oral hypoglycemics in ckd
TRANSCRIPT
1) Metformin
• In CKD: recent evidence indicates a strong
reduction in mortality in CKD 3 diabetic
patients under metformin treatment. (1) (2)
• Dosing: KDIGO 2012 recommended that
metformin be continued in people with GFR≥45
ml/min/1.73 m2,its use should be reviewed in
those with GFR 30–44 ml/min/1.73 m2 and it
should be discontinued in people with GFR<30
ml/min/1.73 m2 (1C)(3)
, Paul Arnouts et al
suggest its use in stage 3 CKD at dose not
exceeding 1.5g/day with eGFR> 45 ml/min and
850mg/day for eGFR 30-45 ml/min and in stage
4 CKD at dose of 500mg/day and lower in stage
5 with careful monitoring of side effects (4)
• Side effects : British National Formulary(BNF)
March 2014 mentioned: anorexia, nausea,
vomiting, diarrhoea (usually transient),
abdominal pain, taste disturbance, rarely lactic
acidosis (withdraw treatment), decreased
vitamin-B12 absorption, erythema, pruritus and
urticaria; hepatitis also reported and to
Withdraw or interrupt treatment in those at risk
of tissue hypoxia or sudden deterioration in
renal function, such as those with dehydration,
severe infection, shock, sepsis, acute heart
failure, respiratory failure or hepatic
impairment, or those who have recently had a
myocardial infarction.
• Comment on Lactic acidosis(LA): It is is an
extremely low-incidence event (estimated to be
<4.3 per 100 000 patient-years ) which occurs
especially when CKD and liver diseases are
concomitant(4)
and a large Cohort trial on 51675
• showed that Metformin was associated with
reduced risk of CVD, acidosis/serious infection
and all-cause mortality compared with insulin
and a reduced risk of all-cause mortality
compared with other
OAD and These effects were consistent in
patients with renal
impairment (eGFR 45-60 ml/min/1.73 m2)
and there were no increased risk of
acidosis/serious infection even in patients with
low renal function
(eGFR 30-45 ml/min/1.73 m2).(5)
KDOQI 2012
stated that: lactic acidosis is still exceedingly
rare even in the presence of comorbid
conditions like congestive heart failure, chronic
obstructive pulmonary disease, and liver
disease.(6) Cochrane review in 2010 indicated
that there is no evidence from prospective
comparative trials or from observational cohort
studies that metformin is associated with an
increased risk of lactic acidosis, or with
increased levels of lactate, compared to other
anti-hyperglycemic treatments.(7) Besides
High blood metformin concentrations are not
necessarily linked to hyperlactatemia or lactic
acidosis.(8) there are areas in India where
insulin is unavailable for economic reasons,
and metformin is standard treatment for CKD
stages 3 and 4 (glomerular filtration rate [GFR]
of 15–60 ml/min). A series of more than 1,000
such patients without any cases of LA has been
reported(9).
• Risk factors for LA(4)
: It is important to
realise that in CKD4 patients with unstable
kidney function(e.g. during episodes of
Oral Anti-Diabetics in CKD Patients
Kareem El-Fass BPharm,PharmD
In the following section we shall shed the light on the Oral Anti-diabetics (OAD) available in the Egyptian
market to date and their position in widely reputable guidelines for Diabetes management, their potential
benefits in CKD, prescribing notes, choice among their different classes and choice within the same class.
diarrhoea or of haemodynamic instability), it
might be advisable to (temporarily) withold
the drug, as in these patients small absolute
increases in GFR might result in large
variations in serum concentration of
metformin. Tissue hypoxia and dehydration
are two important corisk factors of MALA.
Severe dehydration may cause acute renal
failure, hypoperfusion and dysfunction of the
liver. However, mortality in subjects who
develop lactic acidosis is not associated with
metformin levels, reflecting that the primary
underlying causes of acidosis (e.g. hypoxia,
haemodynamic compromise) than the
metformin on itself are the major drivers of
mortality
• Metformin and Contrast : It is
recommended that metformin be stopped 2–3
days before any anticipated surgery or
administration of iodinated radiographic
contrast media because of the risk of acute
kidney injury, with resumption of the drug
only after kidney function has clearly
remained or returned to a normal baseline(10)
It used to be standard in the UK to
discontinue metformin in all patients for 48 h
after the administration of intravenous contrast
material.(11)
• Drug Interactions:
a) According to Micromedex drug
database: Controlled studies have
clearly established that Concurrent use
of fluoroquinolones and anti-diabetics
may result in changes in blood glucose
and increased risk of hypoglycemia or
hyperglycemia.
