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.

References

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risk balance in at-risk patients with type 2

diabetes. Diabetes Metab. Elsevier

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PWF, Smith SC, Goto S, et al. Metformin

use and mortality among patients with

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3. Andrassy KM. Comments on “KDIGO

2012 clinical practice guideline for the

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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)