Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st October, 2016 27

Consensus Statement on Dose Modifications

of Anti Diabetic Agents used in Patients with
Diabetes and Chronic Kidney Disease
Binayak Sinha1, KK Gangopadhyay2, DC Sharma3, Arthur Asirvatham4, Parminder Singh5

which may guide clinicians in

Abstract managing Hyperglycemia in patients
CKD with outcomes in mind.
Patients with Diabetes and declining renal function pose complex challenges to
the clinician, including the management of comorbidities such as hypertension, Methods
hyperlipidemias, cardiovascular (CV) disease, anemia, and abnormal bone
metabolism. The prevalence of stage 3 or worse chronic kidney disease (CKD) in The Consensus group evaluated
patients with T2DM is increasing. Diabetes is a leading cause of end-stage renal existing evidence including current
disease (ESRD) and dialysis. guidelines, published trials and the
prescribing information of various
The aim of the consensus group was to focus on the challenges with glycemic Anti Diabetic agents with respect
management, with particular emphasis to safe use of anti-diabetic agents across to management of Hyperglycaemia
stages of renal dysfunction. in CKD. Existing Guidelines
Published Literature, product information and major clinical guidelines from USA KDOQI recommendations 2012
and India were reviewed and summarized. These drugs included metformin, the was found to be relevant to the
discussion compared to KDIGO. The
second- or third-generation sulfonylureas (SUs), alpha-glucosidase inhibitors
members then discussed and laid
(AGIs), thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP-4) inhibitors,
down recommendations related to
sodium–glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 Glycaemic control in patients with
(GLP-1) receptor agonists, and currently available insulins. CKD and specific recommendations
Consensus Recommendations for Glycemic targets and dose modifications of related to dose modification of each
all Anti Diabetic agents are summarized. class of Anti Diabetic agents.
Glomerular filtration rate is the
best measure of overall kidney
function in health and disease. 15
Introduction many therapeutic challenges,
The normal level of GFR varies
including the management of
Type 2 diabetes mellitus (T2DM) comorbidities such as hypertension, according to age, sex, and body
is by far the most common form hyperlipidaemia, cardiovascular size. Normal GFR in young adults
of diabetes, comprising 90% of all (CV) disease, anemia, and abnormal is approximately 120 to 130 ml/
diabetes cases and is therefore a bone and mineral metabolism. 4 min/1.73m2 and declines with
major health issue. The prevalence There is a dearth of evidence and age. A GFR level less than 60 ml/
of stage 3 or worse chronic kidney recommendations from International min/1.73m 2 represents loss of half
disease (CKD) in patients with and National organizations/bodies or more of the adult level of normal
T2DM is generally reported to be regarding glycaemic management kidney function. Below this level,
between 21% and 38%. 1-8, 12,13 in patients with CKD. Regulatory the prevalence of complications of
bodies across the globe propose chronic kidney disease increases. 16-
Diabetes is a leading cause of 18
Decreased kidney function is
end-stage renal disease (ESRD) and differing statements with respect to
dose modifications of anti-diabetic practically assessed by estimating
dialysis; 40% of patients in France the GFR (eGFR) using either
and 45% in the United States (US) agents. The aim of this consensus
was to evaluate existing evidence Cockcroft–Gault or Modification of
had diabetes at initiation of dialysis. Diet in Renal Disease (MDRD) study
In Canada, 35% of patients who relevant to glycaemic management
of T2DM in the setting of CKD and equations. 19, 20, 22
initiated treatment for ESRD in
2010 had diabetes. Diabetes is also propose a set of recommendations The stages of CKD which will
associated with one of the lowest
5-year survival rates in patients 1
Department of Endocrinology, AMRI Hospital, Kolkata, West Bengal; 2Consultant Endocrinologist, Fortis
receiving dialysis. 9,10,14
Hospital, Kolkata, West Bengal; 3Senior Consultant, Dr. DC Sharma Institute of Diabetes, Thyroid and Hormones-
Pa t i e n t s w i t h d i a b e t e s a n d Srajan Hospital Pvt. Ltd., Udaipur, Rajasthan; 4Arthur Asirvatham Hospital, Madurai, Tamil Nadu; 5Division of
declining kidney function present Endocrinology, Dayanand Medical College and Hospital, Ludhiana, Punjab
28 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st October, 2016

