The Effects of Dapagliflozin on HDL Particles Subtypes and Reverse Cholesterol Transport in Type 2 Diabetic Patients
Condition: Type 2 Diabetes
Study type: Interventional
Phase: Phase 4

Summary: 
      In Phase 2b/3 clinical trials, Dapagliflozin has been shown to raise HDL cholesterol levels
      by about 4 mg/dl (1 mmol/l), which is generally considered a clinically-meaningful change. As
      this HDL cholesterol increase is carried out with concomitant improvement in glucotoxicity
      and body weight reduction, it is possible that treatment with Dapagliflozin also improves HDL
      function. This is important because clinical, epidemiological and experimental studies
      indicate that HDL function may be more important than HDL cholesterol levels in determining
      the protective cardiovascular effects of HDL particles. In addition, knowing the effects of
      Dapagliflozin on HDL function can help interpreting the increase in HDL cholesterol levels
      observed in Dapagliflozin-treated patients. Finally, discovery of extra-glycemic effects of
      Dapagliflozin will shed new light on the potential benefits of therapy with Dapagliflozin and
      SGLT2i in general. So far, no study evaluated the effects of Dapagliflozin (or other SGLT2i)
      on HDL function.

      The investigators hypothesize that Dapagliflozin, in addition to raising HDL cholesterol
      levels, also increases HDL functionality, measured as reverse cholesterol transport and
      anti-oxidant capacity, in patients with T2DM
    

Detailed description: 
      Sodium glucose co-transport-2 (SGLT-2) inhibitors (SGLT-2i), a new class of glucose-lowering
      agents, reduce tubular glucose reabsorption, thus lowering blood glucose without stimulating
      insulin release. SGLT-2i have been found to be effective in improving glucose control in type
      2 diabetic patients at any disease stage, and also when added to insulin in type 1 diabetic
      patients. In addition to the glycosuric effect, SGLT-2i reduce body weight and blood pressure
      and determine an increase in HDL cholesterol levels. HDL mediate reverse cholesterol
      transport, by extracting cholesterol from peripheral tissues and cells and vehiculating it to
      the liver. This function, which is regulated that by enzyme cholesteryl esther transfer
      protein (CETP), is considered a fundamental mechanism of protection from accumulation of
      cholesterol in the vasculature and a physiologic barrier against atherosclerosis development
      and protection. The sophisticated method to precisely assess reverse cholesterol transport in
      vitro are available in our research lab. Although it has been reported that therapy with
      SGLT-2i raise HDL concentrations by about 4 mg/dL (0.1 mmol/L), the mechanisms remains
      unclear and it is important to assess whether or not this quantitative increase is coupled to
      functional improvement in reverse cholesterol transport. In fact, previous studies on
      HDL-raising therapies have clarified that not all HDL particles and functional and HDL
      cholesterol levels might not be representative of the reverse cholesterol transport
      processes. In addition to cholesterol transport, normal HDL particles also have anti-oxidant
      and anti-inflammatory properties, that are important to translate HDL cholesterol levels into
      cardiovascular protection. Several HDL subclasses have been identified, having different
      composition and anti-atherosclerotic properties.

      Dapagliflozin (Bristol-Myers Squibb Company [BMS]-512148) is a highly potent, selective, and
      reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), the major transporter
      responsible for renal glucose reabsorption. Dapagliflozin lowers plasma glucose by inhibiting
      the renal reabsorption of glucose and by promoting its urinary excretion. A tablet
      formulation of dapagliflozin for oral administration has been approved in over 40 countries
      including the European Union (EU) and the United States (US) and is under review in numerous
      countries around the world. Dapagliflozin is approved by AIFA with determination number
      909/2013 dated 16/10/2013, and marketing authorization number 042494070/E. In the Phase 2b
      and 3 program, dapagliflozin has been studied as monotherapy and in combination with
      metformin, pioglitazone, glimepiride, sitagliptin, and insulin. As of 15-Nov-2012 (date of
      most recent pooled analysis), a total of 9,412 subjects with T2DM were treated in 16 Phase 3,
      double-blind, controlled clinical studies conducted to evaluate the safety and efficacy of
      dapagliflozin; 5,952 subjects in these studies were treated with dapagliflozin for up to 80
      weeks. The Phase 2b and 3 program established that dapagliflozin is effective in reducing
      HbA1c in a broad range of subjects regardless of disease progression/duration or concomitant
      use of antidiabetic therapies. Improvements in glycemic control were seen when dapagliflozin
      was given as monotherapy; as add-on combination therapy to sitagliptin or metformin, to
      sulfonylurea (glimepiride), to thiazolidinedione (pioglitazone), or to insulin (± oral
      antidiabetic drugs [OADs]); or as initial combination therapy with metformin.

