Endothelial Effects of Basal Insulin: Detemir Versus Glargine
Condition: Type 2 Diabetes; Endothelial Dysfunction; Cardiovascular Disease
MeSH terms: Cardiovascular Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      Endothelial progenitor cell (EPC) level represents a surrogate marker of cardiovascular risk
      and an indicator of the ongoing vascular damage. Moreover, EPCs are involved in the
      pathogenesis of virtually all diabetic complications. Therefore, ways to modulate EPCs are
      currently considered of utmost importance, especially in high-risk subjects. While many drugs
      with pleiotropic vasculoprotective effects have shown ability to positively modulate EPCs,
      there is no data on the effects of specific insulin formulations.

      This is a human randomised cross-over comparison trial. The purpose is to compare the effects
      of two basal insulin analogues (detemir and glargine) added to oral antidiabetic therapy in
      poorly-controlled type 2 patients with cardiovascular disease on endothelial function and EPC
      levels.

      The aim is to test whether optimized glycemic control with add-on basal insulin analogues
      improves endothelial damage and regeneration in type 2 diabetes with macroangiopathy and to
      compare the effects of glargine vs detemir on markers of endothelial damage and regeneration.

      EPC level is the most innovative outcome measure of this study and represents the primary
      endpoint. Endothelial dysfunction/damage, evaluated using soluble markers, will be the
      secondary outcome. Given the supposed inverse correlation between EPC and endothelial damage,
      it is expected that EPC increase reflects amelioration in endothelial biology, a result that
      may have significant clinical implications in this cohort of high-risk patients.
    

Detailed description: 
      Diabetes mellitus is associated with a strikingly high incidence of cardiovascular events.
      This is likely attributable to the widespread vascular damage due to uncontrolled
      hyperglycaemia and associated risk factors. Endothelial dysfunction is universally recognised
      as the first step in the natural history of atherosclerosis. Therefore, efforts are deserved
      to the understanding of its pathogenesis and to new strategies to prevent or limit its
      development. High glucose concentration is one of the most detrimental factors that
      negatively affect endothelial cell function. Through the classical damage pathways (including
      oxidative stress, PKC and MAP kinase activation and AGE accumulation), hyperglycaemia hampers
      the homeostasis of the vascular endothelial layer. Besides favouring endothelial cell damage,
      hyperglycaemia also prevents endothelial regeneration by negatively modulating endothelial
      progenitor cells (EPCs) [1]. EPCs are bone marrow-derived cells capable of differentiating
      into mature endothelial cells and repopulating the damaged endothelial layer, thus
      contributing to maintain endothelial homeostasis [2]. Consistently, the EPC level is directly
      correlated to measured of endothelial function [3]. The pool of circulating EPCs is reduced
      in the presence of cardiovascular risk factors, and EPC level is considered a biomarker of
      vascular health, which is negatively associated with measures of cardiovascular risk and with
      the extent of vascular damage [4]. Most importantly, EPC depletion predicts cardiovascular
      events independently of risk factors and of other relevant hard measures, such as left
      ventricular function [5]. In fact, a number of clinical and experimental studies indicate
      that alterations in EPCs contribute to the pathogenesis of cardiovascular disease and of
      virtually all diabetic complications [6]. In this light, ways to expand the EPC pool are
      actively pursued: for instance, modulation of EPCs has been studied to demonstrate the
      pleiotropic effects of vasculoprotective drugs, such as statins, glitazones and ACE
      inhibitors (reviewed in [7]. Diabetes is associated with a profound depletion of circulating
      EPCs, which is related to the metabolic control (both HbA1c and fasting glucose), adiposity
      and concomitant risk factors [8, 9]. Short and long-term glycaemic control is probably one of
      the most important determinant of the EPC pool in diabetes. Actually, advanced glycation
      end-products (AGEs) have been shown to exert detrimental effects on EPCs in vitro [10]. We
      have also demonstrated that number and function of EPCs provide a valuable marker of vascular
      damage in both healthy subjects and in type 2 diabetic patients [11, 12]. Interestingly, a
      mild EPC depletion is also present in pre-diabetic states [13], an observation that
      strengthens the link between glucose metabolism and EPC biology. Correction of hyperglycaemia
      with insulin has the potential to restore the circulating EPC pool, likely through
      mobilisation from bone marrow. In fact, we have shown that experimental hyperglycaemia
      (streptozotocin-induced diabetes) impairs ischemia-induced EPC mobilisation, which is
      corrected by basal insulin therapy [13]. The favourable effects of antidiabetic therapy
      intensification has been substantiated in a short-term study in humans [14], but the
      mechanisms responsible for this effect are incompletely understood. One putative mechanism is
      stimulation of nitric oxide production inside the bone marrow microenvironment. This is in
      compliance with one recent observation of ours that insulin indeed stimulates production of
      NO [15]. In the bone marrow, this is followed by activation of MMP9, cleavage of
      membrane-bound c-kit ligand, which, in turn, weakens cell-matrix interactions and triggers
      EPC mobilisation [16]. It is currently unknown whether this phenomenon is mediated by insulin
      per se or by reduction of plasma glucose, and whether there exist differences among insulin
      formulations. Likely, to act on the central EPC compartment (bone marrow), insulin needs to
      reach the marrow microenvironment at sufficiently high concentrations, a goal which could be
      achieved preferentially with specific insulin analogues, such as insulin detemir.

      It has been suggested that weight gain, which follows initiation of insulin therapy, may
      exert negative effects on major cardiovascular outcomes. Related to this notion, not only the
      EPC pool reflects the global cardiometabolic profile, but it is also negatively related to
      visceral adiposity [4]. In a mouse model of obesity and diabetes, generation and function of
      EPC are profoundly altered [17], while it has been suggested that leptin and other adipokines
      may mediate this effect [18]. Hence, the net modulation of EPCs by insulin therapy may result
      from the balance between marrow mobilisation and the negative impact of increased adiposity.
      Therefore, the use of a weight-neutral insulin, such as insulin detemir, may provide
      additional benefits in increasing the EPC pool.

      Study design Randomised cross-over trial comparing insulin detemir and insulin glargine added
      to current oral antidiabetic regimen in poorly-controlled (HbA1c≥8.5%) type 2 diabetic
      patients with cardiovascular disease.

      The crossover design will allow to control for previous treatment and provide a more thorough
      comparison between the two treatments under investigation.

      Recruitment and randomization will be performed during 6 months.

        1. Basal measurements (at time zero)

        2. Randomization to receive insulin detemir or glargine (at time zero)

        3. First 3 months of treatment

        4. Ad interim measurements (at 3 months)

        5. Shift to the other insulin for 3 months

        6. Final measurements (at 6 months)Initial results will be available between 6 and 12
           months from the beginning of the study, depending upon time needed for recruitment.

      Drop-out in case of acute illnesses or infection, acute cardiovascular events, or
      hospitalisation during the study period. Expected drop-out rate <10%.

      Treatment protocol A protocol similar to that described by [19] will be implemented.
      Once-daily subcutaneous insulin detemir or insulin glargine will be added to current oral
      glucose lowering drugs. Doses of oral agents will remain unchanged during the study period.
      Based on self-measured fasting plasma glucose levels (average records from 3 consecutive
      days), insulin doses will be titrated, aiming at fasting concentrations of <110 mg/dl.
      Starting daily dose will be 10 U and then titrated individually by clinic or telephone
      contacts on a weekly basis, using the algorithm described in [19]. HbA1c will be measured at
      the end of the 3-month treatment period. Shifting from the one to the other insulin regimen,
      current daily insulin units will be maintained and then re-titrated as necessary
    

Intervention name(s): Glargine; Detemir
Intervention type(s): Drug; Drug
Intervention description(s): Daily bedtime subcutaneous insulin Glargine in individualized doses.; Daily bedtime subcutaneous insulin Detemir in individualized doses.
Other intervention name(s): Lantus; Levemir
Intervention MeSH terms: Insulin Glargine; Insulin Detemir
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diabetes; Insulin; Endothelium; Cardiovascular disease; Stem cells