Table 1: Stages of CKD risk of the primary endpoints,

Stage Description GFR (mL/min/1.73 m2)
defined by composites of
1 Kidney damage* with normal or increased GFR ≥90
major adverse cardiovascular
disease (CVD) events, in any
2 Kidney damage* with mildly decreased GFR 60-89
of these studies.
3 Moderately decreased GFR 30-59
4 Severely decreased GFR 15–29 15-29 Moreover, there was an
5 Kidney failure <15 or dialysis increase in all-cause mortality
*Kidney damage is defined as abnormalities on pathological, urine, blood, or imaging tests. among the intensively-treated
Adapted. National Kidney Foundation (2012) KDOQI Clinical Practice Guidelines for Diabetes group compared to the
and CKD: 2012 update. Am J Kidney Dis 60:850–886 conventionally-treated group
in the ACCORD study. 27,29,30
feature in further discussions will of fall of GFR in patients with
be as proposed by the NKF-KDOQI type 1 diabetes. 21-25

The reasons for this finding
(Table 1). Defining the stage of are uncertain, although
The EDIC/DCCT follow up
chronic kidney disease is the key first further analysis showed
study recently reported that
step in developing the appropriate that increased mortality was
2.0% (1.6/1000 person-years) of
clinical action plan. 19 not directly attributable to
participants in the previously
hypoglycemia. 31 Therefore,
intensive treatment group and
Consensus 5.5% (3.0/1000 personyears)
l o we r i n g H b A 1 c t o l e ve l s
7.0% is not recommended in
Recommendation 1: of those in the previously
patients with diabetes who
Glycemic Targets conventional treatment group
are at risk for hypoglycemia,
developed sustained estimated
including those treated with
The ADA, the EASD, and glomerular filtration rate
insulin or sulfonylureas and/
the IDF recommend a glycated (eGFR) measurements 60 ml/
or have advanced CKD.
hemoglobin (HbA1c) target of <7% min/1.73 m 2 with a relative
risk (RR) reduction of 50% (p< 1.3 We s u g g e s t t h a t t a r g e t
for most patients with diabetes.
0.006). 26 HbA1c be extended above
Customization of this general target
7.0% in individuals with
is based on patient characteristics, For patients with type 2
co-morbidities or limited
with tighter control. diabetes, intensive treatment
life expectancy and risk of
1.1 We r e c o m m e n d a t a r g e t in the UKPDS was associated
hypoglycemia.
hemoglobin A1c (HbA1c) with a 67% risk reduction
for a doubling of plasma Years of intensive glycemic
of ~7.0% to prevent or
creatinine levels at 9 years control (HbA1c 7%) are
delay progression of the
(0.71% of the intensive group required before a reduction
microvascular complications
and 1.76% of the conventional in the incidence of
of diabetes, including DKD.
group, p<0.027).15 None of complications, such as kidney
1.2 We recommend not treating failure or blindness, becomes
to an HbA1c target of the three more recent studies
mentioned above (ADVANCE, evident. 32,33 . In individuals
<7.0% in patients at risk of 70-79 years of age who are
hypoglycemia. A C C O R D , VA D T ) s h o we d
significant benefits of more taking insulin, the risk of
1.3 We s u g g e s t t h a t t a r g e t intensive glycemic control on hypoglycaemia begins to
HbA1c be extended above creatinine-based estimates of increase with HbA1c 7%. 34
7.0% in individuals with GFR. 27-29 Moreover, in patients with
co-morbidities or limited type 2 diabetes, one study
life expectancy and risk of 1.2 We recommend not treating
to an HbA1c target of showed that the presence of co-
hypoglycemia. morbidities abrogates benefits
<7.0% in patients at risk of
1.1 We r e c o m m e n d a t a r g e t hypoglycemia. of lower HbA1c levels on CVD
hemoglobin A1c (HbA1c) events. 35 Therefore, a target
of ~7.0% to prevent or The three most recent clinical
HbA1c of 7.0% is suggested
delay progression of the trials (ADVANCE, ACCORD,
for patients with diabetes who
microvascular complications a n d VA D T ) a l l s h o w e d
are at risk of hypoglycemia
of diabetes, including DKD. substantial increases (range
and have clinically-significant
1.5-3 fold) in severe and non-
Few long-term observational co-morbidities or limited life
severe hypoglycemia among
cohort studies and secondary expectancy.
patients with type 2 diabetes
or post hoc analyses of w h o we r e r e c e i v i n g m o r e
interventional studies using intensive therapy. Intensifying
ACE-Is or ARBs found that glycemic control beyond
poorer glycemic control was conventional management
associated with a greater rate did not result in decreased
 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st October, 2016 29

