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

NCT02752113 | Completed Phase 3

• 2 other identifiers: IPPMed-2016-01-ELMI2016-000242-57
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 1

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.

Conditions

Diabetes Mellitus Type 2

Keywords

diabetes mellitus type 2; Metformin; Micro- and macrocirculation; HbA1c >= 7%

Outcome Measures

Primary Outcomes (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)

  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.

  at baseline and after 3 months on empagliflozin plus linagliptin or metformin plus insulin glargine, respectively

Secondary Outcomes (3)

• Changes in oxidative stress level of renal vasculature (response of RPF to vitamin C infusion)

  at baseline and after 3 months on empagliflozin plus linagliptin or metformin plus insulin glargine, respectively

• changes in intraglomerular resistances (Ra and Re) and Pglom

  at baseline and after three months

• changes in albuminuria (urinary albumin to creatinine ratio [UACR]), assessed in the 24-hour urine

  at baseline and after three months

Study Arms (2)

Empagliflozin and Linagliptin

ACTIVE COMPARATOR

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

Metformin and Insulin sc

ACTIVE COMPARATOR

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

Interventions

Empagliflozin and Linagliptin DRUG

Empagliflozin and Linagliptin

Also known as: Jardiance, Trajenta

Empagliflozin and Linagliptin

Metformin and Insulin sc DRUG

Metformin and Insulin sc

Also known as: Siofor, Lantus

Metformin and Insulin sc

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Institut für Pharmakologie und Präventive Medizin: lead
• University of Erlangen-Nürnberg Medical School: collaborator

Study Sites (1)

Clinical Research Center, Dept of Nephrology and Hypertenison, University of Erlangen/Nürnberg

Erlangen, Bavaria, 91054, Germany

Location

Related Publications (5)

• Striepe K, Jumar A, Ott C, Karg MV, Schneider MP, Kannenkeril D, Schmieder RE. Effects of the Selective Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin on Vascular Function and Central Hemodynamics in Patients With Type 2 Diabetes Mellitus. Circulation. 2017 Sep 19;136(12):1167-1169. doi: 10.1161/CIRCULATIONAHA.117.029529. No abstract available.

  PMID: 28923906 BACKGROUND

• Gunes-Altan M, Bosch A, Striepe K, Bramlage P, Schiffer M, Schmieder RE, Kannenkeril D. Is GFR decline induced by SGLT2 inhibitor of clinical importance? Cardiovasc Diabetol. 2024 May 29;23(1):184. doi: 10.1186/s12933-024-02223-0.

  PMID: 38811998 DERIVED

• Staef M, Ott C, Kannenkeril D, Striepe K, Schiffer M, Schmieder RE, Bosch A. Determinants of arterial stiffness in patients with type 2 diabetes mellitus: a cross sectional analysis. Sci Rep. 2023 Jun 2;13(1):8944. doi: 10.1038/s41598-023-35589-4.

  PMID: 37268640 DERIVED

• Ott C, Jung S, Korn M, Kannenkeril D, Bosch A, Kolwelter J, Striepe K, Bramlage P, Schiffer M, Schmieder RE. Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine. Cardiovasc Diabetol. 2021 Sep 4;20(1):178. doi: 10.1186/s12933-021-01358-8.

  PMID: 34481498 DERIVED

• Jung S, Bosch A, Kannenkeril D, Karg MV, Striepe K, Bramlage P, Ott C, Schmieder RE. Combination of empagliflozin and linagliptin improves blood pressure and vascular function in type 2 diabetes. Eur Heart J Cardiovasc Pharmacother. 2020 Nov 1;6(6):364-371. doi: 10.1093/ehjcvp/pvz078.

  PMID: 31816038 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

empagliflozin; Linagliptin; Metformin; Insulin Glargine

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quinazolines; Biguanides; Guanidines; Amidines; Organic Chemicals; Insulin, Long-Acting; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Roland Schmieder, Prof MD

  Department of Nephrology and Hypertension, University of Erlangen-Nuremberg

  PRINCIPAL INVESTIGATOR

• Peter Bramlage, Prof MD

  IPPMed

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 19, 2016
• First Posted: April 26, 2016
• Study Start: April 1, 2016
• Primary Completion: November 7, 2018
• Study Completion: May 1, 2019
• Last Updated: July 29, 2019

Record last verified: 2019-07

Locations

DE (1)