A phase 4, monocenter, randomized, double-blind, comparator-controlled, parallel-group, mechanistic intervention trial to assess the effect of 8-week treatment with the dipeptidyl peptidase-4 inhibitor (DPP-4i) linagliptin versus the sulfonylurea (SU) derivative glimepiride on renal physiology and biomarkers in metformin-treated patients with type 2 diabetes mellitus (T2DM)

Diabetic nephropathy (or Diabetic Kidney Disease, DKD) is a common cause of
chronic en end-stage kidney disease (CKD/ESRD). With the increasing rates of
obesity and subsequent type 2 diabetes (T2DM), many more patients with DKD can
be expected in the coming years. DKD is a multi-factorial condition, involving
factors such as chronic hyperglycemia, Advanced Glycation End products (AGEs),
oxidative stress, hypertension, glomerular hyperfiltration, as well as a
pro-inflammatory cytokines. Large-sized prospective RCTs suggest that
intensified glucose and blood pressure control, the latter using agents
interfering with the renin-angiotensin system (RAS), may halt the progression
of DKD, both in T1DM and T2DM. However, despite the wide use of RAS-interfering
drugs, both angiotensin-converting enzyme inhibitors (ACE-i) and angiotensin
receptor blockers (ARB), renal function decline and the occurrence of DKD are
observed during the course of diabetes in a considerable proportion of
patients, suggesting an unmet need for renoprotective therapies. Based on
preclinical and small-sized studies in non-diabetic individuals with normal
renal function, incretin-based therapies, i.e. glucagon-like peptide -1
receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), may
offer an attractive option. However, to date, the potential renoprotective
effects of these agents have not been sufficiently detailed in human diabetes.
The current study proposal aims to explore the mechanistic and clinical effects
of DPP-4i on renal physiology and biomarkers in T2DM patients.

Hypothesis: Treatment with the DPP-4i linagliptin, as compared to the
sulfonylurea (SU) derivative glimepiride, may confer renoprotection, by
improving fasting and postprandial renal hemodynamics, decreasing blood
pressure, and ameliorating inflammation in T2DM patients.

Primary objective: What are the long-term effects (i.e. after 8-week drug
exposure) of the DPP-4i linagliptin versus the SU derivative glimepiride on
fasting and postprandial renal hemodynamics (glomerular filtration rate (GFR)/
effective renal plasma flow (ERPF)) in patients with T2DM?

Secondary objectives: blood pressure, heart rate, renal tubular function,
markers of renal damage

Exploratory objectives: autonomic nervous system balance, systemic hemodynamic
variables, microvascular function, arterial stiffness, metabolic/humoral
biomarkers, markers of inflammation, ACE- and DPP-4 activity, anthropometrics
and body fat content.

A phase 4, monocenter, randomized, double-blind, comparator-controlled,
parallel-group, mechanistic intervention trial to evaluate the effect of 8
weeks of treatment with linagliptin versus glimepiride on renal physiology and
biomarkers in metformin-treated patients with T2DM.

Renal hemodynamics, i.e. glomerular filtration rate (GFR) and effective renal
plasma flow (ERPF) will be measured by the gold-standard inulin- and
para-aminohippurate (PAH) clearance methods, respectively; blood pressure and
heart rate will be measured using an automated oscillometric blood pressure
device (Dinamap®); renal tubular function will be measured by fractional
excretion of sodium and urea and urine osmolality; markers of renal damage will
include urinary albumin/creatinine-ratio, neutrophil gelatinase-associated
lipocalin (NGAL) and kidney injury molecule-1 (KIM-1); autonomic nervous system
balance (heart rate variability) and systemic hemodynamic variables (stroke
colume, cardiac index, total peripheral resistance) will be measured by
continuous beat-to-beat hemodynamic monitor (NexFin®); microvascular function
will be measured by capillary videomicroscopy and Laser Doppler; arterial
stiffness will be assessed by applanation tonometry, (SphygmoCor®); blood
samples will be obtained to determine metabolic, biochemical and humoral
biomarkers, markers of inflammation and ACE- and DPP-4 activity;
anthropometrics, including body weight, height, body-mass index and waist
circumference, and body fat contents (by bio-impedance analysis) will be
measured.

Subjects will be randomized to either of the following arms:

Treatment arm 1: Linagliptin 5 mg oral once daily
Treatment arm 2: Glimepiride 1 mg oral once daily

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 are 1*/1 hour (screening- and control visit, resp.)
and 7.5 - 8 hours (visits 2 and 4). The total amount of drawn blood will be 460
mL during a total period of 16 weeks. Side effects are not expected because the
blood volume taken per visit is relatively small, especially in comparison with
regular blood donation, which amounts 500 mL per donation (and is allowed 5
times a year for men and 3 times for women). 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, enabling participants to
receive the newest study medication (that for most of them would not be
reimbursed in daily practice) and offering follow-up care in our out-patient
clinic. During test-days, we provide meals and allow participants to read or
watch TV/DVDs when possible.
The study examinations/tests are considered to be safe. No invasive procedures
(besides intravenous peripheral catheters) are involved. During the study
tests, two *diagnostic agents* (i.e. inulin and PAH) need to be administered;
both agents are inert and have no side effects.
Both study medications (linagliptin and glimepiride) have been approved (FDA,
EMA) for blood-glucose lowering treatment in T2DM patients and, based on
currently available data, are considered to be safe. To date, DPP-4i use has
not been associated with side effects that occur more frequently than with
placebo. The blood-glucose lowering effect of linagliptin is glucose-dependent
and hypoglycemia rates are low when this agent is combined with metformin.
Glimepiride is a 3rd generation SU derivative, the use of which is associated
with relatively low hypoglycemia risk and little weight gain. Of note, the
glimepiride in this study will be used at a relatively low dose (i.e. 1 mg per
day) for a relatively short treatment duration of 8 weeks. Therefore, also
given the inclusion- and exclusion criteria of the study participants, the
overall risk of hypoglycemia is believed to be small. As these agents have been
used in previous studies at the VU University Medical Center, there is ample
experience. 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. Moreover, the research physician is available
for questions at all times.