Table 2: Guidelines and Prescribing information for the use of Sulphonylureas in information though proposes
CKD a conservative approach to
Agent KDOQI 2012 Prescribing Information initiation and titration of the
Glipizide No dose adjustment dose in patients with CKD.36-41
Glimepiride Start conservatively at 1 mg daily Start conservatively at 1 mg daily Given the propensity of
Glyburide Avoid use Initial dosing, dose increments, and sulphonylureas to cause
maintenance dosage should be conservative hypoglycemia in patients with
Gliclazide No dose adjustment Contraindicated in severe renal failure, dose CKD who are already at a high
reduction necessary starting dose should be risk to develop hypoglycemia,
30mg in mild to moderate renal failure we recommend a watchful
Table 3: Guidelines and Prescribing information for the use of Thiazolidinediones approach in using these
in CKD agents. They are to be avoided
in patients with a history
Agent KDOQI guidelines 2012 Prescribing Information
of hypoglycemic episodes.
eGFR in ml/min/1.72 m2
Gliclazide and Glipizide can
<90 - >60 <60 - >30 <30 <90 - >60 <60 - >30 <30
be the better options within
Pioglitazone No dose adjustment No dose adjustment
the class of sulphonylureas.
Consensus contraindicated when Serum
2.3: Thiazolidinediones
Creatinine is ≥ 1.5 mg/dl in men
Recommendation 2: Oral and ≥1.4 mg/dl in women. 19 2.3.1 Thiazolidinediones can be
Anti Diabetic agents in The current prescribing labels used with caution.
CKD for metformin use reflect a 2.3.2 These agents are to be avoided
more conservative approach in patients with fluid retention.
While patients with mild renal than is seen in clinical practice, The summary of Guidelines and
i n s u f f i c i e n c y c a n r e c e i ve m o s t or in most recent diabetes prescribing information for
antihyperglycemic treatments guidelines. 36 the use of Thiazolidinediones
without concern, patients with Based on available data, we in CKD is provided in Table
stages 3, 4, or 5 CKD often require recommend that metformin 3. Available PK data suggest
treatment adjustments according to may be suitable for patients that there is no difference in
the degree of renal insufficiency. with eGFR >30 and <60 ml/ pioglitazone serum half-life
These adjustments include lowering min/1.73 m 2, with appropriate in patients with severe CKD
the dose or discontinuing a drug caution and monitoring. Care and those with normal renal
altogether and, if necessary, m u s t a l wa y s b e t a k e n i n function. 42, 43
initiating treatment with another patients with other risk factors Given the elimination
agent. The following sections of this for lactic acidosis. characteristics of pioglitazone,
consensus paper summarize key 2.2 Sulphonylureas we recommend that
information from North American
2.2.1 To be avoided in patients Pioglitazone can be used with
and European labels, clinical studies,
prone to Hypoglycemia i n pa t i e nt s w i t h CKD b ut
and guidelines for each of the major
with caution. The existing
antihyperglycemic medications, 2.2.2 Gliclazide and Glipizide can
data on fluid retention and
relevant to the treatment of adults be recommended as safer
Congestive Heart Failure as
with T2DM and CKD. agents among sulphonylureas.
mentioned in the product
2. Oral Anti Diabetic Agents in The summary of Guidelines leaflets mandate us to restrict
CKD: and Prescribing information the use of Pioglitazone in
2.1 Metformin: for the use of Sulphonylureas patients with a history of fluid
in CKD is provided in Table 2. retention.
2.1.1 Metformin must be avoided The NFK-KDOQI recommends
when the eGFR <30 ml/ 2.4 Alpha Glucosidase inhibitors
no dose adjustment with
min/1.73 m 2. Glipizide and Gliclazide in 2.4.1 To be avoided in patients with
2.1.2 Dose Modification is necessary CKD stages 3-5. Glimepiride eGFR< 30 ml/min/1.73m 2
when eGFR <45 and >30 ml/ may need to be started Wi t h a c a r b o s e , i n c r e a s e d
min/1.73 m 2 conservatively at a dose of levels of the parent drug and
2.1.3 Monitor eGFR every 3 months 1 mg daily and then titrated metabolites are observed with
The British National formulary to reach targets. Glyburide, CKD, although an increased
and The Japanese society a second generation agents risk of hypoglycemia has
of Nephrology state that an substantially eliminated n o t b e e n d o c u m e n t e d . 46
eGFR of ≤30 ml/min/1.73 m 2 by the kidney, is better Miglitol has greater systemic
mandates discontinuation avoided and other agents absorption that acarbose,with
of Metformin. The USFDA a r e t o b e p r e f e r r e d . 19 T h e 50–100% of a dose being
states that Metformin is glyburide prescribing absorbed. This drug has
 30 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st October, 2016

