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

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ClinicalTrials.gov Identifier: NCT02752113
Recruitment Status : Recruiting
First Posted : April 26, 2016
Last Update Posted : August 8, 2018
Sponsor:
Collaborator:
University of Erlangen-Nürnberg Medical School
Information provided by (Responsible Party):
Institut für Pharmakologie und Präventive Medizin

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 (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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Type 2 Drug: Empagliflozin and Linagliptin Drug: Metformin and Insulin sc Phase 3

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 2016
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : November 2018


Arm Intervention/treatment
Active Comparator: Empagliflozin and Linagliptin
After the 4 weeks run-in phase (stable metformin medication), patients will be consecutively randomized (1:1) to empagliflozin 10 mg and linagliptin 5 mg orally once daily. After 14 days empagliflozin will be up-titrated to 25 mg (once daily), if fasting blood glucose is ≥ 100 mg /dl and no hypoglycemic symptoms are recognized.
Drug: Empagliflozin and Linagliptin
Empagliflozin and Linagliptin
Other Name: Jardiance, Trajenta

Active Comparator: Metformin and Insulin sc
Metformin p.o. and insulin sc After the 4 weeks run-in phase (stable metformin medication), patients will maintain on their metformin dosage (850 or 1000 mg orally twice daily) and insulin glargine (Lantus™) once daily subcutaneous will be added. Initially 2 - 4 U Lantus™ daily (depending on body weight) will be given, and adjusted every third day (telephone counseling) by adding 2 U if fasting blood glucose is not ≤ 125 mg/dl (16). After a stable dosage (i.e. no change of dosage for 1 week) has been reached, adjustments regarding an increment of Lantus™ will be based on confirmed fasting blood glucose of ≥ 126 mg/dl (on at least two consecutive day).
Drug: Metformin and Insulin sc
Metformin and Insulin sc
Other Name: Siofor, Lantus




Primary Outcome Measures :
  1. Effect of empagliflozin plus linagliptin vs metformin plus insulin glargine on basal NO activity of renal vasculature (response of RPF (renal plasma flow) to L-NMMA (NG-monomethyl-L-arginine) infusion) [ Time Frame: at baseline and after 3 months on empagliflozin plus linagliptin or metformin plus insulin glargine, respectively ]
    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.


Secondary Outcome Measures :
  1. Changes in oxidative stress level of renal vasculature (response of RPF to vitamin C infusion) [ Time Frame: at baseline and after 3 months on empagliflozin plus linagliptin or metformin plus insulin glargine, respectively ]
  2. changes in intraglomerular resistances (Ra and Re) and Pglom [ Time Frame: at baseline and after three months ]
  3. changes in albuminuria (urinary albumin to creatinine ratio [UACR]), assessed in the 24-hour urine [ Time Frame: at baseline and after three months ]


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 2 diabetes mellitus, using already metformin (850 or 1000 mg twice daily) for at least 2 months prior to screening visit or type 2 diabetes switched to metformin at least 3 months prior to randomisation visit
  • HbA1c ≥6.5 % if on antidiabetic montherapy or HbA1c ≥ 6.0 if on two antidiabetic drugs - Age of 18 - 75 years
  • Male and female patients (females of child bearing potential must be using adequate contraceptive precautions)
  • Females of childbearing potential or within two years of the menopause must have a negative urine pregnancy test at screening visit
  • Informed consent (§ 40 Abs. 1 Satz 3 Punkt 3 AMG) has to be given in written form.

Exclusion Criteria:

  • Any other form of diabetes mellitus than type 2 diabetes mellitus
  • Use of insulin, glitazone, gliptin or SGLT-2 inhibitor within the past 2 months
  • HbA1c > 10.5% if on antidiabetic monotherapy and > 9.5% if on two antidiabetic drugs
  • Fasting plasma glucose > 240 mg/dl
  • Any history of stroke, transient ischemic attack, instable angina pectoris, or myocardial infarction within the last 6 months prior to study inclusion
  • UACR ≥ 300 mg/g (early morning spot urine)
  • Estimated GFR (eGFR) < 60 ml/min/1.73m²
  • Uncontrolled arterial hypertension (blood pressure ≥ 180/110 mmHg)
  • Congestive heart failure NYHA stage III and IV
  • Severe disorders of the gastrointestinal tract or other diseases which interfere the pharmacodynamics and pharmacokinetics of study drugs
  • Significant laboratory abnormalities such as serum Glutamate-Oxaloacetate-Transaminase (SGOT) or serum Glutamate-Pyruvate-Transaminase (SGPT) levels more than 3 x above the upper limit of normal range
  • Drug or alcohol abuses
  • Pregnant or breast-feeding patients
  • Use of loop diuretics
  • History of repetitive urogenital infection per year
  • Body mass index > 40 kg/m²
  • Triglyceride levels > 1000 mg/dl
  • High density lipoprotein (HDL)-cholesterol levels < 25 mg/dl
  • Any patient currently receiving chronic (>30 consecutive days) treatment with an oral corticosteroid
  • Patients being treated for severe auto immune disease e.g. lupus
  • Participation in another clinical study within 30 days prior to visit 1
  • Individuals at risk for poor protocol or medication compliance
  • Subject who do not give written consent, that pseudonymous data will be transferred in line with the duty of documentation and the duty of notification according to § 12 and § 13 GCP-V

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02752113


Contacts
Contact: Roland Schmieder, Prof MD 49-9131-85 ext 362445 roland.schmieder@uk-erlangen.de

Locations
Germany
Clinical Research Center, Dept of Nephrology and Hypertenison, University of Erlangen/Nürnberg Recruiting
Erlangen, Bavaria, Germany, 91054
Contact: Christian Ott, MD    +49-9131-85 ext 36245    christian.ott@uk-erlangen.de   
Contact: Roland Schmieder, Prof. MD    +49 9131 85 ext 36245    roland.schmieder@uk-erlangen.de   
Principal Investigator: Roland Schmieder, Prof. MD         
Sub-Investigator: Christian Ott, MD         
Sponsors and Collaborators
Institut für Pharmakologie und Präventive Medizin
University of Erlangen-Nürnberg Medical School
Investigators
Principal Investigator: Roland Schmieder, Prof MD Department of Nephrology and Hypertension, University of Erlangen-Nuremberg
Study Chair: Peter Bramlage, Prof MD IPPMed

Publications:
Responsible Party: Institut für Pharmakologie und Präventive Medizin
ClinicalTrials.gov Identifier: NCT02752113     History of Changes
Other Study ID Numbers: IPPMed-2016-01-ELMI
2016-000242-57 ( EudraCT Number )
First Posted: April 26, 2016    Key Record Dates
Last Update Posted: August 8, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Institut für Pharmakologie und Präventive Medizin:
diabetes mellitus type 2
Metformin
Micro- and macrocirculation
HbA1c >= 7%

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin, Globin Zinc
Empagliflozin
Insulin
Metformin
Insulin Glargine
Linagliptin
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action