Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D™ trial

Per Henrik Groop; Mark E. Cooper; Vlado Perkovic; Kumar Sharma; Guntram Schernthaner; Masakazu Haneda; Berthold Hocher; Maud Gordat; Jessica Cescutti; Hans Juergen Woerle; Maximilian Von Eynatten

doi:10.1177/1479164115579002

Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D^™ trial

Per Henrik Groop, Mark E. Cooper, Vlado Perkovic, Kumar Sharma, Guntram Schernthaner, Masakazu Haneda, Berthold Hocher, Maud Gordat, Jessica Cescutti, Hans Juergen Woerle, Maximilian Von Eynatten

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA-T2D™ is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.

Original language	English (US)
Pages (from-to)	455-462
Number of pages	8
Journal	Diabetes and Vascular Disease Research
Volume	12
Issue number	6
DOIs	https://doi.org/10.1177/1479164115579002
State	Published - Nov 1 2015
Externally published	Yes

Keywords

Dipeptidyl peptidase-4 inhibition
albuminuria
chronic kidney disease
glycaemic control
linagliptin
type 2 diabetes

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Cardiology and Cardiovascular Medicine

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Groop, P. H., Cooper, M. E., Perkovic, V., Sharma, K., Schernthaner, G., Haneda, M., Hocher, B., Gordat, M., Cescutti, J., Woerle, H. J., & Von Eynatten, M. (2015). Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D^™ trial. Diabetes and Vascular Disease Research, 12(6), 455-462. https://doi.org/10.1177/1479164115579002

Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction : Rationale and design of the MARLINA-T2D^™ trial. / Groop, Per Henrik; Cooper, Mark E.; Perkovic, Vlado; Sharma, Kumar; Schernthaner, Guntram; Haneda, Masakazu; Hocher, Berthold; Gordat, Maud; Cescutti, Jessica; Woerle, Hans Juergen; Von Eynatten, Maximilian.

In: Diabetes and Vascular Disease Research, Vol. 12, No. 6, 01.11.2015, p. 455-462.

Research output: Contribution to journal › Article › peer-review

Groop, PH, Cooper, ME, Perkovic, V, Sharma, K, Schernthaner, G, Haneda, M, Hocher, B, Gordat, M, Cescutti, J, Woerle, HJ & Von Eynatten, M 2015, 'Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D^™ trial', Diabetes and Vascular Disease Research, vol. 12, no. 6, pp. 455-462. https://doi.org/10.1177/1479164115579002

Groop PH, Cooper ME, Perkovic V, Sharma K, Schernthaner G, Haneda M et al. Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D^™ trial. Diabetes and Vascular Disease Research. 2015 Nov 1;12(6):455-462. https://doi.org/10.1177/1479164115579002

Groop, Per Henrik ; Cooper, Mark E. ; Perkovic, Vlado ; Sharma, Kumar ; Schernthaner, Guntram ; Haneda, Masakazu ; Hocher, Berthold ; Gordat, Maud ; Cescutti, Jessica ; Woerle, Hans Juergen ; Von Eynatten, Maximilian. / Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction : Rationale and design of the MARLINA-T2D^™ trial. In: Diabetes and Vascular Disease Research. 2015 ; Vol. 12, No. 6. pp. 455-462.

@article{2c96ac042e6743369ab75c569cdbdb00,

title = "Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: Rationale and design of the MARLINA-T2D{\texttrademark} trial",

abstract = "Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D{\texttrademark}), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA-T2D{\texttrademark} is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.",

keywords = "Dipeptidyl peptidase-4 inhibition, albuminuria, chronic kidney disease, glycaemic control, linagliptin, type 2 diabetes",

author = "Groop, {Per Henrik} and Cooper, {Mark E.} and Vlado Perkovic and Kumar Sharma and Guntram Schernthaner and Masakazu Haneda and Berthold Hocher and Maud Gordat and Jessica Cescutti and Woerle, {Hans Juergen} and {Von Eynatten}, Maximilian",