minimal protein binding eliminated by a predominantly S G LT 2 i n h i b i t o r s h a v e o n l y

and is not metabolized, but hepatobiliary route. recently been approved and have
undergoes renal excretion, Patients with CKD represent not been included in many of
with as much as 95% of a dose a specific subpopulation that the available guidelines. The 2013
recovered in the urine. 47 may take advantage of using AACE guidelines mention that

Prescribing information for a DPP-4 inhibitor instead of canagliflozin should not be used if
these 2 agents are consistent a sulphonylurea in order to eGFR is \45 mL/min/ 1.73 m2 , and
with the recommendations reduce the potential risk of the 2015 AACE/ACE update reminds
from the KDOQI (Table 4). 48,49 hypoglycaemia. 50 us that these agents have limited
Given the lack of clinical data efficacy in patients with CKD since
The KDOQI guidelines
for use in this population, we they exert their glycemic effects in
2012 and the prescribing
do not recommend the use of the kidney. The 2015 update of the
information for these
alpha glucosidase inhibitors ADA/EASD position statement state
agents are consistent with
below the eGFR of 30 ml/ that the labels have varying renal
d o s e c h a n g e s . 19 B a s e d o n
min/1.73m 2. restrictions.
t h i s d a t a , we r e c o m m e n d
2.5 DPP4 Inhibitors. that DPP4 inhibitors can be Elevations in serum creatinine,
used safely in CKD though and decreases in eGFR, occurring
2.5.1 D P P 4 i n h i b i t o r s c a n b e
dose modifications may be during the initial period of clinical
used safely though dose
necessary. use, have been demonstrated with
modifications have to be done
all three of the SGLT2 inhibitors, and
based on eGFR. 2.6 SGLT2 inhibitors
seem to be most notable in patients
The summary of Guidelines 2.6.1 Avoid when eGFR <45 ml/ with moderate CKD. 56-61
and prescribing information min/1.73m 2 BSA.
Based on the available evidence
for the use of DPP4 Inhibitors These agents have reduced efficacy in with this class of agents, we
in CKD is provided in Table patients with renal impairment. recommend that SGLT2 inhibitors
5. Most DPP-4 inhibitors
None of the SGLT2 inhibitors in be avoided when the eGFR <45 ml/
(sitagliptin, vildagliptin,
use currently need dose adjustment min/1.73 m 2. Clinicians also need
saxagliptin, alogliptin)
in patients with mild renal to be aware that there is loss of
are predominantly
impairment, and these drugs are glycaemic efficacy with deteriorating
excreted by the kidneys.
generally not recommended or are renal function while using SGLT2
Thereby, pharmacokinetic
contraindicated in patients with inhibitors.
s t u d i e s s h o we d t h a t t o t a l
severe CKD or ESRD.Usage and
exposure to the drug is Consensus
dose recommendations in moderate
increased in proportion to
CKD vary between the labels for Recommendation 3: Non-
the decline of GFR, leading
the different agents (canagliflozin,
to recommendations for
dapagliflozin, and empagliflozin), Insulin Anti Injectables in
appropriate dose reductions
according to the severity of
with some agents not recommended CKD:
below CrCl of 60 mL/min and others
CKD. In contrast, linagliptin is 3.1 GLP1 Analogues
below 45 mL/min. 55
3.1.1 G L P 1 A n a l o g u e s c a n b e
Table 4: Guidelines and Prescribing information for the use of Alpha Glucosidase considered when eGFR >30
2
Inhibitors in CKD ml/min/1.73 m BSA.
Agent KDOQI guidelines 20122 Prescribing Information 3.1.2 Liraglutide has demonstrated
eGFR in ml/min/1.72 m
efficacy and safety in
<90 - >60 <60 - >30 <30 <90 - >60 <60 - >30 <30
patients with moderate renal
Acarbose <25 ml/
dysfunction.
min/1.73m2
Miglitol <25 ml/ <25 ml/ Pharmacokinetic studies have
min/1.73m2 min/1.73m2 been performed with all of the GLP-1
receptor agonists in patients with
  Safe   Cautious Use   Contraindicated
Table 5: Guidelines and Prescribing information for the use of DPP4 Inhibitors in CKD
KDOQI 2012 Prescribing Information
Agent eGFR (ml/min/1.73 m2)
>50 50-30 <30 >50 50-30 <30
Sitagliptin 100mg OD 50 mg OD 25 mg OD 100mg OD 50 mg OD 25 mg OD
Saxagliptin 5 mg OD 2.5 mg OD 5 mg OD 2.5 mg OD
VIldagliptin 50 mg BD 50 mg OD 50 mg BD 50 mg OD
Linagliptin No dose adjustment No dose adjustment
  Safe   Cautious Use   Contraindicated
 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st October, 2016 31

