To examine the effects of mono- and combination therapy with linagliptin and empagliflozine on renal hemodynamics
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Nephropathies
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the effects of 8-week empagliflozin (SGLT-2 inhibitor) monotherapy
(10 mg QD), followed by 8-week empagliflozin and linagliptin (DPP-4 inhibitor)
combination therapy (10/5 mg QD) versus 8-week linagliptin monotherapy (5 mg
QD), followed by 8-week linagliptin and empagliflozin combination therapy (5/10
mg QD) versus 8-week gliclazide (Sulfonylurea) monotherapy (30 mg QD), followed
by 8-week gliclazide intensification (30 mg BID) on renal hemodynamics in both
the fasting and postprandial state in metformin-treated T2DM patients, measured
as:
* GFR (measured by the iohexol-clearance technique)
* Effective renal plasma flow (ERPF; measured by the para-aminohippurate acid
(PAH) clearance technique)
Secondary outcome
To investigate the effects of the above-indicated interventions on:
* Renal damage markers (Week 0, 2, 8, 10, 16):
o 24-hour urinary albumin excretion (glomerular)
o Albumin-creatinine ratio (glomerular)
* Renal tubular function (Week 0, 8, 16), measured as:
o Fractional and cumulative (24-hour urine collection) sodium-, potassium-,
chloride-, calcium-, magnesium-, phosphate-, uric acid, bicarbonate-, ammonium-
and urea excretion
o Urinary glucose excretion
o Urine osmolality
o Urinary pH
* GFR trajectory (Week 0, 2, 8, 10, 16), measured by:
o Creatinine clearance (24-hour urine collection)
* Systemic hemodynamics, measured by:
o Week 0, 2, 8, 10, 16: SBP, DBP, MAP and heart rate, measured by automated
oscillometric blood pressure monitor (Dinamap®)
o Week 0, 8, 16: SBP, DBP, MAP, heart rate (HR), stroke volume (SV), cardiac
output (CO)/-index (CI), and total systemic vascular resistance (TSVR)) derived
from non-invasive beat-to-beat finger blood pressure measurements (Finger
photoplethysmography, Nexfin®)
* Autonomic nervous system activity (Week 0, 8, 16), measured by:
o Heart rate variability derived from automated, beat-to-beat blood pressure
and ECG recording monitor (Finger photoplethysmography, Nexfin®)
* Vascular function (Week 0, 8, 16), measured as:
o Arterial stiffness (Pulse Wave Analysis), measured by radial artery
applanation tonometry (SphygmoCor®)
* Metabolic biomarkers
o Glycated hemoglobin (HbA1c), and fasting and postprandial glucose, lipids
(triglycerides (TG), total-cholesterol (TC), high density lipoprotein
cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and free fatty
acids (FFA)), insulin, glucagon.
* Body anthropometrics
o Height, weight, BMI and waist/hip circumference
o Body fat content, total body water (TBW) and body cell mass (BCM) measured by
body impedance analysis (BIA) (Soft Tissue Analyzer®)
Exploratory Objectives
(The extent of these complementary measurements is conditional to feasibility
and available budget)
To investigate the effects of the above-indicated interventions on:
* Complementary markers of renal function / damage (NGAL, KIM-1, plasma
cystatin C, fibroblast growth factor -23 (FGF-23), parathyroid hormone (PTH),
soluble Klotho, urinary transforming growth factor-*1 (TGF-*1), collagen type
IV, nephrin, podocin, urinary microparticles, 8-hydroxy-2' -deoxyguanosine
(8-OHdG), Calcitriol, Monocyte Chemoattractant Protein-1 (MCP-1), tumor
necrosis factor alpha (TNF-*))
* (Cardiovascular)-biomarkers (N-terminal pro-B-Type Natriuretic Peptide
(NT-proBNP), Brain Natriuretic Peptide (BNP), Atrial Natriuretic Peptide (ANP),
plasma renin activity (PRA), angiotensin II, angiotensin 1-7, aldosterone,
urinary angiotensinogen, endothelin, catecholamines, soluble receptor for
advanced glycation end products (sRAGE), zonulin, fructosamine, uric acid,
ketone bodies, FGF-21, isoprostanes, urinary adenosine, plasma co-peptin,
urinary cortisol, urinary dopamine
* Additional markers of inflammation (hsCRP, interleukin-6 (IL-6), plasminogen
activator inhibitor-1 (PAI-1))
* Deoxyribonucleic acid (DNA) (to study the influence of genetic factors on the
parameters measured and the response to DPP-4 inhibitor and / or SGLT-2
inhibitor) This will only be performed after specific and separate consent by
the participant.
* DDP-4 substrates (GLP-1, GIP, substance-P, Neuropeptide Y (NPY), Stromal
cell-derived factor 1 (SDF-1*), erythropoietin) and DPP-4 activity.
* 24h ambulatory blood pressure monitor (not mandatory, assed only when
feasible (i.e. extra visit to pick up monitor; distance to CRU and willingness
participant. Office blood pressure will also be measured after 1 hour rest in
semi-recumbent position)
* Gut microbiome composition from fecal samples
* Insulin sensitivity (M-value ) as derived from the glucose infusion rate
during the euglycemic clamp
* Insulin sensitivity (OGIS, Matsuda index) as derived from the meal tolerance
test
* Beta-cell function measures as derived from HOMA-B, insulinogenic index and
ratio of postprandial glucose and C-peptide area under the curve
Safety Objectives
* To evaluate the safety and tolerability of empagliflozin, linagliptin and
their combination, compared to gliclazide, in the target patient population
(Hb, Ht, erythrocytes, leucocytes, thrombocytes, sodium, potassium, AST, GGT,
creatinine and urine screening).
Background summary
Worldwide, diabetic nephropathy or diabetic kidney disease (DKD), is the most
common cause of chronic and end stage kidney disease. With the increasing rates
of obesity and type 2 diabetes (T2DM), many more patients with DKD may be
expected in the coming years. DKD is a multi-factorial condition, involving
factors such as obesity, chronic hyperglycemia, advanced glycation end
products, oxidative stress, pro-inflammatory cytokines, systemic- and
glomerular hypertension. Large-sized prospective randomized clinical trials
suggest that intensified glucose and blood pressure control, the latter
especially by using agents that interfere with the
renin-angiotensin-aldosterone system (RAAS), may halt the progression of DKD,
both in type 1 diabetes and T2DM. However, despite the wide use of
angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, a
considerable amount of patients develop DKD during the course of diabetes,
indicating an unmet need for renoprotective therapies. Dipeptidyl peptidase-4
(DPP-4) inhibitors and sodium-glucose linked transporters (SGLT-2) inhibitors
are novel glucose-lowering drugs for the treatment of T2DM. These agents seem
to exert pleiotropic actions *beyond glucose control*. SGLT-2 inhibitors
decrease proximal sodium reabsorption and decrease glomerular pressure and
albuminuria in rodents and type 1 diabetes patients. In addition, SGLT-2
inhibitors reduce blood pressure, urine acid and body weight. In rodents,
SGLT-2 inhibitors also improved histopathological abnormalities associated with
DKD. DPP-4 inhibitors are considered weight neutral, improve lipid profiles and
slight reductions in blood pressure have been reported. To date, the potential
renoprotective effects and mechanisms of these agents have not been
sufficiently detailed in human type 2 diabetes. The current study aims to
explore the clinical effects and mechanistics of mono- and combination therapy
with SGLT-2 inhibitors and the DPP-4 inhibitors on renal physiology and
biomarkers in metformin-treated T2DM patients with normal kidney
function.
Hypothesis: Mono- and combination therapy with SGLT-2 inhibitor empagliflozin
and DPP-4 inhibitor linagliptin, as compared to sulfonylurea (SU) derivate
gliclazide may confer renoprotection by improving renal hemodynamics.