note = "Funding Information: CKD is a common and complex disease with an increasing prevalence across the world. The primary unmet need to improve outcomes related to CKD in patients with type 2 diabetes is clearly evident. Therefore, well-designed trials are of paramount importance in this high-risk population. However, a recent systematic review of ClinicalTrials.gov revealed a critical underrepresentation of the numbers of clinical trials in nephrology as compared with other specialties, such as cardiology. 32 The MARLINA–T2D will contribute to further narrow the research-to-practice gap in the treatment of patients with type 2 diabetes and CKD. The study objectives of this trial combine established (glucose-lowering) and potential novel pleiotropic (albuminuria) targets of DPP-4 inhibition. The study should be considered as a proof-of-concept approach to explore the potential treatment effect of linagliptin on the renal surrogate parameter albuminuria. Conclusive evidence on the impact of altering the natural course of CKD in type 2 diabetes, however, will have to emerge from larger, long-term and adequately powered studies. Such research has to target and assess hard renal outcomes, such as progression to end-stage renal disease (ESRD), renal death or significant loss of renal function over time (historically expressed as doubling of serum Cr). Therefore, and complementary to the ongoing MARLINA–T2D study, the CARMELINA {\textregistered} (Cardiovascular and Renal Microvascular Outcome Study with Linagliptin; NCT01897532) trial has been recently initiated to determine whether linagliptin has the potential to improve long-term cardiovascular and/or renal outcomes. In brief, CARMELINA will enrol approximately 8300 subjects with type 2 diabetes at high-risk of cardiovascular and renal events defined by (1) albuminuria and previous macrovascular disease and/or (2) impaired renal function with and without residual albuminuria. It should be noted that participants in MARLINA–T2D are more likely to present with early stages of CKD, whereas CARMELINA aims to recruit a majority of patients at more advanced stages of CKD (often with concomitant macrovascular disease). Thus, these two trials will investigate a new treatment strategy with linagliptin aiming to not only prevent overt nephropathy but also slow progression of more advanced stages of diabetic kidney disease. In addition to DPP-4 inhibition, further interventional and novel therapeutic strategies are currently being tested in late-stage development for patients with type 2 diabetes and CKD ( Table 4 ). Given previous unsuccessful experiences in renal outcomes trials in type 2 diabetes, 33 embarking on renal outcomes studies in this population is still viewed as a challenging endeavour. However, it is important to consider that previous {\textquoteleft}failed{\textquoteright} studies and novel interventional strategies significantly vary in the underlying pathophysiological concepts and/or in the targeted mechanisms being examined ( Table 4 and Supplementary Table 1). With the addition of novel proteomic and metabolomic strategies, it is hoped that novel markers of disease progression and treatment effects will be identified in upcoming clinical trials in patients with type 2 diabetes and CKD. Table 4. Major ongoing, phase 3, randomized, placebo-controlled clinical trials with renal outcomes in patients with type 2 diabetes and CKD. Trial Drug Target Estimated enrolment Estimated treatment duration (months) Predefined renal outcomes Estimated completion date CARMELINA {\textregistered} NCT01897532 Linagliptin DPP-4 inhibition 8300 48 ESRD, sustained decrease of eGFR , renal death January 2018 CREDENCE NCT02065791 Canagliflozin SGLT2 inhibition 3627 66 ESRD, doubling of serum Cr, renal or CV death February 2019 SONAR NCT01858532 Atrasentan Endothelin receptor antagonist 4148 48 ESRD, doubling of serum Cr March 2017 PIONEER NCT02156843 Pyridorin Vitamin B6 600 42 ESRD, doubling of serum Cr March 2018 CKD: chronic kidney disease; CARMELINA {\textregistered} : Cardiovascular and Renal Microvascular Outcome Study with Linagliptin; DPP-4: dipeptidyl peptidase-4; ESRD: end-stage renal disease; eGFR: estimated glomerular filtration rate; CREDENCE: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; SGLT2: sodium-glucose co-transporter 2; CV: cardiovascular; SONAR: Study Of Diabetic Nephropathy With Atrasentan; PIONEER: Pyridorin in Diabetic Nephropathy. In conclusion, growing clinical evidence supports the likelihood of renal effects of DPP-4 inhibitors building on a number of hypothesis-generating studies, 28 , 34 which have reported an albuminuria-lowering effect of this drug class. In addition, a large body of experimental evidence has shown that DPP-4 inhibition may improve the progressive course of kidney disease due to these agents{\textquoteright} antifibrotic, anti-oxidative and anti-inflammatory properties. However, hard evidence defining the renal effects of DPP-4 inhibition is not yet available. Utilizing the DPP-4 inhibitor linagliptin, MARLINA–T2D and CARMELINA represent two randomized clinical trials, which have been adequately designed and powered to provide more robust and reliable clinical data on both surrogate and hard renal outcomes in the high-risk population of patients with type 2 diabetes and renal disease. Members of the trial executive committee provided critical advice on study design and reviewed the study protocol in collaboration with clinical researchers employed by Boehringer Ingelheim. Members of the executive committee led the manuscript development, and all authors approved the final version of the present report. We thank Audrey Ko{\"i}tka-Weber, PhD, for scientific consulting and medical writing services, supported financially by Boehringer Ingelheim. Trial registration: Clinicaltrials.gov NCT01792518. Declaration of conflicting interests P.-H.G., M.E.C., V.P., K.S., G.S., M.H. and B.H. have received fees for advisory services to Boehringer Ingelheim. V.P. has received honoraria from AbbVie, and his employer holds research contracts with AbbVie and Janssen. M.G., J.C., H.-J.W. and M.v.E. are full-time employees of Boehringer Ingelheim. Funding MARLINA–T2D{\texttrademark} is funded and conducted by Boehringer Ingelheim, the manufacturer of linagliptin. Publisher Copyright: {\textcopyright} 2015 The Author(s).",