Table 6: Recommendations for the contraindicated or not recommended Exogenous insulin is primarily
use of oral anti diabetic for patients with eGFR\30 mL/ cleared via renal metabolism 73-75 ,
agents in CKD min/1.73 m2. The 2015 AACE/ACE impaired renal function in patients
Agent Recommendation guidelines state that there are no with diabetes can result in
Proposed noted precautions for liraglutide decreased clearance of insulin and,
Metformin Avoid if eGFR 2< 30 in patients with CKD. Lixisenatide, consequently, prolonged exposure.19
ml/min/1.73 m BSA, Albiglutide and Dulaglutide are Diabetes patients with impaired
Dose modification not yet mentioned in the guideline renal function may therefore be at
when eGFR between2 statements. increased risk of hypoglycemia.
30-45 ml/min/1.73 m 76-78
In addition, deterioration of
All GLP-1 receptor agonists may
Monitor eGFR every renal function can lead to increased
be used without dose adjustment in
3stmonths exposure to insulin therapy,
mild CKD. Exenatide should be used
Sulphonylureas 1ndchoice Gliclazide, potentially increasing the risk of
2 choice: Glipizide with caution in patients with eGFR
30–50 mL/min/1.73 m2, and not at all hypoglycaemia.
Avoid in
patients prone to in patients with severe CKD. Some authors recommend
Hypoglycemia We can summarize that there is avoiding intermediate- and long-
Treatment should be general agreement between product acting insulins while others are
individualised. labels and guidelines that the GLP-1 active proponents. The absence of
Thiazolidinediones Can be used with receptor agonists may be used in comparative studies does little to
caution recommend usage, as does the little
mild CKD with no dose adjustment.
To be avoided in For moderate CKD, Exenatide should information available on clinical
patients with fluid consequences for the different types
retention
be used with caution, and in severe
CKD, not used at all. For the GLP-1 of insulin in such patients. 46,79
Alpha Glucosidase Avoid in patients
Inhibitors with eGFR <30 ml/ receptor agonists, which are cleared Impaired renal function in
min/1.73 m2 BSA by general protein catabolism, patients with Diabetes can affect
DPP4 inhibitors Dose to be titrated there are varying recommendations, the pharmacokinetics of some
based on eGFR, safe with the EU/Canada generally not insulin formulations including
recommending use in severe CKD regular Human Insulin and insulin
SGLT2 inhibitors Avoid when eGFR 2 (for which there was limited clinical Lispro.80-82 Insulin Aspart and Insulin
<45 ml/min/1.73 m
BSA. experience), and with no restrictions detemir though have demonstrated
and no dose adjustments in the US unaffected pharmacokinetics.
Loss of efficacy
in reduced renal labels. 55 Published evidence indicates that
function Based on the available evidence Insulin analogs may maintain their
with this class of agents, we pharmacokinetic profiles in this
varying degrees of renal impairment. patient population. 83-86
recommend that GLP1 Analogues
For exenatide (twice daily) which is
can be considered when the eGFR Pharmacokinetic properties
eliminated by glomerular filtration,
