselves.
Schematic overview of the study timeline
Visit 1 Screening (week -1): Clinical examination, vital signs (systolic and diastolic blood pressure and pulse), anthropometric measures, HbA1c, FPG, haematology and biochemistry, pro-BNP, high sensitivity C-reactive protein (hsCRP), troponin T, renal function, albumin/creatinine ratio (ACR), evaluation criteria for inclusion and exclusion, electrocardiogram (ECG), echocardiogram, Holter ECG.
Visit 2 Randomization (week 0 baseline): Hyperinsulinemic euglycemic clamp combined with 18F-FDG PET. Assignment two treatment arms randomly with ratio of 1: 1. Beginning of treatment with empagliflozin 10 mg/day in one arm and the other glimepiride.
Visit 3 (week 4): Clinical examination, security monitoring (systolic and diastolic blood pressure), hypoglycemia and adverse events evaluation
Visit 4 (week 8): Clinical examination, security monitoring (ECG (assessment of P Wave, QRS Complex, QT Interval), systolic and diastolic blood pressure), hypoglycemia and adverse events evaluation
Visit 5 (week 12): Clinical examination, security monitoring, hypoglycemia and adverse events evaluation
Visit 6 (week 26): Clinical examination, vital signs (systolic and diastolic blood pressure and pulse), anthropometric measures, haematology and biochemistry, pro-BNP, high sensitivity C-reactive protein (hsCRP), troponin T, renal function, ACR, ECG, echocardiogram, Holter ECG
Visit 7 (week 26+ 1 day): Hyperinsulinemic euglycemic clamp combined with 18F-FDG PET (shift of the treatment groups).
Visit 8 (week 30): Clinical examination, security monitoring (systolic and diastolic blood pressure), hypoglycemia and adverse events evaluation
Visit 9 (week 34): Clinical examination, security monitoring (ECG, blood pressure), hypoglycemia and adverse events evaluation
Visit 10 (week 40): Clinical examination, security monitoring, hypoglycemia and adverse events evaluation
Visit 11 (week 52): Clinical examination, vital signs, anthropometric measures, haematology and biochemistry, pro-BNP, high sensitivity C-reactive protein (hsCRP), troponin T, renal function, ACR, ECG, echocardiogram, Holter ECG.
Visit 12 (week 52 + 1 day): Hyperinsulinemic euglycemic clamp combined with 18F-FDG PET
Hyperinsulinemic euglycemic clamp combined with 18F-FDG-PET scan for assessment of peripheral insulin sensitivity and myocardial glucose uptake.
Myocardial metabolic rate of glucose (Global MRGlu - mmol/min/100mg) will be measured by 18F-FDG-PET acquired in the course of euglycemic hyperinsulinemic clamp as previously described. Subjects will be received a priming dose of insulin (Humulin R 100UI/ml; Eli Lilly) during the initial 10 min to acutely raise the desired levels of plasma insulin, followed by continuous insulin infusion fixed at 40 mU/m2 x min. The blood glucose level will be maintained constant at 90 mg/dl for the next 120 min by infusing 20% glucose at varying rates according to blood glucose measurements performed at 5-min intervals (mean coefficient of variation of blood glucose was \<4%). Glucose metabolized by the whole body (M) will be calculated as the mean rate of glucose infusion measured during the last 60 minutes of the clamp examination (steady state) and was expressed as milligrams per minute per kilogram fat-free mass (MFFM).
The 18F-FDG PET imaging procedure will be performed on a hybrid PET/CT scanner (GE Discovery ST8- 2D PET scanner), starting 60 minutes after the insulin infusion. 60-min dynamic acquisition will be started simultaneously with the intravenous injection of 370 MBq18F-FDG and the insulin-glucose infusion will be continued during entire PET acquisition. The estimation of myocardial MRGlu will be performed using a Patlak compartmental modelling, a widely diffuse technique provided by a graphical tool specific for cardiac images analysis (PCARD) in PMOD Software platform (Version 3.806). PCARD allows to measure the global MRGlu as well as the segmental myocardial glucose uptake by using a segmentation algorithm to divide myocardium into standard 17 segments model according to ASNC (American Society of Nuclear Cardiology) guideline and the American Heart Association (AHA).
Sample size
The "Sample Size" in the study is of 26 subjects (13 subjects per group). The same result has been calculated considering a significant reduction in group Empagliflozin of 40 % in myocardial metabolic rate of glucose estimated through 18F-FGD-PET, compared to a change in the treatment arm glimepiride of 15% and assuming a standard deviation of 5%, a "dropout" of 10%, with a power of 85% and an alpha error of 0.05%, using the power calculation available at the following website https://clincalc.com/Stats/SampleSize.aspx.
The randomization of the subjects will be done using the program "Research Randomizer (www.randomizer.org). The subjects will be allocated to one of two arms of the study (1 = Treatment Empagliflozin; 2 = Treatment Glimepriride;) according to the outline generated by the program indicated above and attached to the protocol.
Safety assessment
During the course of the present study all adverse events (including hypoglycemic episodes), both those suspected to be study drug-related and those not suspected to be related to study medications, will be collected.