year = "2015",

month = nov,

day = "1",

doi = "10.1177/1479164115579002",

language = "English (US)",

volume = "12",

pages = "455--462",

journal = "Diabetes and Vascular Disease Research",

issn = "1479-1641",

publisher = "SAGE Publications Ltd",

number = "6",

}

TY - JOUR

T1 - Dipeptidyl peptidase-4 inhibition with linagliptin and effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction

T2 - Rationale and design of the MARLINA-T2D™ trial

AU - Groop, Per Henrik

AU - Cooper, Mark E.

AU - Perkovic, Vlado

AU - Sharma, Kumar

AU - Schernthaner, Guntram

AU - Haneda, Masakazu

AU - Hocher, Berthold

AU - Gordat, Maud

AU - Cescutti, Jessica

AU - Woerle, Hans Juergen

AU - Von Eynatten, Maximilian

N1 - Funding Information: CKD is a common and complex disease with an increasing prevalence across the world. The primary unmet need to improve outcomes related to CKD in patients with type 2 diabetes is clearly evident. Therefore, well-designed trials are of paramount importance in this high-risk population. However, a recent systematic review of ClinicalTrials.gov revealed a critical underrepresentation of the numbers of clinical trials in nephrology as compared with other specialties, such as cardiology. 32 The MARLINA–T2D will contribute to further narrow the research-to-practice gap in the treatment of patients with type 2 diabetes and CKD. The study objectives of this trial combine established (glucose-lowering) and potential novel pleiotropic (albuminuria) targets of DPP-4 inhibition. The study should be considered as a proof-of-concept approach to explore the potential treatment effect of linagliptin on the renal surrogate parameter albuminuria. Conclusive evidence on the impact of altering the natural course of CKD in type 2 diabetes, however, will have to emerge from larger, long-term and adequately powered studies. Such research has to target and assess hard renal outcomes, such as progression to end-stage renal disease (ESRD), renal death or significant loss of renal function over time (historically expressed as doubling of serum Cr). Therefore, and complementary to the ongoing MARLINA–T2D study, the CARMELINA ® (Cardiovascular and Renal Microvascular Outcome Study with Linagliptin; NCT01897532) trial has been recently initiated to determine whether linagliptin has the potential to improve long-term cardiovascular and/or renal outcomes. In brief, CARMELINA will enrol approximately 8300 subjects with type 2 diabetes at high-risk of cardiovascular and renal events defined by (1) albuminuria and previous macrovascular disease and/or (2) impaired renal function with and without residual albuminuria. It should be noted that participants in MARLINA–T2D are more likely to present with early stages of CKD, whereas CARMELINA aims to recruit a majority of patients at more advanced stages of CKD (often with concomitant macrovascular disease). Thus, these two trials will investigate a new treatment strategy with linagliptin aiming to not only prevent overt nephropathy but also slow progression of more advanced stages of diabetic kidney disease. In addition to DPP-4 inhibition, further interventional and novel therapeutic strategies are currently being tested in late-stage development for patients with type 2 diabetes and CKD ( Table 4 ). Given previous unsuccessful experiences in renal outcomes trials in type 2 diabetes, 33 embarking on renal outcomes studies in this population is still viewed as a challenging endeavour. However, it is important to consider that previous ‘failed’ studies and novel interventional strategies significantly vary in the underlying pathophysiological concepts and/or in the targeted mechanisms being examined ( Table 4 and Supplementary Table 1). With the addition of novel proteomic and metabolomic strategies, it is hoped that novel markers of disease progression and treatment effects will be identified in upcoming clinical trials in patients with type 2 diabetes and CKD. Table 4. Major ongoing, phase 3, randomized, placebo-controlled clinical trials with renal outcomes in patients with type 2 diabetes and CKD. Trial Drug Target Estimated enrolment Estimated treatment duration (months) Predefined renal outcomes Estimated completion date CARMELINA ® NCT01897532 Linagliptin DPP-4 inhibition 8300 48 ESRD, sustained decrease of eGFR , renal death January 2018 CREDENCE NCT02065791 Canagliflozin SGLT2 inhibition 3627 66 ESRD, doubling of serum Cr, renal or CV death February 2019 SONAR NCT01858532 Atrasentan Endothelin receptor antagonist 4148 48 ESRD, doubling of serum Cr March 2017 PIONEER NCT02156843 Pyridorin Vitamin B6 600 42 ESRD, doubling of serum Cr March 2018 CKD: chronic kidney disease; CARMELINA ® : Cardiovascular and Renal Microvascular Outcome Study with Linagliptin; DPP-4: dipeptidyl peptidase-4; ESRD: end-stage renal disease; eGFR: estimated glomerular filtration rate; CREDENCE: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy; SGLT2: sodium-glucose co-transporter 2; CV: cardiovascular; SONAR: Study Of Diabetic Nephropathy With Atrasentan; PIONEER: Pyridorin in Diabetic Nephropathy. In conclusion, growing clinical evidence supports the likelihood of renal effects of DPP-4 inhibitors building on a number of hypothesis-generating studies, 28 , 34 which have reported an albuminuria-lowering effect of this drug class. In addition, a large body of experimental evidence has shown that DPP-4 inhibition may improve the progressive course of kidney disease due to these agents’ antifibrotic, anti-oxidative and anti-inflammatory properties. However, hard evidence defining the renal effects of DPP-4 inhibition is not yet available. Utilizing the DPP-4 inhibitor linagliptin, MARLINA–T2D and CARMELINA represent two randomized clinical trials, which have been adequately designed and powered to provide more robust and reliable clinical data on both surrogate and hard renal outcomes in the high-risk population of patients with type 2 diabetes and renal disease. Members of the trial executive committee provided critical advice on study design and reviewed the study protocol in collaboration with clinical researchers employed by Boehringer Ingelheim. Members of the executive committee led the manuscript development, and all authors approved the final version of the present report. We thank Audrey Koïtka-Weber, PhD, for scientific consulting and medical writing services, supported financially by Boehringer Ingelheim. Trial registration: Clinicaltrials.gov NCT01792518. Declaration of conflicting interests P.-H.G., M.E.C., V.P., K.S., G.S., M.H. and B.H. have received fees for advisory services to Boehringer Ingelheim. V.P. has received honoraria from AbbVie, and his employer holds research contracts with AbbVie and Janssen. M.G., J.C., H.-J.W. and M.v.E. are full-time employees of Boehringer Ingelheim. Funding MARLINA–T2D™ is funded and conducted by Boehringer Ingelheim, the manufacturer of linagliptin. Publisher Copyright: © 2015 The Author(s).

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA-T2D™ is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.

AB - Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA-T2D™ is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.

KW - Dipeptidyl peptidase-4 inhibition

KW - albuminuria

KW - chronic kidney disease

KW - glycaemic control

KW - linagliptin

KW - type 2 diabetes

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AN - SCOPUS:84945315616

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