Effects of Empagliflozin + Linagliptin vs Metformin + Insulin Glargine on Renal and Vascular Changes in Type 2 Diabetes

Overview

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.

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.