Consensus Statement On Dose Modifications of Antidiabetic Agents in Patients With Hepatic Impairment

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Review Article
Consensus Statement on Dose Modifications of Antidiabetic

Agents in Patients with Hepatic Impairment
Kalyan Kumar Gangopadhyay, Parminder Singh1
Consultant Endocrinologist, Fortis Hospital, Kolkata, West Bengal, 1Division of Endocrinology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
Abstract
Liver disease is an important cause of mortality in type 2 diabetes mellitus (T2DM). It is estimated that diabetes is the most common cause of
liver disease in the United States. Virtually, entire spectrum of liver disease is seen in T2DM including abnormal liver enzymes, nonalcoholic
fatty liver disease, cirrhosis, hepatocellular carcinoma, and acute liver failure. The treatment of diabetes mellitus (DM) in cirrhotic patients has
particular challenges as follows: (1) about half the patients have malnutrition; (2) patients already have advanced liver disease when clinical DM
is diagnosed; (3) most of the oral antidiabetic agents (ADAs) are metabolized in the liver; (4) patients often have episodes of hypoglycemia.
The aim of this consensus group convened during the National Insulin Summit 2015, Puducherry, was to focus on the challenges with glycemic
management, with particular emphasis to safety of ADAs across stages of liver dysfunction. Published literature, product labels, and major
clinical guidelines were reviewed and summarized. The drug classes included are biguanides (metformin), the second‑ or third‑generation
sulfonylureas, alpha‑glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase‑4 inhibitors, sodium‑glucose co‑transporter 2 inhibitors,
glucagon‑like peptide‑1 receptor agonists, and currently available insulins. Consensus recommendations have been drafted for glycemic targets
and dose modifications of all ADAs. These can aid clinicians in managing patients with diabetes and liver disease.
Keywords: Antidiabetic agents, hepatic impairment, type 2 diabetes mellitus
Introduction diabetes, by most estimates, is now the most common cause

of liver disease cryptogenic cirrhosis and has become the
The liver has an important role in carbohydrate metabolism.
third leading indication for liver transplantation in the United
It is responsible for the balance of blood glucose levels by
States. DM has been commonly associated with nonalcoholic
means of neoglucogenesis and glycogenolysis.[1] The metabolic
fatty liver disease (NAFLD), including its most severe form,
homeostasis of glucose is impaired in the presence of chronic
nonalcoholic steatohepatitis (NASH). NASH is a chronic
liver disease (CLD) resulting in insulin resistance (IR),
necroinflammatory condition that can lead to liver fibrosis,
glucose intolerance, and diabetes.[1‑3] According to a report, the
cirrhosis, and subsequently to HCC.[8] In addition, there is an
prevalence of diabetes mellitus (DM) in patients with CLD is
unexplained association of diabetes with hepatitis C. Recent
reportedly 18%–71%.[4] In another report, glucose intolerance
studies suggest that the core protein of hepatitis C virus (HCV)
is seen in up to 80% of patients with CLD and diabetes in
impairs insulin receptor substrate 1 (IRS‑1) signaling, which
30%–60%.[5] Moreover, in case of liver cirrhosis, glucose
plays an important role in the metabolic effects of insulin.[7]
intolerance and diabetes is present in approximately 96% of
the patients.[6] Hence, diabetes and CLD often coexist and NAFLD, a common cause of CLD in diabetic patients, is
existing evidence suggests that CLD increases complications characterized by excess fat in liver. NAFLD increases the risk
and premature mortality in patients with diabetes.[7] Association of mortality, estimated to be prevalent in 30%–74% of patients
between diabetes and CLD is given in Figure 1.
In contrast to the involvement of liver disease in causing Address for correspondence: Dr. Kalyan Kumar Gangopadhyay,
Fortis Hospital, Kolkata, West Bengal, India.
diabetes, diabetes has also been proposed as a risk factor
E‑mail: [email protected]
for both CLD and hepatocellular carcinoma (HCC). In fact,
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DOI: How to cite this article: Gangopadhyay KK, Singh P. Consensus statement
10.4103/ijem.IJEM_512_16 on dose modifications of antidiabetic agents in patients with hepatic
impairment. Indian J Endocr Metab 2017;21:341-54.
© 2017 Indian Journal of Endocrinology and Metabolism | Published by Wolters Kluwer - Medknow 341
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Gangopadhyay and Singh: Consensus statement on dose modifications of antidiabetic agents in patients with hepatic impairment
Figure 2: Etiology of liver disease associated with diabetes mellitus. DM:

Diabetes Mellitus; HCC: Hepatocellular Carcinoma; NASH: Nonalcoholic
Figure 1: Relationship between diabetes and chronic liver disease. HCV: Steatohepatitis
Hepatitis C Virus; HCC: Hepatocellular Carcinoma; NAFLD: Nonalcoholic
Fatty Liver Disease; DM: Diabetes Mellitus; T2DM: Type 2 Diabetes Mellitus as well as other reports and guidelines published within
India and other countries related to the management of
with diabetes.[7,9] Despite unclear pathogenesis, IR in diabetes glycemic control in this patient population
is considered to be a critical contributing factor of NAFLD. • Propose consensus recommendations for the dose
IR causes downregulation of IRS‑1 signaling, thereby leading modifications of different ADAs based on published
to excess free fatty acids accumulation in the liver.[10] Another guidelines, evidence, and clinical experience.
factor which contributes to NAFLD in patients with type 2
diabetes mellitus (T2DM) is dyslipidemia. The risk of all‑cause Methods
mortality is found to be 2.2‑fold more in T2DM patients with
The expert group identified the following classes of
NAFLD.[11] In India, various cohort studies had shown that
drugs for proposed recommendations upon consensus:
NAFLD is highly prevalent, i.e., 30.5%–64.2% in patients with
biguanides (metformin), SUs (glipizide, glimepiride, glyburide,
T2DM.[12‑14] Etiology of liver disease associated with DM can
and gliclazide), TZDs (pioglitazone), AGIs (acarbose and
be classified into three groups as shown in Figure 2.
miglitol), dipeptidyl peptidase 4 (DPP‑4) inhibitors (sitagliptin,
Management of diabetes in patients with CLD is challenging saxagliptin, vildagliptin, and linagliptin), sodium‑glucose
because the liver is the major site of metabolism for co‑transporter 2 (SGLT2) inhibitors (dapagliflozin,
most of the antidiabetic agents (ADAs). Moreover, CLD canagliflozin, and empagliflozin), glucagon‑like peptide‑1
was associated with complications such as impaired receptor agonists (GLP1‑RAs) (liraglutide, exenatide, and
renal function, hypoalbuminemia, lactic acidosis, and dulaglutide), and various types of insulin products.
hypoglycemia. In addition, more than 50% of patients with
liver disease were malnourished and were at higher risk of Each class of drugs was subsequently evaluated for relevant
developing hypoglycemia in the presence of predisposing and published clinical and epidemiological evidence as well
factors.[7,15,16] Data on efficacy and safety of commonly as defined place in guidelines/algorithms from the national
prescribed glucose‑lowering agents such as metformin, and global professional associations. These evaluations were
sulfonylureas (SUs), alpha‑glucosidase inhibitors (AGIs), then factored into the national context based on inputs from the
and thiazolidinedione’s (TZDs) in patients with DM and consensus committee members. The final proposed consensus
CLD are very limited. To derive a consensus towards optimal recommendation captured the collective outcome of the above
dose modifications with ADAs in patients with T2DM with process in easily implementable steps under each therapeutic
coexisting CLD, a group of experts from India held a consensus drug class.
meeting at the National Insulin Summit in Puducherry, India, The Child‑Pugh (also called as Child‑Turcotte‑Pugh score)
on November 8, 2015. The objectives of the meeting were to: classification [Table 1], commonly used to represent severity
• Exa m i ne t he published ev idence a nd product of CLD, is the basis for the proposed recommendations.[17]
prescribing information (PI) of each antidiabetic Patients are classified into three classes (A–C) with different
therapy on dose modification and their pharmacokinetic/ expected survival: Child‑Pugh A = 5–6 points, Child‑Pugh
pharmacodynamics (PK/PD) behavior in hepatic B = 7–9 points, and Child‑Pugh C = 10 or more points.[18,19]
impairment (HI) patients
• Examine algorithms published as part of the established Challenges in the management of diabetes in patients
t reat ment g uidelines f rom globally recog nized with chronic liver disease
professional bodies such as the American Diabetes Renal impairment
Association (ADA), the European Association for the Patients with CLD are more prone to acute kidney injury.[20]
Study of Diabetes (EASD), the American Association Liver disease can sometimes alter kidney function, leading
of Clinical Endocrinologists, the American College of to accumulation of drugs/metabolites even if they are not
Endocrinology and International Diabetes Federation eliminated by the liver.[20]
342 Indian Journal of Endocrinology and Metabolism ¦ Volume 21 ¦ Issue 2 ¦ March-April 2017
glycemic control with limited clinical effectiveness and

Table 1: Child‑Pugh score parameters
is less cost‑effective.[36] On the other hand, though CGM
Parameters 1 point 2 points 3 points is recommended for those on insulin treatment or those
Serum bilirubin total <34 (<2) 34‑50 (2‑3) >50 (> 3) with recurrent hypoglycemic attacks, it is not specified for
(mg/dL) Patients with diabetes and liver disease.[37] It is suggested to
Serum albumin (mg/dL) >35 28-35 <28 use indicators of glycemic control compositely to reduce the
INR* <1.7 1.71-2.20 >2.20
discrepancy between different parameters of glycemic control.
Ascites None Suppressed with Refractory
medication Dose modification of oral antidiabetic drugs in chronic
Hepatic encephalopathy None Grade I-II Grade III-IV liver disease
(or suppressed (or refractory)
with medication) Biguanides (metformin)
*INR: International Normalized Ratio; Child‑Pugh A=5-6 points, Published scientific evidence
Child‑Pugh B=7-9 points, Child‑Pugh C=10 or more points Metformin is first‑line therapy for T2DM patients.[16] It does
not undergo hepatic metabolism and is excreted unchanged
Altered metabolism by tubular secretion and glomerular filtration in the urine.[38]
The liver is a primary site of drug metabolism, and the Metformin may cause lactic acidosis in predisposed patients.[38]
impairment of drug metabolism is proportional to the liver Lactic acidosis can occur through two mechanisms. Metformin
dysfunction. CLD is characterized by numerous metabolic shifts intracellular oxidation‑reduction potential toward
alterations, predominantly catabolic.[21] Hepatic blood flow, anaerobic metabolism augmenting lactate production. It
liver enzyme activity, and plasma protein concentration can also suppresses conversion of glucose from lactate in liver
be impacted, and this in turn affects hepatic metabolism of and hence decreases lactate clearance.[39] However, there
drugs.[22] Bioavailability of drugs, metabolized by cytochromes are only a few reported cases of hepatotoxic side effects for
P450 (CYP 450) enzyme system, may also be altered.[23] metformin. Nevertheless, there may be an enhanced risk of
developing lactic acidosis in the clinical setting of impaired
Insulin resistance and hypoglycemia
liver function.[38] It is estimated that incidence of lactic acidosis
Increased IR is frequently associated with CLD.[4] It significantly
is 0.03–0.5 cases/1000 patient‑years in metformin‑treated
affects endogenous glucose production, oxidative and
population. However, the incidence of lactic acidosis among
nonoxidative glucose disposal, lipolysis, and lipid oxidation.[24]
patients with T2DM who consume metformin does not
The rate at which insulin is degraded in the liver is reduced
differ from the incidence in T2DM patients not receiving
resulting in peripheral hyperinsulinemia and hypoglycemia.[25‑27] metformin. [39] Systematic review and meta‑analysis of
Lactic acidosis 194 comparative trials revealed no cases of fatal or nonfatal
Patients with decompensated liver disease, in the setting lactic acidosis in metformin group compared to nonmetformin
of sepsis or hemorrhage, may have increased serum lactate group (36,893 vs. 30,109 patient‑years). Moreover, there
levels[28] due to poor utilization and metabolism.[29] Lactic was no difference in lactate levels for metformin compared
acidosis may be precipitated by biguanides as they inhibit to placebo or other nonbiguanide therapies.[40] Hence, there
mitochondrial respiration predominantly in the liver.[30] is no evidence to date that metformin therapy is associated
with an increased risk of lactic acidosis compared to other
Malnutrition antihyperglycemic treatments.
Patients with CLD develop malnutrition as the liver plays a
Metformin is not expected to cause or exacerbate liver injury.
key role in carbohydrate, protein, lipid, vitamin, and mineral
It is probably beneficial in patients with NAFLD.[15] However,
metabolism and energy balance.[31,32] Hypoalbuminemia
metformin has not been studied in patients with liver disease
results from protein deficiency in malnutrition.[33] Highly
to date. All available information about liver dysfunction
protein bound drugs may cause toxicity in the presence of
predisposing to metformin‑associated lactic acidosis is drawn
hypoalbuminemia as their free plasma concentrations increase. from case reports and postulated mechanisms.[39] Most of those
Tools to measure long‑term glycemic control in patients patients had cirrhosis, with some degree of renal impairment.
with chronic liver disease For this reason, it seems reasonable to use metformin with
Glycosylated hemoglobin (HbA1c), serum fructosamine, caution in patients with moderate CLD and to avoid its
self‑monitoring of blood glucose (SMBG), and continuous use in patients with severe CLD. Furthermore, identifying
glucose monitoring (CGM) are some of the available tools patients with cirrhosis and controlling renal function before
initiating metformin seem prudent. Any circumstance
to measure long‑term glycemic control in patients with CLD.
favoring dehydration should promote the interruption of
Of all the tools, serum fructosamine seems to be more metformin, especially in such fragile patients.[15] Patients
suitable test for monitoring blood glucose levels as HbA1c with multiple comorbidities, such as renal, liver, and cardiac
levels are frequently falsely low in patients with diabetes diseases, particularly in acute deterioration, when treated with
and liver cirrhosis.[34,35] Repeated SMBG shows short‑term metformin, appear to be at higher risk of lactic acidosis.[16]
Indian Journal of Endocrinology and Metabolism ¦ Volume 21 ¦ Issue 2 ¦ March-April 2017 343
Tissue hypoxia is supposed to be a risk factor for lactic acidosis.

Table 2: Expert group recommendation 2: Dose
In practice, not all cases of CLD are associated with hypoxia.
modification of metformin in chronic liver disease
Instances where concurrent pulmonary or heart diseases are
Metformin may be used with caution up to a maximum dose of
present may be considered as hypoxic states.[39]
1500 mg/day
Current place in guidelines/recommendations Metformin can be used in mild liver disease
The Canadian Diabetes Association (CDA) recently Its dose needs to be reduced/avoided in patients with moderate liver
recommended the avoidance of metformin in hepatic failure disease
Metformin should be avoided in severe hepatic dysfunction
patients.[41] The Australian Diabetes Society also restricts the
use of metformin in patients with severe hepatic failure.[42] In
addition, ADA also recommends avoidance of metformin in SUs are extensively bound to serum proteins and excreted
patients with severe liver disease or in binge drinkers due to mainly through renal pathway.[48‑51] The major risk associated
incidence of lactic acidosis.[43] The Indian Council of Medical with SUs is hypoglycemia.[15]
Research (ICMR) proposes to avoid metformin usage in PK studies regarding the use of SUs in patients with hepatic
patients with hepatic insufficiency.[44] The British National insufficiency are lacking. However, the use of SUs in hepatic
Formulary (BNF) recommends to withdraw metformin if failure may be challenging as most of the SUs are metabolized
tissue hypoxia is likely in HI patients to reduce the risk of in liver. [52] Furthermore, SUs exert their hypoglycemic
lactic acidosis.[45] effects by stimulating insulin secretion from the pancreatic
Consensus guidelines by the Egyptian Association for the beta‑cell.[53] Hence, there may be chances of drug‑induced
Study of Liver and Gastrointestinal Disease (EASLGD) hypoglycemia due to reduced inactivation of SUs in liver. In
elaborates that metformin is an appropriate first‑line therapy addition, protein binding of SUs may also be reduced due to
for most patients, except those with advanced liver disease hypoalbuminemia. This in turn enhances free drug plasma
who have an increased risk of lactic acidosis.[38] A review by concentrations resulting into frequent hypoglycemia.[52] In
Khan et al. suggested that if a patient has stable CLD and few severe HI, there may be diminished gluconeogenic capacity.[49]
other comorbidities, metformin is likely to be reasonably safe, Moreover, SUs may also exhibit additive hypoglycemia in case
but the dose should be decreased to a maximum of 1500 mg of decompensated liver cirrhosis which is characterized by
daily, and the drug should be withdrawn if liver or renal peripheral hyperinsulinism, resulting from both reduced insulin
function is deteriorating, or in the setting of acute illness or hepatic clearance and higher insulin secretion rate.[54] NASH
decompensation.[16] can also be associated with impaired defense in countering
hypoglycemia.[38,52] CLD patients who are malnourished are
Prescribing information at higher risk of hypoglycemia.[15] Alcohol‑induced enzyme
Warning section of manufacturer’s PI states, “Since impaired degradation of SUs in patients with alcoholic liver disease may
hepatic function has been associated with some cases of lactic manifest decreased clinical effectiveness of SUs.[52] Therefore,
acidosis, metformin should generally be avoided in patients SUs may also not be suitable where both IR and defects in
with clinical or laboratory evidence of hepatic disease.” In insulin secretion are coexistent. It has been suggested that
addition, it also quotes that metformin should be promptly SUs with a short half‑life such as glipizide or glyburide are
withheld in the presence of any condition associated with preferred in CLD patients.[7]
hypoxemia, dehydration, or sepsis.[46]
Current place in guidelines/recommendations
Based on the available evidence, we recommend that Position statement of the ADA and EASD states that in severe
metformin should be used with caution up to a maximum dose hepatic disease, insulin secretagogues should be avoided
of 1500 mg/day. It may be advisable to either reduce the dose due to the risk of hypoglycemia.[55] CDA suggests the use
or to avoid metformin in patients with moderate liver disease. of alternate agents in hepatic failure patients.[41] BNF also
The agent is better avoided in patients with severe hepatic mentions, “Insulin secretagogues should be avoided or used
dysfunction [Table 2]. with caution at low doses in patients with T2DM and CLD.”
However, glimepiride must be avoided in severe hepatic
Sulfonylureas (second or third generation)
Published scientific evidence failure patients.[45] Guidelines from ICMR also recommend
The first‑generation SUs are rarely used and are not discussed. avoidance of SUs in hepatic insufficiency and acute hepatitis.[44]
The second‑ and third‑generation SUs are currently positioned Consensus guidelines by EASLGD restricted the usage of SUs
in severe hepatic disease due to high risk of hypoglycemia.[38]
as the second‑line treatment options after failure of metformin
therapy. Glyburide/glibenclamide, glipizide, gliclazide, and Khan et al. recommended that dosage of SUs should be halved,
glimepiride belong to second‑ and third‑generation SUs, especially if patients do not abstain from alcohol.[16] Expert
respectively.[47] The liver is the major site of biotransformation opinion by Scheen suggests the use of SUs with caution
for all SUs. They are metabolized into active and inactive in patients with advanced CLD as hypoglycemia may be a
metabolites through hepatic oxidative enzymes (CYP P450s). concern.[15]