b) According to Lexicomp drug database:
data do suggest that the thiazides may
impair insulin sensitivity, increase
insulin resistance, increase basal
insulin concentrations, and increase
plasma glucose concentrations
2) SulphonylUreas
Glipizide, glyburide (glibenclamide), gliclazide,
and glimepiride are so-called second-generation
sulfonylureas. They have structural
characteristics that allow them to be given in
much lower doses than the first-generation
sulfonylureas. Nevertheless, the different
sulfonylureas are equally effective in lowering
blood glucose concentrations. The
administration of sulfonylureas in end-stage
renal disease (ESRD) requires careful attention
to dosing and routes of elimination .The
sulfonylureas are strongly protein bound,
particularly to albumin. Thus, elevated plasma
drug levels cannot be efficiently reversed by
hemodialysis.(12). Insulin
secretagogues(including sulphonylureas) do not
seem to provide for additional HbA1creduction
or prevention of hypoglycemia or weight gain
after insulin is started, especially after the dose
is titrated and stabilized. When basal insulin is
used, continuing the secretagogue may
minimize initial deterioration of glycemic
control. However, secretagogues should be
avoided once prandial insulin regimens are
employed(13).
• In CKD: The United Kingdom Prospective
Diabetes Study (UKPDS) and more recently the
ADVANCE study demonstrated that newer
agents (glipizide and gliclazide) do not appear
to confer such a risk and are associated with
benefits when used to achieve tighter glycemic
control.(14) The second-generation SU
glimepiride is contraindicated in dialysis
patients, but low-dose initiation can be used in
patients with CKD. Glipizide and gliclazide are
the preferred agents and no dose adjustment has
been necessary in a dialysis population in
US(14). KDIGO 2012: Avoid agents that are
mainly renally excreted (e.g., glyburide/
glibenclamide) Other agents that are mainly
metabolized in the liver may need reduced dose
whenGFR<30 ml/min/1.73 m2(e.g.,
gliclazide)(3).Some reports state that:
glibenclamide, the use of glimepiride is
contraindicated in patients with a GFR of<60
ml/min(15) while others state :Glimepiride to be
used as 1 mg/day till CKD stage 4 and to be
avoided in stage 5 CKD(4)
• Choice within Sulphonylureas in CKD: is
confined to Glipizide or Gliclazide due to their
favourable pharmacokinetics of being mainly
metabolized by the liver and excretion of
metabolites with no/very limited hypoglycemic
activity in urine. Some authors consider
glipizide should be the sulfonylurea of choice in
patients with advanced kidney dysfunction(10)
while BNF stated that: Glipizide should also be
avoided if the patient has both renal and hepatic
impairment. If necessary, the short-acting drug
tolbutamide can be used in renal impairment, as
can gliclazide which is principally metabolised
in the liver, but careful monitoring of blood-
glucose concentration is essential; care is
required to use the lowest dose that adequately
controls blood glucose.
• Dosing : See Figure 1
• Side effects: Hypoglycaemia, the most common
side effect, is more frequently observed with
long-acting sulfonylureas(4)
.BNF stated that:
ide-effects of sulfonylureas are generally mild and
infrequent and include gastro-intestinal disturbances
such as nausea, vomiting, diarrhoea, and
constipation. Hyponatraemia has been reported with
glimepiride and glipizide.
Sulfonylureas can occasionally cause a
disturbance in liver function, which may rarely
lead to cholestatic jaundice, hepatitis, and
hepatic failure.
• Drug interactions:
a) Sulfonylureasare strongly protein-bound
( particularly to albumin) and their
displacement by β-blockers, salicylates
and warfarin can lead to
hypoglycaemia.(4)
b) Micromedex Drug Database:Concurrent
use of Glipizide and
Hydrochlorothiazide may result in
decreased glipizide effectiveness
3) Meglitinides(Repaglinide)
• In CKD(4)
: no relationship was found between
the degree of renal impairment and the risk of
hypoglycaemia in patients who were treated
with Repaglinide. No difference in maximal
plasma concentrations was observed, thus
suggesting that CKD somewhat affects
metabolism and hepatic clearance of
repaglinide, rather than its bioavailability. In
CKD Stage 2–3, repaglinide maintains the
same pharmacokinetic characteristics as seen in
diabetics with normal renal function.In patients
with an eGFR <30 mL/min, repaglinide shows
a 4-fold increase in half-life after 1 week of
treatment and an increased AUC when
compared with subjects with normal renal
function. The use of repaglinide is not
contraindicated in patients with renal
impairment or dialysis patients(15)
. BNF stated
that: Repaglinide may be given as monotherapy
for patients who are not overweight or for those
in whom metformin is contra-indicated or not
tolerated, or it may be given in combination
with metformin.