      HDL levels and function. Observational studies provide overwhelming evidence that a low
      high-density lipoprotein (HDL)-cholesterol level increases the risk of coronary events, both
      in healthy subjects and in patients with coronary heart disease. Based on in vitro
      experiments, several mechanistic explanations for the atheroprotective function of HDL have
      been suggested. The HDL functions currently most widely held to account for the
      antiatherogenic effect include participation in reverse cholesterol transport, protection
      against endothelial dysfunction, and inhibition of oxidative stress. Yet, several recent
      pharmacological and genetic studies have failed to demonstrate that increased plasma levels
      of HDL-C resulted in decreased cardiovascular disease risk, giving rise to a controversy
      regarding whether plasma levels of HDL-C reflect HDL function, or that HDL is even as
      protective as assumed. The evidence from preclinical and clinical studies shows that HDL can
      promote the regression of atherosclerosis when the levels of functional particles are
      increased from endogenous or exogenous sources. The data show that regression results from a
      combination of reduced plaque lipid and macrophage contents, as well as from a reduction in
      its inflammatory state. Although more research will be needed regarding basic mechanisms and
      to establish that these changes translate clinically to reduced cardiovascular disease
      events, that HDL can regress plaques suggests that the recent trial failures do not eliminate
      HDL from consideration as an atheroprotective agent but rather emphasizes the important
      distinction between HDL function and plasma levels of HDL-C. While HDL from healthy subjects
      can directly stimulate endothelial cell production of nitric oxide and anti-inflammatory,
      anti-apoptotic, and anti-thrombotic effects as well as endothelial repair processes, growing
      evidence suggests that the vascular effects of HDL can be highly heterogeneous and
      vasoprotective properties of HDL are altered in patients with coronary disease. In fact, HDL
      has been shown to undergo a loss of function in several pathophysiological states, as in the
      acute phase response, obesity and chronic inflammatory diseases. Some of these diseases were
      also shown to be associated with increased risk for cardiovascular disease. One such disease
      that is associated with HDL dysfunction and accelerated atherosclerosis is diabetes mellitus,
      a disease in which the HDL particle undergoes diverse structural modifications that result in
      significant changes in its function, such as glycation and oxidation.

      In Phase 2b/3 clinical trials, Dapagliflozin has been shown to raise HDL cholesterol levels
      by about 4 mg/dl (1 mmol/l), which is generally considered a clinically-meaningful change. As
      this HDL cholesterol increase is carried out with concomitant improvement in glucotoxicity
      and body weight reduction, it is possible that treatment with Dapagliflozin also improves HDL
      function. This is important because clinical, epidemiological and experimental studies
      indicate that HDL function may be more important than HDL cholesterol levels in determining
      the protective cardiovascular effects of HDL particles. In addition, knowing the effects of
      Dapagliflozin on HDL function can help interpreting the increase in HDL cholesterol levels
      observed in Dapagliflozin-treated patients. Finally, discovery of extra-glycemic effects of
      Dapagliflozin will shed new light on the potential benefits of therapy with Dapagliflozin and
      SGLT2i in general. So far, no study evaluated the effects of Dapagliflozin (or other SGLT2i)
      on HDL function.We hypothesize that Dapagliflozin, in addition to raising HDL cholesterol
      levels, also increases HDL functionality, measured as reverse cholesterol transport and
      anti-oxidant capacity, in patients with T2DM.

      This will be a randomized, placebo controlled, parallel group study in 36 type 2 diabetic
      patients to assess the effects of Dapagliflozin on HDL levels and function.

      The general objective of the project is to detect a significant differences in the changes
      versus baseline of the patients' HDL cholesterol efflux capacity, HDL levels, HDL subclasses,
      HDL anti-oxidant activity, CETP activity, serum/plasma cytokines and adipokines (IL-6, IL-8,
      PAI-1, TNF-α, visfatin, resistin, adiponectin, leptin) in patients randomized to
      dapagliflozin compared to those randomized to placebo
    

Intervention name(s): Dapagliflozin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Sodium glucose cotransporter-2 inhibitor; Tables of Dapagliflozin placebo
Other intervention name(s): Forxiga
Intervention MeSH terms: Dapagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment