Effects of Empagliflozin + Linagliptin vs Metformin + Insulin Glargine on Renal and Vascular Changes in Type 2 Diabetes
Condition: Diabetes Mellitus Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      Diabetes mellitus is a wide-spread disease accompanied by strongly increased morbidity and
      mortality due to micro- and macrovascular complications. However, in studies with patients
      suffering from diabetes mellitus type 2 (DM 2), early changes and impairments in large and
      small blood vessels as well as organ damage (e. g. to the kidneys) have been only
      insufficiently investigated (1). The newest substance class in oral antidiabetics, i. e.
      SGLT-2-inhibitors (such as empagliflozin) cause an increased renal excretion of glucose. In
      addition, the concurrent increased sodium excretion brings about an improvement of vascular
      function and thus a decrease in blood pressure. In the EMP-REG-OUTCOME study (2), the
      cardiovascular mortality rate was significantly lower in the empagliflozin group (3.7% versus
      5.9%; 38% relative RR) compared to placebo.For another new substance class, the
      dipeptidylpeptidase-4-inhibitors, a number of pleiotropic effects have been described (3). In
      one of our recently conducted trials, we could demonstrate a positive effect of linagliptin
      on renal an inflammatory parameters compared to placebo (4). Thus, the combination of both
      substance classes with regard to positive effects on micro- and macrocirculation, even though
      not sufficiently proven as yet, suggests itself. The therapy with metformin and long-acting
      insulin (BOT), as well as a twofold oral medication is possible according to the
      recommendations of the "Deutsche Diabetes Gesellschaft (DDG)" and the positional paper of the
      "American Diabetes Association (ADA)". Accordingly, the aim of the present paper is the
      analysis of the effects of a combined therapy with empagliflozin plus linagliptin compared to
      metformin plus insulin glargine on renal and vascular changes in type 2 diabetes mellitus.
    

Detailed description: 
      Diabetes mellitus, considered at the beginning as a metabolic disorder, mutates into a
      predominantly vascular disease, once its duration extends over several years or/and when
      additional cardiovascular (CV) risk factors coexist, in particular arterial hypertension. As
      a consequence, treatment of type 2 diabetes should focus not only on metabolic control but
      also on improving the vascular structure and function in the micro- and macrocirculation (1).
      Glomerular hyperfiltration and hyperperfusion pointing to altered intraglomerular
      hemodynamics, e.g. reduced preglomerular (i.e. resistance of the afferent arteriole [Ra])
      resistance and increased postglomerular (i.e. resistance of the efferent arteriole [Re])
      resistance (resulting in an increased intraglomerular pressure [Pglom]) are considered to be
      pivotal hemodynamic hallmarks of renal impairment in early diabetes (2). Endothelium
      dysfunction is a key pathogenetic process leading to increased leakage of albumin through the
      glomerular barrier and represents a pivotal determinant of glomerular filtration rate (GFR)
      (3; 4). Poor glycemic control is related to hyperperfusion and increased basal nitric oxide
      (NO) activity secondary to increased oxidative stress that leads to impaired endothelial
      function in early diabetes (5). Indeed, endothelial function increased after reducing
      oxidative stress as evidenced by the results with the infusion of vitamin C (6). The
      assessment of pulse wave velocity (PWV), pulse wave analysis (PWA), central (aortic) systolic
      pressure and pulse pressure, forward and backward wave amplitude are tools to detect early
      vascular changes related to a faster wave reflection in the arterial tree and are considered
      valid intermediate (surrogate) endpoints of vascular damage (7; 8). These parameters are only
      infrequently measured in studies with type 2 diabetes (9), mainly due to lack of expertise
      required to assess these vascular and renal markers, and lack of awareness that vascular
      changes are the key prognostic factor in type 2 diabetes. Empagliflozin is a novel selective
      inhibitor of the sodium-glucose cotransporter 2 (SGLT-2) that has been shown to improve
      glycemic control after 12, and 24 weeks as well as after 1 year (10). Empagliflozin produced
      dose dependent increases in glucosuria and clinically meaningful changes of glycemic
      parameters in type 2 diabetes (e.g. Glycosylated Hemoglobin [HbA1c]), in addition to weight
      loss and blood pressure reduction. In parallel to glucosuria, sodium is excreted in the urine
      and loss of sodium leads to a less reactive contraction of the small arteries in response to
      sympathetic activity, angiotensin II and catecholamines. The reduction in blood pressure
      might be related to weight loss and loss of intravascular volume and sodium content as well
      as to improved vascular function. In the EMPA-REG-OUTCOME trial (11) the empagliflozin group
      had significantly lower rates of death from CV causes (3.7%, vs. 5.9% in the placebo group;
      38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively;
      35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32%
      relative risk reduction). These beneficial effects on hard outcome parameters might be
      related to the effects of empagliflozin described above. Furthermore, among patients
      receiving empagliflozin, there was admittedly an increased rate of genital infection but no
      increased incidence in other adverse events or any other safety parameter was observed.
      Dipeptidyl peptidase-4 (DPP-4) inhibitors, the other new drug class of antidiabetic agents,
      are also attractive agents to treat type 2 diabetes. So far, the predominant focus was on its
      antidiabetic efficacy, but several pleiotropic effects of DPP-4 inhibitors have been
      described (12). Indeed, we observed beneficial renal effects with linagliptin, e.g. preserved
      preglomerular resistance and NO activity in the renal vascular bed, compared to placebo, as
      well as reduced inflammatory markers (13). Thus, to combine empagliflozin with linagliptin is
      obvious and the antiglycemic potency and safety have been and still are examined in a large
      phase 3 program (14). Moreover, due to the pleiotropic effects of these 2 compounds
      (described above), synergistic beneficial effects on the micro- and macrocirculation
      (vascular and renal effects) can be expected (though not yet proven) and may explain to great
      extent the observed beneficial effects of empagliflozin on CV death and total mortality (11).
      According to the guidelines the combination of insulin and metformin is still, however,
      considered a valid and well established combination to control hyperglycemia. However,
      according to the update of the Position Statement of the American Diabetes Association (ADA)
      and European Association for the Study of Diabetes (EASD) advancing to dual oral combination,
      and even triple oral antiglycemic therapy is a recommended alternative (15). Hence, at least
      when metformin is contraindicated or not tolerated, the combination of DPP-4 inhibitors and
      SGLT-2 inhibitors may be a preferably choice. The goal of the current proposal is to prove
      the hypothesis that at similar levels of glycemic control the combination empagliflozin and
      linagliptin exert beneficial effects on the renal and vascular endothelium and on vascular
      surrogate endpoints in patients with type 2 diabetes as opposed to the combination of
      metformin and insulin.
    

Intervention name(s): Empagliflozin and Linagliptin; Metformin and Insulin sc
Intervention type(s): Drug; Drug
Intervention description(s): Empagliflozin and Linagliptin; Metformin and Insulin sc
Other intervention name(s): Jardiance, Trajenta; Siofor, Lantus
Intervention MeSH terms: Metformin; Empagliflozin; Linagliptin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: diabetes mellitus type 2; Metformin; Micro- and macrocirculation; HbA1c >= 7%