Study objective
To examine the effects of mono- and combination therapy with linagliptin and
empagliflozine on renal hemodynamics
Study design
A phase 4, monocenter, randomized, double-blind, comparator-controlled, 3-armed
parallel mechanistic intervention trial to assess the effect of 8-week
empagliflozin (SGLT-2 inhibitor) monotherapy, followed by 8-week empagliflozin
and linagliptin (DPP-4 inhibitor) combination therapy versus 8-week linagliptin
monotherapy, followed by 8-week linagliptin and empagliflozin combination
therapy versus 8-week gliclazide (Sulfonylurea), followed by 8-week gliclazide
intensification therapy on renal physiology and biomarkers in metformin-treated
patients with type 2 diabetes mellitus
Intervention
8-weeks of empagliflozin 10 mg QD monotherapy, followed by 8-weeks of
empagliflozin and linagliptin 10/5 mg QD combintation therapy versus 8-weeks of
linagliptin 5 mg QD monotherapy, followed by 8-weeks of linagliptin and
empagliflozin 5/10 mg QD combination therapy versus 8-weeks of gliclazide 30 mg
QD treatment, followed by 8-weeks of gliclazide 30 mg BID
Study burden and risks
We are aware of the fact that in the current study participants will undergo
multiple tests that demand a considerable time investment from their end. The
total duration of visits is 1-2 hours (screening- and control visit) and 21
hours (visit 2, 3, 4, 5, 6) or 32 hours (visits 2, 2c, 3, 4, 4c, 5, 6). The
total amount of drawn blood will be 602 mL (subgroup surplus 196 mL, subgroup
total 798 mL) during a total period of 22 weeks. Visit 2 & Visit 2c and Visit
4 & 4c are scheduled in one week, which makes the maximum amount of blood drawn
in one week 277 mL. The total amount of blood loss is approximately similar to
the volume drawn with regular blood donations, which amounts 500 mL per
donation and is allowed every 2.5 months for men and every 4 months for women.
Female participants within the subgroup will lose a maximum of 787 mL in 16
weeks (~50 mL/week), similar to 2 blood donations in 5 months (~50 mL/week).
Participants with a history of recent blood donation (< 6 months) are excluded
from this study. In addition, the renal/cardiovascular test-days may be
perceived as demanding: in particular, the combined renal/cardiovascular
physiology test, that amongst others involves frequent blood and urine
collection, infusions, blood pressure, heart rate and microvascular
measurements. During the cardiac autonomous nervous system function tests
participants may experience transient dizziness or lightheadedness.
However, we have gained ample experience with similarly demanding mechanistic
drug intervention studies in T2DM patients. We have built in different ways to
alleviate the burden for participants, including clear, repeated communication,
frequent contacting, intensified (diabetes) care, 24-hour availability of
research staff, study and travel reimbursement and offering follow-up care in
our out-patient clinic.
The study examinations/tests are considered to be safe. No invasive procedures
(besides intravenous peripheral catheters) are
involved. During the study tests, one *diagnostic agent* (i.e. iohexol and PAH)
need to be administered; these agent are inert and
have no side effects.
All study medications (empagliflozin, linagliptin and gliclazide) have been
approved (FDA, EMA) for blood-glucose lowering treatment in
T2DM patients and, based on currently available data, are considered to be
safe. The most common adverse effects for empagliflozin are genital mycotic-
and urinary tract infections, pruritus, polyuria, frequent voiding and
nycturia. When used in combination with a SU derivative or insulin (which is
not the case in our study) hypoglycemia can occur. In addition, a slight
empagliflozin-induced increase in LDL-cholesterol and increased hematocrit have
been reported. Long-term (adverse) effects of SGLT-2 inhibitors are currently
under investigation in large-scaled outcome trials, however empagliflozin has
shown to reduce mortality and heart and renal failure in the EMPA-REG OUTCOME
Trial (12). For linagliptin, nasopharyngitis and a cough are the most common
adverse effects. The adverse effects of both these drugs are usually mild and
transient. For gliclazide, hypoglycemia and blurred vision in the initiation
phase of treatment (due to changes in blood glucose levels) are the most common
adverse effects. Also, albeit incidental, gastrointestinal adverse-effects
(nausea, vomiting, diarrhea or constipation) have been reported. Of note, to
compensate for the dose of gliclazide that will be used in this study (i.e.
30-60 mg per day) for a relatively short treatment duration (16 weeks),
inclusion criteria for HbA1C will be at 7.0-9.5%. Therefore, also given the
other inclusion- and exclusion criteria of the study participants, the overall
risk of hypoglycemia is believed to be low to moderate.
Patients will be provided with a self-monitoring blood glucose (SMBG) device
and instructed to perform ambulatory blood glucose checks in case of symptoms,
during the course of the study. Also, they will receive standardized diabetes
education, including information regarding carbohydrate use and self-management
/ resolution of hypoglycemia. As in all drug intervention trials, in this
study, we will closely monitor patients for adverse drug and study events
during the follow-up visit and by telephone consultation according to GCP (see
Appendix A). Participants can contact the research staff 24 hours a day. As in
all drug intervention trials, in this study, we will closely monitor patients
for adverse drug and study events
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
Main study
* Caucasian*
* Both genders (females must be post-menopausal; no menses >1 year; in case of
doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off
defined as >31 U/L)
* Age: 35 - 75 years
* BMI: >25 kg/m2
* HbA1c: 7.0 * 9.5% Diabetes Control and Complications Trial (DCCT) or 53 - 80
mmol/mol International Federation of Clinical Chemistry (IFCC)
* Treatment with a stable dose of metformin monotherapy for at least 3 months
prior to inclusion
* Hypertension should be controlled, i.e. *140/90 mmHg, and treated with an
ACE-I or ARB (unless prevented by side effect) for at least 3 months.
* Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB)
for at least 3 months.
* Written informed consent, * In order to increase homogeneity
Sub study
* Treatment with a stable dose of oral antihyperglycemic agents for at least 3
months prior to inclusion
* Metformin monotherapy
* Combination of metformin and low-dose SU derivative
Exclusion criteria
Main study:
* Estimated GFR <45 mL/min/1.73m2 (determined by the Modification of Diet in
Renal Disease (MDRD) study equation)
* Hemoglobin level < 7.0 mmol/L
* Current urinary tract infection and/or active nephritis
* History of unstable or rapidly progressing renal disease
* Macroalbuminuria; defined as ACR of >300 mg/g.
* Current/chronic use of the following medication: thiazolidinediones,
sulfonylurea derivatives, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2
inhibitor, oral glucocorticoids, immune suppressants, antimicrobial agents,
chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and
monoamine oxidase inhibitors (MOAIs).
* Patients on diuretics will only be excluded when these drugs cannot be
stopped 3 months prior randomization and for the duration of the study.
* Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be
allowed, unless used as incidental medication (1-2 tablets) for non-chronic
indications (i.e. sports injury, head-ache or back ache). However, no such
drugs can be taken within a time-frame of 2 weeks prior to renal-testing
* Pregnancy
* History of or actual severe mental disease
* History of or actual severe somatic disease (e.g. systemic disease)
* History of or actual malignancy (except basal cell carcinoma)
* History of or actual pancreatic disease
* (Unstable) thyroid disease
* Severe hepatic insufficiency and/or significant abnormal liver function
defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN)
* Recent (<6 months) history of cardiovascular disease, including
o Acute coronary syndrome
o Stroke or transient ischemic neurologic disorder or chronic heart failure
(NYHA grade II-IV)
* Complaints compatible with or established neurogenic bladder and/or
incomplete bladder emptying (as determined by ultrasonic bladder scan)
* Substance abuse (alcohol: defined as >3 units alcohol/day)
* History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g.,
emergency room visit and/or hospitalization) within 1 month prior to the
Screening visit.
* Recent blood donation (< 6 months)
* Allergy to any of the agents used in the study
* Inability to understand the protocol and/or give informed consent
* Individuals who are investigator site personnel, directly affiliated with the
study, or are immediate (spouse, parent, child, or sibling, whether biological
or legally adopted) family of investigator site personnel directly affiliated
with the study
Sub study:
Exclusion criteria
* History of gout
* Current/chronic use of the following medication: diuretics, SGLT-2 inhibitor,
uric acid lowering medication, pyranizamide, vitamin K antagonists,
salicylates, thiazide diuretics.
* Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in
Renal Disease (MDRD) study equation)
* Current urinary tract infection and active nephritis
* Recent (<6 months) kidney stones
* History of unstable or rapidly progressing renal disease
* Macroalbuminuria; defined as ACR of >300 mg/g.
* Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be
allowed, unless used as incidental medication (1-2 tablets) for non-chronic
indications (i.e. sports injury, head-ache or back ache). However, no such
drugs can be taken within a time-frame of 2 weeks prior to renal-testing
* Pregnancy
* History of or actual malignancy (except basal cell carcinoma)
* (Unstable) thyroid disease
* Severe hepatic insufficiency and/or significant abnormal liver function
defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN)
* Recent (<6 months) history of cardiovascular disease, including
o Acute coronary syndrome
o Stroke or transient ischemic neurologic disorder or chronic heart failure
(NYHA grade II-IV)
* History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g.,
emergency room visit and/or hospitalization) within 1 month prior to the
Screening visit.
* Allergy to any of the agents used in the study
* Inability to understand the protocol and/or give informed consent
* Individuals who are investigator site personnel, directly affiliated with the
study, or are immediate (spouse, parent, child, or sibling, whether biological
or legally adopted) family of investigator site personnel directly affiliated
with the study
*
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-001547-12-NL |
| CCMO | NL61691.029.17 |
| Other | U1111-1195-3269 |