Conditions
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Type 2 Diabetes
Cardiovascular Risk Factor
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
CROSSOVER
52-weeks, single-center, prospective, controlled, randomized, open-label, two parallel group and switch, active-comparator.
13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, will be treated with empagliflozin for 26 weeks and will be compared with a group of 13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, treated with glimepiride (both in addition to metformin) for 26 weeks. At the end of 26 weeks of treatment, subjects belonging to the first group will be shifted to glimepiride therapy, while subjects belonging to the second group will be shifted to empagliflozin treatment for 26 weeks. All subjects, then, will control themselves.
13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, will be treated with empagliflozin for 26 weeks and will be compared with a group of 13 subjects with T2DM, poorly controlled on metformin monotherapy, and without a history of ischemic heart disease, treated with glimepiride (both in addition to metformin) for 26 weeks. At the end of 26 weeks of treatment, subjects belonging to the first group will be shifted to glimepiride therapy, while subjects belonging to the second group will be shifted to empagliflozin treatment for 26 weeks. All subjects, then, will control themselves.
Primary Study Purpose
PREVENTION
Blinding Strategy
SINGLE
Participants
Study Groups
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Empagliflozin
Eligible patients (meeting all inclusion criteria) will be randomized to receive empagliflozin in addition to existing metformin background therapy (daily dose of ≥1.500 mg, which has to remain unchanged throughout the study) for 26 weeks.
At the end of 26 weeks of treatment, subjects belonging to empagliflozin arm will be shifted to glimepiride treatment.
Group Type
EXPERIMENTAL
Empagliflozin 10 MG
Intervention Type
DRUG
10 mg tablet daily
Glimepiride
Eligible patients will be randomized to receive glimepiride (starting dose: 2 mg daily) treatment arm, can undergo to up-titration of glimepiride to a maximum of 6 mg/day, if they experience fasting plasma glucose (FPG) levels \> 112 mg/dl (6,2 mmol/l) at scheduled visit at 6th week or at any later scheduled visit.
Whereas, glimepiride-treated patients experiencing recurrent hypoglycemic episodes should down-titrate glimepiride to a dose, considered as appropriate by Investigator.
Hypoglycemic events are defined as symptoms suggestive of low blood glucose confirmed by self monitored blood glucose (SMBG) \< 56 mg/dl (3,1 mmol/l).
Severe hypoglycemia is defined as any hypoglycemic episode requiring the assistance of another party for recovery.
At the end of 26 weeks of treatment, subjects belonging to glimepiride arm will be shifted to treatment with empagliflozin for 26 weeks.
Group Type
ACTIVE_COMPARATOR
Glimepiride 2 mg
Intervention Type
DRUG
starting dose: 2 mg tablet daily, 1 mg for lunch and 1 mg for dinner, can undergo to up-titration of glimepiride to a maximum of 6 mg daily
Interventions
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Empagliflozin 10 MG
10 mg tablet daily
Intervention Type
DRUG
Glimepiride 2 mg
starting dose: 2 mg tablet daily, 1 mg for lunch and 1 mg for dinner, can undergo to up-titration of glimepiride to a maximum of 6 mg daily
Intervention Type
DRUG
Other Intervention Names
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Jardiance
Solosa
Amaryl
Eligibility Criteria
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Inclusion Criteria
* Type 2 diabetes, in treatment with metformin
* Written informed consent
* Written informed consent
Exclusion Criteria
* Type 1 diabetes
* eGFR \<60 ml/min/1.73 m2. or dialysis patients
* HbA1c \<6.5 o \>9%
* Previous treatment with insulin (except for short-term treatment with insulin in connection with intercurrent illness, at the discretion of the Investigator), with SGLT2 inhibitors or with GLP-1R agonists or DPPIV inhibitors
* Patients who do not tolerate empagliflozin and/or glimepiride or in whom empagliflozin and/or glimepiride are contraindicated
* Uncontrolled hypertension (BP\>140/90 mmHg)
* Prior cardio- cerebral-vascular events
* Hepatic disease
* Pathology neoplastic (past or present)
* Pregnancy women or childbearing female without adequate and approved birth control method
* eGFR \<60 ml/min/1.73 m2. or dialysis patients
* HbA1c \<6.5 o \>9%
* Previous treatment with insulin (except for short-term treatment with insulin in connection with intercurrent illness, at the discretion of the Investigator), with SGLT2 inhibitors or with GLP-1R agonists or DPPIV inhibitors
* Patients who do not tolerate empagliflozin and/or glimepiride or in whom empagliflozin and/or glimepiride are contraindicated
* Uncontrolled hypertension (BP\>140/90 mmHg)
* Prior cardio- cerebral-vascular events
* Hepatic disease
* Pathology neoplastic (past or present)
* Pregnancy women or childbearing female without adequate and approved birth control method
Minimum Eligible Age
45 Years
Maximum Eligible Age
75 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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University of Catanzaro
OTHER
Sponsor Role
lead
Responsible Party
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Elena Succurro
Associate Professor in Internal Medicine
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Giorgio Sesti, MD
Role: STUDY_DIRECTOR
University Sapienza of Rome
Locations
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Universital Hospital Mater Domini
Catanzaro, , Italy
Site Status
Countries
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Italy
References
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Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, Malanda B. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018 Apr;138:271-281. doi: 10.1016/j.diabres.2018.02.023. Epub 2018 Feb 26.
