Effects of empagliFlozin on myocardIal metabOlic Rate of glucosE Estimated Through 18FDG PET (FIORE Study)
Condition: Type 2 Diabetes; Cardiovascular Risk Factor
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Empagliflozin 10 MG; Glimepiride 2 mg
Intervention type(s): Drug; Drug
Intervention description(s): 10 mg tablet daily; 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
Other intervention name(s): Jardiance; Solosa; Amaryl
Intervention MeSH terms: Empagliflozin; Glimepiride
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 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.
Masking: Single (Participant)
Primary purpose: Prevention
Keywords: Empagliflozin; Type 2 diabetes; Myocardial glucose uptake; Cardiovascular risk