Prescribing information caffeine clearance in CLD patients but not in healthy control,
Manufacturer’s PI of all SUs suggests cautious use in patients repaglinide clearance is significantly reduced in HI patients.
at higher risk of hypoglycemia such as hepatic and renal Therefore, it should be used with caution in patients with
impairment, the elderly, malnourished, and patients on other CLD and is contraindicated in patients with diabetes and
antidiabetic medications. Initial dosing, dose increments, severe HI.[58] As with SUs, rare case reports of either acute
and maintenance dosage should be conservative to avoid hepatotoxicity or cholestatic hepatitis have also been reported
hypoglycemia. However, gliclazide is contraindicated in severe with repaglinide.[59,60]
hepatic insufficiency.[48‑51]
On the contrary, no significant PK alteration of nateglinide
Based on the available evidence, we recommend that SUs occurs in patients with mild HI. PKs of nateglinide was
should be avoided in patients with CLD due to greater risk of compared in individuals with cirrhosis and matched healthy
hypoglycemia and paucity of evidence. If used, lower doses controls in a single‑dose, open‑label, and parallel‑group study.
should be preferred in Child‑Pugh Class A and B. SUs should In groups, Tmax (0.5 h) and mean t1/2 values were comparable.
be avoided in patients with Child‑Pugh Class C [Table 3]. However, exposure was slightly increased (+30% for AUC
Meglitinides and + 37% for Cmax). Mean apparent total clearance and mean
Published scientific evidence renal clearance of nateglinide were comparable in both groups.
Meglitinides have the potential to produce a rapid, short‑lived Fractions bound to protein were also equivalent. Hence,
insulin output. Two analogs are currently available for no statistically significant or clinically relevant alterations
clinical use: repaglinide and nateglinide. Meglitinides are in PK parameters of nateglinide were observed in hepatic
extensively (>98%) bound to serum albumin protein. They are dysfunction; therefore, adjustment of nateglinide dosage is
completely metabolized by oxidative biotransformation (CYP not required in individuals with mild to moderate cirrhosis.[61]
450) and conjugation with glucuronic acid in liver.[56,57] No data are available in patients with severe HI.
Meglitinides are characterized by shorter half‑lives and Furthermore, nateglinide was tested in a pilot 20‑week study
absence of significant renal excretion.[15] in diabetic patients with NASH who were randomly divided
PK characteristics of glinides have been evaluated in patients into two groups, with and without nateglinide treatment.
with HI. Drug exposure and elimination of repaglinide are Postprandial blood glucose, oral glucose tolerance test, HbA1c,
significantly affected by HI, whereas in the case of nateglinide, abdominal ultrasound and computerized tomography imaging
HI has only minimal impact upon these parameters. The tests, liver function, and liver histological findings were
reasons of this discrepancy are not clear. However, the two improved after treatment with nateglinide. Hence, nateglinide
meglitinides are metabolized by different CYP isoforms, 2C8 was considered as useful and safe in the treatment of NASH
for repaglinide and 2C9 for nateglinide. Besides, solute carrier in patients with T2DM.[62]
organic anion transporter family member 1B1 (SLCO1B1) Current place in guidelines/recommendations
polymorphism exerts different effects on the PK/PD of No specific guidelines are available pertaining to meglitinides.
repaglinide (significant PK changes) and nateglinide (PK
Expert opinion by Scheen suggests that meglitinides may
unaffected).[15]
represent an alternative to SUs, with a preference for
PKs and tolerability of a single 4 mg dose of repaglinide nateglinide compared to repaglinide.[15] Moreover, Khan et al.
were compared in an open‑label, parallel‑group study in recommended that dosage of repaglinide should be halved,
healthy controls and patients with CLD. Values for area especially if the patient is not abstinent from alcohol.[16]
under the concentration‑time curve (AUC) and maximum
Prescribing information
plasma concentration (Cmax) were significantly higher in
Repaglinide PI suggests caution due to elevation in plasma
CLD patients compared to healthy controls. Values for time
levels, and therefore, risk of added hypoglycemia may be there
to reach Cmax (Tmax) did not differ between the groups, but
while prescribing repaglinide to HI patients. It emphasizes that
terminal elimination half‑life (t1/2) was significantly prolonged
proper patient selection, dosage, and instructions to the patients
in CLD patients compared with previously determined values
are important to avoid hypoglycemic episodes. In addition, rare
in healthy controls. Since AUC was inversely correlated with
adverse events such as severe hepatic dysfunction including
jaundice and hepatitis have also been observed in patients
Table 3: Expert group recommendation 3: Dose taking repaglinide. Nateglinide PI advises cautious use in
modification of SU in chronic liver disease patients with moderate to severe liver disease.[56,57]
SU should be avoided due to risk of hypoglycemia and the lack of
On the basis of available evidence, we recommend that
published evidence
SU should be used with caution and need to be initiated at low doses in
repaglinide should be cautiously used in CLD patients.
Child‑Pugh Class A and B Although nateglinide may be used in Child‑Pugh Class A
They should be avoided in Class C patients, it is not preferred in Child‑Pugh Class B and C
SU: Sulfonylureas patients [Table 4].
Thiazolidinediones and total bilirubin before initiating therapy. Caution is

Published scientific evidence advised in patients with abnormal liver tests. Patients who
Pioglitazone is the only drug of this class available for clinical have serum ALT >3 times the reference range and serum total
use in India.[63] It is extensively metabolized by hydroxylation bilirubin >2 times the reference range without alternative
and oxidation; the metabolites also partly convert to etiologies are at risk for severe drug‑induced liver injury and
glucuronide or sulfate conjugates. It is excreted primarily as should not be restarted on pioglitazone.[64]
metabolites and their conjugates in bile and feces.[64] Edema is On the basis of available evidence, we recommend that
one of the most frequent side effects of TZDs.[65] TZDs are also pioglitazone should be used with caution in CLD patients. It
thought to increase vascular permeability in several tissues.[66] should be avoided in patients whose liver enzymes are >3 times
On the other hand, TZDs improve insulin sensitivity.[16] They ULN range. Pioglitazone may be used in Child‑Pugh Class A
exert improved insulin sensitivity through diverse mechanisms, patients. However, it should be avoided in Class B and C patients.
both direct and indirect, and both at the level of the liver and It is better to avoid pioglitazone in case of edema [Table 5].
extrahepatic tissues.[38]
Alpha‑glucosidase inhibitors
Hepatic safety of pioglitazone in more than 20,000 patients with Published scientific evidence
T2DM in Japan was evaluated in a prospective observational Acarbose and miglitol are available in India. Acarbose exerts its
study. No case of hepatic failure was reported, and neither action within the gastrointestinal tract and is characterized by
temporal nor dose relations were found between pioglitazone a low systemic bioavailability.[15] It is exclusively metabolized
and alanine aminotransferase (ALT) abnormalities.[67] within the gastrointestinal tract.[38] However, miglitol is not
Pioglitazone may also have a specific role in patients with considered to be metabolized in humans and it is eliminated
NAFLD and NASH. There is preliminary evidence that by renal excretion as unchanged drug.[70] Therefore, AGIs may
patients with fatty liver may get benefitted from pioglitazone. be particularly useful in patients with liver disease.
A randomized study, on patients with NASH treated with Due to lack of intestinal absorption and hepatic metabolism,
pioglitazone, showed improvement in histological indices. several documents clearly report good tolerability and the
Serum ALT and aspartate aminotransferase (AST) levels were absence of toxic effects of acarbose on liver. Because of these
reduced with pioglitazone as compared with placebo (P < 0.001). characteristics, no PK studies are available with this compound in
Moreover, hepatic steatosis and lobular inflammation were also patients with CLD. However, clinical studies demonstrated that
reduced after pioglitazone treatment.[68] In addition, it is evident acarbose can be safely and effectively used in diabetic patients
from several clinical trials that TZD treatment can prevent with CLD, alcoholic cirrhosis, well‑compensated nonalcoholic
subsequent events, such as increase in oxidative stress, lipid cirrhosis, and low‑grade hepatic encephalopathy.[71‑74] Acarbose
peroxidation, and pro‑inflammatory cytokines that contribute is considered a promising therapeutic strategy for the treatment
to the development of NAFLD to NASH.[65] of patients with NASH.[75] However, there may be a possibility
Current place in guidelines/recommendations of hyperammonemia when acarbose is prescribed to the patients
The guidelines from ADA and the Association of Physicians with DM and advanced liver cirrhosis.[71] Moreover, acarbose
of India‑Indian College of Physicians suggest that in case of frequently causes mild transient elevations of ALT and, on rare
active liver disease or clinical evidence of serum ALT level occasions, severe liver disease.[7]
exceeding 2.5 times of upper normal limit, glitazones should Current place in guidelines/recommendations
be avoided.[43,69] However, ADA highlighted importance of BNF states that liver function should be monitored while
TZDs in the treatment of NASH.[43] Consensus guideline using acarbose and restricts its use in patients with liver
by EASLGD recommends undergoing periodic monitoring
of liver enzymes and glitazones not be initiated in patients
exhibiting clinical evidence of active liver disease or increased Table 4: Expert group recommendation 4: Dose
serum transaminase levels (ALT >2.5 times the upper limit of modification of meglitinides in chronic liver disease
normal [ULN]). It also suggests using glitazones with caution Repaglinide should be used with caution
in HI patients. Also states that pioglitazone may be beneficial Nateglinide can be used in Child‑Pugh Class A
for fatty liver disease patients.[38] However, according to BNF, Nateglinide is not preferred in Child‑Pugh Class B and C
liver function test should be performed before the treatment
with pioglitazone and periodically thereafter. It advises to
discontinue treatment if jaundice occurs. Pioglitazone is also Table 5: Expert group recommendation 5: Dose
contraindicated in case of HI.[45] Khan et al. recommended modification of pioglitazone in chronic liver disease
maximum, 30 mg daily dose of pioglitazone with careful Pioglitazone should be used with caution; Pioglitazone to be avoided
when liver enzymes >3 times ULN
monitoring of liver function in CLD patients.[16]
It can be used in Child‑Pugh Class A patients
Prescribing information Pioglitazone should be avoided in Child‑Pugh Class B and C patients
Pioglitazone PI recommends patient assessment and a group Pioglitazone should be avoided when patients have edema
of liver tests such as serum ALT, AST, alkaline phosphatase, ULN: Upper limit of normal
disease. It warns about risk of hypoglycemia in case of liver In an open‑label, single‑dose study in patients with moderate
dysfunction.[45] However, consensus guidelines by EASLGD HI (Child‑Pugh’s scores ranged from 7 to 9) and matched
and ADA recommend that acarbose is safe, useful, and well healthy controls, the mean AUC∞ and Cmax for sitagliptin
tolerated in CLD patients.[38,43] were numerically, but not significantly, higher in patients
with moderate HI compared with healthy matched controls.
These small differences were not considered to be clinically
PI of acarbose reveals that a treatment emergent increase in
significant. Furthermore, Tmax, apparent terminal t1/2, and
serum transaminase levels was observed in postmarketing
renal clearance were not statistically significant.[79] In an
study. However, these elevations were symptomatic,
another reported case–control study, efficacy and safety of
reversible upon discontinuation, more common in females
sitagliptin was assessed for patients with diabetes complicated
and in general were not associated with other evidence of
by CLD caused by HCV. There were no significant changes
liver dysfunction. In addition, these serum transaminase
of average AST and ALT level reported during follow‑up of
elevations appeared to be dose related. However, acarbose
48 weeks in both sitagliptin group and control group. The
is contraindicated in diabetic cirrhosis.[76] Miglitol PI states
study concluded that sitagliptin is effective and safe for the
that PK of miglitol is not altered in cirrhotic patients as
treatment of T2DM complicated with HCV positive CLD.[80]
compared to control. Since it is not metabolized by liver,
In an observational pilot study, paired liver biopsies from
therefore, no influence of hepatic function on the kinetics of
15 patients with diabetes and NASH before and after 1 year
miglitol is expected.[70]
of therapy with sitagliptin 100 mg once daily were studied.
On the basis of available evidence, we recommend that AGIs Sitagliptin resulted in a significant decrease in ballooning
are relatively safe and could be used without dose modification and NASH scores, while the reduction in the steatosis score
in CLD patients. Hence, AGIs are safe in Child‑Pugh was of borderline statistical significance. These effects were
Class A and B. However, they are not preferred in Class C accompanied by a significant reduction in body mass index,
patients [Table 6]. AST, and ALT levels.[81]
Dipeptidyl‑peptidase‑4 inhibitors PKs of vildagliptin (100 mg) was assessed in an open‑label,
Published scientific evidence parallel‑group study in patients with mild, moderate, or severe
Hepatic metabolism is a minor pathway for sitagliptin and HI and healthy controls. There was no significant difference
vildagliptin, and major part of the administered drug is either in exposure to vildagliptin in patients with mild, moderate,
excreted unchanged by renal pathway or through hydrolysis or severe HI compared to healthy controls; therefore, it was
by multiple tissues/organs, respectively. [77,78] Similarly, concluded that no dose adjustment of vildagliptin is necessary
metabolism also represents minor pathway for linagliptin in patients with HI.[82]
and ~80% of administered dose is eliminated through
Linagliptin undergoes enterohepatic cycling; therefore, a
enterohepatic recycling. On the other hand, saxagliptin is
potential effect of HI on the PKs of linagliptin may have
primarily metabolized by hepatic CYP3A4/5 and eliminated
important implications for dosing recommendations. An
through renal and hepatic routes.[77]
open‑label, parallel‑group, study enrolled patients with mild,
Higher serum DPP‑4 activity has been reported in few liver moderate, or severe CLD and healthy controls to investigate
disorders such as chronic hepatitis‑C and NAFLD patients, whether HI affects linagliptin PKs, PDs, and tolerability.
known to be associated with T2DM and IR. Therefore, DPP‑4 Healthy controls and patients with mild and moderate HI
inhibitors might offer the prevention of further metabolic received 5 mg linagliptin for 7 days, whereas patients with
deterioration, especially in NAFLD. [38] It has also been severe HI received linagliptin 5 mg single dose. Compared to
reported that NAFLD may worsen glycemic control afforded healthy controls, steady state exposure (AUCss) of linagliptin
by sitagliptin.[15] All four DPP‑4 inhibitors are particularly was slightly lower in mild and moderate HI patients. However,
well studied in patients with various degrees of HI as far as in severe HI patients, single‑dose AUC(0‑24) was similar to that
PK characteristics are concerned. However, no clinical study in healthy controls whereas Cmax was lower. Accumulation of
with a chronic administration of a DPP‑4 inhibitor in patients linagliptin (≤7%) based on AUC or Cmax and renal excretion
with CLD is yet available.[15] of unchanged linagliptin were comparable across the groups.
Median plasma DPP‑4 inhibition at steady state trough
concentration for healthy controls and mild and moderate HI
Table 6: Expert group recommendation 6: Dose patients was also similar, i.e., 91%, 90%, and 89%, respectively.
modification of alpha‑glucosidase inhibitors in chronic However, it was 84% in patients with severe HI after 24 h of a
liver disease single‑dose administration. Thus, mild, moderate, or severe HI
Alpha‑glucosidase inhibitors can be used without dose modification did not result in any increase in linagliptin exposure after single
Relatively safe and multiple dosing compared with normal hepatic function.
Safe in Child‑Pugh Class A and B patients The authors suggested that dose adjustment with linagliptin
Not preferred in Child‑Pugh Class C patients is not required in patients with HI.[83]
The PK of saxagliptin (10 mg) and its pharmacologically requires caution in Class B patients. Administration of DPP‑4
active metabolite, 5‑hydroxy saxagliptin, were compared in inhibitors is not preferred in Class C patients [Table 7].
individuals with mild, moderate, or severe CLD without
DM and in healthy adults in an open‑label, parallel‑group,
Sodium‑glucose co‑transporter 2 inhibitors
Published scientific evidence
and single‑dose study. Compared to healthy controls, the
Canagliflozin, dapagliflozin, and empagliflozin are agents
AUC∞ values for saxagliptin were 10%, 38%, and 77% higher
currently available in India. SGLT2 inhibitors share similar
in patients with mild, moderate, or severe HI, respectively.
PK characteristics. They possess long elimination half‑life
The corresponding values were 22%, 7%, and 33% lower,
allowing once‑daily administration and undergo extensive
respectively, for 5‑hydroxy saxagliptin, compared with
hepatic metabolism mainly through glucuronidation, and
matched healthy controls. Saxagliptin Cmax values were
small proportions of the parent drug are eliminated through
8% higher, 16% higher, and 6% lower in patients with
renal route.[93]
mild, moderate, and severe HI, respectively, compared to
controls (corresponding values for 5‑hydroxy saxagliptin: Single‑dose PKs of canagliflozin (300 mg) was studied in
−17%, −16%, and − 59%, respectively). Hence, increase of mild and moderate HI patients and compared with healthy
saxagliptin exposure was compensated by a corresponding volunteers. Mean Cmax and AUC0‑∞ values differed by <11%
decrease of the exposure to its active metabolite. Therefore, between the group with normal hepatic function and those
dose adjustment is recommended for patients with any degree with mild and moderate HI. It was concluded that PKs of
of HI.[84] canagliflozin was not affected by mild or moderate HI and
that single dose was well tolerated.[94] There is no clinical
There is little evidence that DPP‑4 inhibitors such as sitagliptin experience in patients with severe HI.
and vildagliptin may be associated with hepatic risk. Pooled
analysis of 12 large, double‑blind, Phase IIb and III studies Plasma concentrations of dapagliflozin could be affected by HI.
shows that sitagliptin treatment is associated with ALT A study with 10 mg single dose of dapaglifozin showed that
elevations with concomitant increase in bilirubin. However, mean Cmax was 12% lower in patients with mild HI compared
there was no meaningful difference between sitagliptin to healthy controls. However, in moderate and severe HI
exposed and nonexposed patients. These cases resolved on patients, Cmax was 12% and 40% higher, respectively. Mean
treatment and overall no increased risk of hepatic events was exposure AUC(0‑∞) of dapagliflozin was 3%, 36%, and 67%
reported.[85,86] higher in mild, moderate, and severe HI patients, respectively,
compared to healthy controls. As long‑term safety and efficacy
Further, in a meta‑analysis of safety data, pooled from 38 of dapagliflozin have not been studied, benefit: risk ratio should
Phase II and III clinical trials, greater proportion of vildagliptin be individually assessed due to its greater exposure in severe
recipients were found to have mild elevations in liver enzymes HI patients.[95] Caution has been advised when HI is combined
compared to comparators. Vildagliptin was also not associated with some degree of renal impairment.[96]
with an increased risk of hepatic adverse events. Only two
patients experienced severe elevations in liver enzymes (AST/ The PK profile of empagliflozin in HI patients was investigated
ALT ≥10x ULN or AST/ALT ≥3x ULN and bilirubin ≥2x in an open‑label and parallel‑group study. A single dose of 50 mg
ULN) attributable to vildagliptin treatment. Both cases empagliflozin was administered to patients with mild, moderate,
were asymptomatic and resolved upon discontinuation of and severe HI and to the matched controls with normal hepatic
treatment.[87,88] function. Exposure to empagliflozin (both Cmax and AUC∞)
progressively increased with the severity of HI compared with
Current place in guidelines/recommendations individuals with normal hepatic function. However, as the
A consensus guideline by EASLGD mentions that DPP‑4 increase in empagliflozin exposure was less than 2‑folds in
inhibitors, especially sitagliptin, demonstrated effectiveness patients with impaired liver function, it was concluded that no
and safety in T2DM patients with HCV‑positive CLD.[38] dose adjustment of empagliflozin is required in these patients.[97]
However, vildagliptin should be avoided in liver disease
patients.[45] Meta‑analysis and review reports from large Phase II–III trials
showed that dapagliflozin, canagliflozin, and empagliflozin
The United States PI of sitagliptin, saxagliptins, and linagliptin
recommends no dosage adjustments in patients with HI.[89‑91] Table 7: Expert group recommendation 7: Dose
However, summary of product characteristic of vildagliptin modification of dipeptidyl peptidase 4 inhibitors in
suggests that it should not be used in patients with HI, including chronic liver disease
patients with pretreatment ALT or AST >3x the ULN.[92] DPP‑4 inhibitors (except vildagliptin) may be used with caution without
dose modification
On the basis of available evidence, we recommend that except DPP‑4 inhibitors can be used in Child‑Pugh Class A
for vildagliptin, DPP‑4 inhibitors can be used with caution They should be used with caution in Child‑Pugh Class B
without dose modification. More specifically, DPP‑4 inhibitors DPP‑4 inhibitors are not preferred in Child‑Pugh Class C patients
may be used in Child‑Pugh Class A patients while their use DPP‑4: Dipeptidyl peptidase‑4
do not cause hepatotoxicity.[98‑100] No case reports describing at baseline had a slight but significant reduction of ALT from
alterations of liver tests with SGLT‑2 inhibitors have been baseline and 39% achieved normal ALT by week 104. Hence,
reported so far. adjunctive exenatide treatment was well tolerated and caused
improvements in hepatic biomarkers, ALT, and AST.[107]
Current place in guidelines/recommendations
Guidelines are inconclusive regarding the use of SGLT2 PKs of liraglutide was studied in an open‑label trial in which
inhibitors in patients with liver dysfunction. a single‑dose (0.75 mg injected subcutaneously) of liraglutide
Prescribing information was compared in four groups of six patients each with
PI available with dapagliflozin and canagliflozin recommends healthy, mild, moderate, and severe HI.[108] In this study, mean
no dosage adjustment for patients with mild, moderate, or AUC ∞ was highest for healthy controls and lowest for patients
severe HI.[101,102] However, it is suggested that benefit‑risk with severe HI (severe/healthy: 0.56, with 90% confidence
for the use in patients with severe HI should be individually interval [CI] 0.39, 0.81). Cmax also tended to decrease with
assessed since the safety and efficacy had not been specifically HI (severe/healthy: 0.71, with 90% CI 0.52, 0.97), but Tmax was
studied in this population. Empagliflozin may be used in similar across groups (11.3–13.2 h). However, half‑life was not
patients with HI.[103] affected by HI. It was concluded that differences in the overall
exposure (AUC∞) of liraglutide might result primarily from
On the basis of available evidence, we recommend that SGLT‑2 differences in absorption of the drug from the subcutaneous
inhibitors can be used with caution and lower doses should depot rather than differences in its subsequent metabolism.
be considered during initiation of therapy in CLD patients. Nevertheless, a decrease in albumin concentration in CLD may
These agents are contraindicated in severe liver dysfunction. also result in an increased rate of metabolism of liraglutide by
The risk of dehydration and hypotension is associated with the various enzymes as it is majorly bound to plasma albumin.
use SGLT‑2 inhibitors; hence, caution is required. Precisely, However, this PK effect, resulting in lower plasma levels,
SGLT‑2 inhibitors are safe in Child‑Pugh Class A patients; might be compensated for by a possible enhanced PD effect
however, they should be used with caution in Class B patients. in the setting of reduced circulation. Thus, the results indicate
Agents of this class should better be avoided in Class C that patients with T2DM and CLD can use standard treatment
patients [Table 8]. regimens of liraglutide. There is, however, currently limited
clinical experience with liraglutide in patients with HI.[108]
Dose modification of injectable drugs in chronic liver
disease The effectiveness of liraglutide was studied in Japanese patients
Glucagon‑like peptide‑1 receptor agonists with NAFLD. Liraglutide not only improved T2DM but also
Published scientific evidence resulted in improvement of liver inflammation, alteration of
Hepatic metabolism is not the main pathway for the elimination liver fibrosis, and reduction of body weight.[109] A meta‑analysis
of GLP‑1RAs. Exenatide is primarily eliminated by kidney. of the “Liraglutide Effect and Action in Diabetes” program
Liraglutide and dulaglutide are endogenously metabolized into concluded that a 26‑week therapy with liraglutide 1.8 mg is
their component amino acids by general protein catabolism safe, well tolerated and improves liver enzymes in patients
pathways. No specific organ is presumed to be major route of with T2DM.[110]
elimination for GLP‑1RAs.[104‑106] Dulaglutide is now available for use in India. Not enough
No PK study has been performed in patients with a diagnosis information is available about its PK behavior in HI patients.
of acute or chronic HI for exenatide.[15,104] An interim analysis PI states that systemic exposure of dulaglutide decreased by
of data from the open‑label, uncontrolled extension of 23%, 33%, and 21% for mild, moderate, and severe HI groups,
three double‑blind, placebo‑controlled trials examined the respectively, compared to individuals with normal hepatic
metabolic effects of 2 years of exenatide treatment in patients function, and Cmax was decreased by a similar magnitude.[106]
with T2DM. Patients with normal baseline ALT had no Current place in guidelines/recommendations
significant ALT change. However, patients with elevated ALT A review article by Khan et al. recommends no dose adjustment
of GLP‑1RAs as there is limited experience of use in HI
Table 8: Expert group recommendation 8: Dose patients. However, it should be used with caution.[16]
modification of sodium‑glucose co‑transporter 2 inhibitors Prescribing information
in chronic liver disease There is limited information available about the safety and
SGLT‑2 inhibitors may be used with caution efficacy of GLP‑1RAs in HI patients; hence, PI of respective
These agents are contraindicated in severe liver dysfunction products advises cautious use in this patient population.
SGLT‑2 inhibitors are safe in Child‑Pugh Class A patients However, there is no dosage adjustment recommended.[104‑106]
SGLT‑2 inhibitors should be used with caution in Child‑Pugh Class B
patients On the basis of available evidence, we recommend that
They should be avoided in Child‑Pugh Class C patients GLP‑1RAs should be used with caution without dose
Caution is advised due to risk of dehydration and hypotension modification in CLD patients. Drugs of this class can be
SGLT‑2: Sodium‑glucose co‑transporter 2 administered to Child‑Pugh Class A patients. However, due to
scarcity of data in HI patients, GLP‑1RAs should be avoided and reduced appetite and hence have the option of using
in Class B and C patients [Table 9]. rapid‑acting insulin analogs just after their meals depending
on their intake.
Insulin and insulin analogs
Published scientific evidence Current place in guidelines/recommendations
The major site of the metabolism for circulating insulin is liver. Guidelines from the ADA highlight the importance of insulin
Approximately 40%–50% of the endogenous insulin produced and suggest frequent dose adjustment and careful glucose
by the pancreas is metabolized by the liver.[111] Insulin therapy monitoring for T2DM and CLD patients. [43] Similarly,
is considered as the safest and most effective therapy in patients consensus guideline by EASLGD recommends use of insulin
with liver dysfunction, with the limitation of increased risk of with caution and suggests that dose should be adjusted
hypoglycemia. frequently in CLD patients.[38] Indian guidelines also supported
the use of insulin in hepatic decompensation patients.[44,69]
Hyperinsulinemia and peripheral IR are frequent and Expert opinion by Scheen et al. mentions that insulin can be
well‑documented complications of advanced liver fibrosis used in patients with all stages of CLD and does not exert
and cirrhosis. In cirrhosis, higher insulin secretion rate and hepatotoxic effects. However, the dose of insulin required
markedly reduced hepatic clearance may be responsible for in cirrhotic patients for optimal glucose control without
hyperinsulinemia. However, insulin requirement may vary hypoglycemia should be carefully adjusted upon individual
in decompensated liver disease patients. It may be decreased basis and blood glucose monitoring. Insulins may be the safest
due to reduced capacity for gluconeogenesis and reduced agents and dose adjustment should be individualized.
hepatic breakdown of insulin; however, it can be increased to
compensate for IR. Due to these opposing factors, daily dose Prescribing information
required to control blood glucose is difficult to predict in case PI of insulin glargine, insulin glulisine, insulin aspart 30/70,
when exogenous insulin is necessary.[15,38] insulin degludec, and insulin degludec/insulin aspart was
reviewed for dose modification or special recommendations
Insulin is the first‑line agent to treat diabetes in CLD such as in HI patients. It is suggested that frequent glucose
cirrhosis or chronic hepatitis. Short‑acting insulins are preferred monitoring and dose adjustments are required to minimize
because the duration of action may vary in such situations.[112] the risk of hypoglycemia or hyperglycemia in this patient
Without increasing costs, insulin analogs may offer equivalent population.[116‑119]
or improved glycemic control compared to standard insulin
Based on the available evidence, we recommend that dose
while being associated with a lower risk for hypoglycemia,
of insulin should be titrated to requirements to reduce risk of
particularly nocturnal and severe hypoglycemia.
hypoglycemia. Moreover, newer insulin analogs are preferred
Insulin therapy can be used at any stage of HI although clinical in CLD patients as their PK is unaltered and possesses low
studies are scarce in insulin‑treated diabetic patients with CLD. risk of hypoglycemia [Table 10].
There is no single study reporting extensive experience with
insulin analogs in patients with CLD.[15] In a study with insulin Conclusion
degludec, 24 individuals (normal hepatic function, Child‑Pugh
T2DM and CLD may need to be managed together. The major
Grade A, B, or C) were administered a single subcutaneous
challenge is the risk of altered metabolism of ADAs in case
dose of 0.4 U/kg insulin degludec. No difference was observed
of HI; hence, there are chances of exaggerated response to a
in area under the 120‑h serum insulin degludec concentration–
standard dose of medication and a higher risk of side effects.
time curve (AUC0‑120), Cmax, and apparent clearance (CL/F)
for individuals with impaired versus normal hepatic function.
It was concluded that ultra‑long PK properties of insulin Table 9: Expert group recommendation 9: Dose
degludec were preserved in patients with HI and there were no modification of glucagon‑like peptide‑1 receptor agonists
statistically significant differences in absorption or clearance in chronic liver disease
compared to normal controls.[113] GLP‑1 agonists may be used with caution without dose modification
GLP‑1 agonists can be used in Child‑Pugh Class A patients
PKs of insulin aspart was studied in patients with varying
They should be avoided in Child‑Pugh Class B patients
degrees of HI without diabetes. There was no clinically
GLP‑1 agonists should be avoided in Child‑Pugh Class C patients
significant impact of HI on PKs of insulin aspart.[114] In a GLP‑1: Glucagon‑like peptide‑1
case report, efficacy of insulin (detemir) was studied in two
patients with significant NAFLD and hypertriglyceridemia.
Insulin (detemir) appeared less efficacious in achieving Table 10: Expert group recommendation 10: Dose
glycemic control in such patients. Very high insulin doses were modification of insulin in chronic liver disease
required, and weight gain was problematic.[115] Dose of insulin needs to be titrated to requirements to reduce risk of
hypoglycemia
The PKs and PDs of rapid‑acting insulin analogs suggest Newer insulin analogs may be preferred as their PK is unaltered in CLD
that they can be given just after meals. This is of benefit to and have a low risk of hypoglycemia
many patients with advanced CLD as they may have nausea CLD: Chronic liver disease, PK: Pharmacokinetic
Therefore, careful and judicial selection of an antidiabetic Conflicts of interest

agent is important in patients with associated CLD. There are no conflicts of interest.
Older antidiabetic drugs such as metformin and SUs have
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Consensus Statement On Dose Modifications of Antidiabetic Agents in Patients With Hepatic Impairment

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Consensus Statement on Dose Modifications of Antidiabetic

Keywords: Antidiabetic agents, hepatic impairment, type 2 diabetes mellitus

Introduction diabetes, by most estimates, is now the most common cause

Figure 2: Etiology of liver disease associated with diabetes mellitus. DM:

glycemic control with limited clinical effectiveness and

Tissue hypoxia is supposed to be a risk factor for lactic acidosis.

Thiazolidinediones and total bilirubin before initiating therapy. Caution is

Therefore, careful and judicial selection of an antidiabetic Conflicts of interest

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