Reference Type
BACKGROUND
Vaccaro O, Eberly LE, Neaton JD, Yang L, Riccardi G, Stamler J; Multiple Risk Factor Intervention Trial Research Group. Impact of diabetes and previous myocardial infarction on long-term survival: 25-year mortality follow-up of primary screenees of the Multiple Risk Factor Intervention Trial. Arch Intern Med. 2004 Jul 12;164(13):1438-43. doi: 10.1001/archinte.164.13.1438.
Reference Type
BACKGROUND
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34. doi: 10.1056/NEJM199807233390404.
Reference Type
BACKGROUND
Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation. 1979 Jan;59(1):8-13. doi: 10.1161/01.cir.59.1.8.
Reference Type
BACKGROUND
Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.
Reference Type
BACKGROUND
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53.
Reference Type
BACKGROUND
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR; TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 16;373(3):232-42. doi: 10.1056/NEJMoa1501352. Epub 2015 Jun 8.
Reference Type
BACKGROUND
Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015 May;3(5):356-66. doi: 10.1016/S2213-8587(15)00044-3. Epub 2015 Mar 17.
Reference Type
BACKGROUND
Standards of medical care in diabetes--2015: summary of revisions. Diabetes Care. 2015 Jan;38 Suppl:S4. doi: 10.2337/dc15-S003. No abstract available.
Reference Type
BACKGROUND
Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011 Aug;32(4):515-31. doi: 10.1210/er.2010-0029. Epub 2011 May 23.
Reference Type
BACKGROUND
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227. Epub 2014 Jan 27.
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BACKGROUND
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17.
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Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015 Dec;17(12):1180-93. doi: 10.1111/dom.12572. Epub 2015 Oct 9.
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BACKGROUND
Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ; EMPA-REG BP Investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015 Mar;38(3):420-8. doi: 10.2337/dc14-1096. Epub 2014 Sep 30.
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Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, Broedl UC; EMPA-REG MDI Trial Investigators. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014 Jul;37(7):1815-23. doi: 10.2337/dc13-3055. Epub 2014 Jun 14.
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BACKGROUND
Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, Flores E, Garcia-Ropero A, Sanz J, Hajjar RJ, Fuster V, Badimon JJ. Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics. J Am Coll Cardiol. 2019 Apr 23;73(15):1931-1944. doi: 10.1016/j.jacc.2019.01.056.
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Iozzo P, Chareonthaitawee P, Dutka D, Betteridge DJ, Ferrannini E, Camici PG. Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. Diabetes. 2002 Oct;51(10):3020-4. doi: 10.2337/diabetes.51.10.3020.
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Nishikawa J, Ohtake T, Yokoyama I, Watanabe T, Momose T, Sasaki Y. Simple method to quantify myocardial glucose metabolism from MB ratio in myocardial FDG PET. Ann Nucl Med. 1996 Aug;10(3):323-8. doi: 10.1007/BF03164739.
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Gerber BL, Ordoubadi FF, Wijns W, Vanoverschelde JL, Knuuti MJ, Janier M, Melon P, Blanksma PK, Bol A, Bax JJ, Melin JA, Camici PG. Positron emission tomography using(18)F-fluoro-deoxyglucose and euglycaemic hyperinsulinaemic glucose clamp: optimal criteria for the prediction of recovery of post-ischaemic left ventricular dysfunction. Results from the European Community Concerted Action Multicenter study on use of(18)F-fluoro-deoxyglucose Positron Emission Tomography for the Detection of Myocardial Viability. Eur Heart J. 2001 Sep;22(18):1691-701. doi: 10.1053/euhj.2000.2585.
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Marini MA, Succurro E, Frontoni S, Mastroianni S, Arturi F, Sciacqua A, Lauro R, Hribal ML, Perticone F, Sesti G. Insulin sensitivity, beta-cell function, and incretin effect in individuals with elevated 1-hour postload plasma glucose levels. Diabetes Care. 2012 Apr;35(4):868-72. doi: 10.2337/dc11-2181. Epub 2012 Feb 22.
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BACKGROUND
Morbelli S, Marini C, Adami GF, Kudomi N, Camerini G, Iozzo P, Massollo M, Capitanio S, Bodrato S, Verardi MT, Papadia F, Cordera R, Knuuti J, Scopinaro N, Sambuceti G. Tissue specificity in fasting glucose utilization in slightly obese diabetic patients submitted to bariatric surgery. Obesity (Silver Spring). 2013 Mar;21(3):E175-81. doi: 10.1002/oby.20003.
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BACKGROUND
Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS; American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002 Jan 29;105(4):539-42. doi: 10.1161/hc0402.102975. No abstract available.
Reference Type
BACKGROUND
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
2016.43
Identifier Type: -
Identifier Source: org_study_id
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