• Dosing: A preprandial dose of 0.5–4 mg should
be titrated according to the postprandial blood
glucose response(15). Although hypoglycemia
has not been demonstrated to increase
substantially with progressive falls in GFR,it
wouldseem prudent to start treatment with a 0.5
mg dose of repaglinide with each meal and
titrate upwards cautiously when the GFR is30
mL/min/1.73 m2
• Side effects: BNF stated that: abdominal pain,
diarrhoea, constipation, nausea,
vomiting; rarely hypoglycaemia,
hypersensitivity reactions including pruritus,
rashes, vasculitis, urticaria, and visual
disturbances. According to Arnoust et al :
Common side-effects of meglitinides are
hypoglycaemia and weight gain. In addition
they have the disadvantage of the need for a
frequent dosingschedule.(4)
• Drug Interactions :
a) According to Micromedex Ddrug
databse: Concurrent use of gemfiprozil
and repaglinide may result in increased
plasma concentrations of repaglinide
4) Thiazolidinedione(Glitazones)
• In CKD: The thiazolidinediones, pioglitazone
and rosiglitazone, do not lead to hypoglycemia,
are metabolized by the liver, and thus can be
used in CKD. However, fluid retention is a
major limiting side effect and they should not be
used in advanced heart failure and CKD. The
FDA has restricted use of rosiglitazone based on
information linking the medicine with increased
cardiovascular events(16)
It is possible that
thiazolidinedione-induced facilitation of the
formation of “third space” fluid could make
dialysis ultrafiltration (and achievement of dry
weight) more difficult.(12)
• Dosing : No dose adjustment needed for both
drugs but should be used with caution due to
fluid retention.(16)
• Side effects: according to BNF: Pioglitazone
appeared to have a modest benefit on
cardiovascular events as a secondary outcome in
one large trial involving patients with overt
macrovascular disease, The European Medicines
Agency has advised that there is a small increased
risk of bladder cancer associated with pioglitazone
use. However, in patients who respond adequately to
treatment, the benefits of pioglitazone continue to
outweigh the risks. Pioglitazone should not be
used in patients with active bladder cancer or a
past history of bladder cancer, or in those who
have uninvestigated macroscopic haematuria.
Pioglitazone should be used with caution in
elderly patients as the risk of bladder cancer
increases with age.
5) Alpha-Glucosidase Inhibitors
(Acarbose)
• In CKD/Dosing: with reduced kidney
function, serum levels of the drug and its
metabolites increase significantly. Although no
adverse effects have been reported, its use in
patients with a GFR<26 mL/min/ 1.73 m2 is
not recommended(16)
. Information about the
long-term use of acarbose in patients with
reduced kidney function is sparse and its use in
patients with later stage 3 and stages 4 and 5
CKD is not recommended(10)
• Side effects: according to BNF: flatulence, soft
stools, diarrhoea (may need to reduce dose or
withdraw), abdominal distention and
pain; rarely, nausea, abnormal liver function
tests and skin reactions; very rarely ileus,
oedema, jaundice, and hepatitis. Antacids
unlikely to be beneficial for treating side-
effects.
6) Dipeptidyl peptidase IV (DPP-4)
Inhibitors(Gliptins:Vildagliptin,Sitagl
-iptin)
• In CKD: All can be used in CKD patients
but sitagliptin, saxagliptin, and vildagliptin
need downward dose adjustments(16)
.
Although some DPP-IV inhibitors have been
studied in patients with kidney dysfunction,
the data are limited, and, therefore.However,
limited data suggest that these agents are
effective and relatively safe in CKD and
ESRD patients
• Sitagliptin: sitagliptin dose-adjustment
treatment reduced hemoglobin A1c by 0.7%
at 54 weeks in patients with moderate to
severe renal insufficiency(14)
. The normal
dose100 mg once a day (o.d.)] should be
halved (50 mg o.d.) for patients with
moderate renal impairment (creatinine
clearance ≥30 to <50 ml/min), and halved
again (25 mg o.d.) for those with severe
impairment (<30 ml/min) or end-stage renal
disease requiring renal replacement
therapy.(11)(16)
Side effects stated by BNF:
gastro-intestinal disturbances; peripheral
oedema; upper respiratory tract infection,
nasopharyngitis; pain; less commonly dry
mouth, anorexia, headache, drowsiness,
dizziness, hypoglycaemia, osteoarthritis; also
reported pancreatitis, rash, cutaneous
vasculitis, and Stevens-Johnson syndrome
• Vildagliptin: recent randomized, controlled
trial (RCT) 50 mg of vildagliptin once daily
in addition to standard hypoglycaemic
therapy showed good efficacy and tolerance
over a 1-year follow-up in diabetic subjects
with moderate (eGFR 30–50 mL/min) or
severe (eGFR < 30 mL/min) renal
impairment.(4)
Dose of 50 mg twice daily, this
should be halved to 50 mg o.d. in patients
with moderate or severe renal impairment
and it can be used with caution in those with
end-stage renal disease(11)(16)
Side effects
stated by BNF: nausea, peripheral oedema,
headache, tremor, asthenia, dizziness;less
commonly constipation, hypoglycaemia,
arthralgia; rarely hepatic dysfunction (see
also Liver Toxicity above); very
rarely nasopharyngitis, upper respiratory
tract infection; also reported pancreatitis,
exfoliative and bullous skin reactions.
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Appendices
Figure 1: Dose adjustment of Insulin and selected OAD(16)
Adapted from American Diabetes Association Guidelines 2014(17)
Adapted from American Association of Clinical Endocrinologists Guidelines
2013(18)
Adapted from American Association of Clinical Endocrinologists Guidelines
2013(18)