>30 ml/min/1.73 m 2 . Liraglutide of insu lin deg lu de c in sub ject s
systemic exposure was increased
has efficacy and safety data from w i t h va r y i n g d e g r e e s o f r e n a l
in patients with moderate or worse
a trial conducted in patients with function; normal, mild, moderate
CKD.63-66 Liraglutide and dulaglutide
moderate renal failure and thus can o r s e ve r e r e n a l i m p a i r m e n t ; o r
are large proteins, which are broken
be considered as a therapeutic option end-stage renal disease (ESRD)
down by general protein catabolism.
in this population. u n d e r g o i n g h e m o d i a l y s i s wa s
Liraglutide showed no increase in
evaluated in 30 patients. The ultra-
systemic exposure in patients with
worsening CKD.68,69 Dulaglutide also
Consensus long pharmacokinetic properties of
showed small increases in systemic Recommendation 4: insulin degludec were preserved
with no statistically significant
exposure that were not clinically Insulins in CKD: differences in absorption or
relevant. 70,71
4.1 Newer Insulin Analogs to clearance, compared with subjects
Liraglutide has been evaluated for with normal renal function. 87
efficacy and safety as an add-on to be preferred as they have
pharmacokinetics unaltered The NFK- KDOQI 2012 guidelines
existing glucose-lowering edications
in CKD including ESRD. do not recommend dose adjustment
in patients with inadequately
4.2 Insulin to be initiated at small with long acting insulins such as
controlled type 2 diabetes and
doses with strict monitoring Insulin Glargine, Insulin Detemir,
moderate renal impairment. No
Neutral Protamine Hagedorn or
changes in renal function were 4.3 Insulin dose needs to be titrated rapid acting insulins such as Regular
observed. No difference in to requirements to reduce the Human Insulin, Insulin Aspart,
hypoglycemic episodes was observed risk of Hypoglycemia Insulin Lispro or Insulin Glulisine. 19
between treatment groups. 72
4.4 Insulin pumps are an option The prescribing information for
A l l t h e r e v i e we d g u i d e l i n e s for suitable patients. these insulin formulations including
state that exenatide is either
32 Supplement to Journal of The Association of Physicians of India ■ Published on 1st of Every Month 1st October, 2016

Table 7: Recommendations for the Table 8: Recommendations for the use of Insulins in CKD
use of Non Insulin Injectable
Insulin Recommendation Proposed
Anti Diabetic Agents in CKD
Glargine
Agent Recommendation Detemir
Proposed
Neutral Protamine
GLP1 analogs Not recommended when
Hagedorn (NPH) • Newer Insulin Analogs may be preferred as they have
eGFR <30 ml/min/1.73 m2
BSA. Regular pharmacokinetics unaltered in CKD including ESRD.

Efficacy in CKD better • Initiate at small doses with strict monitoring

Aspart
than other oral agents • Dose needs to be titrated to requirements to reduce risk of
Lispro
Hypoglycemia
newer analogues such as Insulin Glulisine
• Insulin pumps are an option for suitable patients.
Degludec and co-formulation of Biphasic Insulin
Insulin Degludec with Insulin Aspart Aspart
recommend that dose adjustment Insulin Degludec +
may be necessary. 88-97 Insulin Aspart

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