Ignite Creation Date:
2024-05-06 @ 8:31 AM
Last Modification Date:
2024-10-26 @ 12:01 PM
Study NCT ID:
NCT02752113
Status:
COMPLETED
Last Update Posted:
2019-07-29
First Post:
2016-04-19
Brief Title:
Effects of Empagliflozin Linagliptin vs Metformin Insulin Glargine on Renal and Vascular Changes in Type 2 Diabetes
Sponsor:
Institut für Pharmakologie und Präventive Medizin
Organization:
Institut für Pharmakologie und Präventive Medizin
Study Overview
Official Title:
ELMI - Prospective Randomized Controlled Parallel-arm Study to Assess the Effects of the Combined Therapy of Empagliflozin and Linagliptin Compared to Metformin and Insulin Glargine on Renal and Vascular Changes in Type 2 Diabetes
Status:
COMPLETED
Status Verified Date:
2019-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ELMI
Brief 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 37 versus 59 38 relative RR compared to placeboFor 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 orand 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 eg reduced preglomerular ie resistance of the afferent arteriole Ra resistance and increased postglomerular ie 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 eg 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 37 vs 59 in the placebo group 38 relative risk reduction hospitalization for heart failure 27 and 41 respectively 35 relative risk reduction and death from any cause 57 and 83 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 eg 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2016-000242-57 | EUDRACT_NUMBER | None | None |