Oral Antidiabetics in Specific Conditions

Budiman Darmowidjojo

Introduction
With the advancement of science and technology, now there are various antidiabetic agents
available in the market. Each of them has their own benefits and side effects. This article will
discuss oral antidiabetics use in specific conditions, which are chronic liver disease, chronic renal
disease, cerebrovascular disease, and cardiovascular disease.

Oral Antidiabetics in Chronic Liver Disease

While some antidiabetics are remained safe to be used in chronic liver disease, other
antidiabetics are contraindicated. See Table 1 for discussion of each oral antidiabetics in chronic
liver disease.1

Table 1. Oral antidiabetics in chronic liver disease1

Antidiabetics Comments
Alpha-glucosidase Safe in chronic liver disease, alcoholic cirrhosis, and mild hepatic
inhibitor encephalopathy.
Biguanide  Not recommended in liver cirrhosis because risk of lactic acidosis
(however, this complication was reported only in anecdotal cases
with concomitant alcohol intake).
 Conflicting results in simple stetosis and nonalcoholic fatty liver
disease. Most results showing normalization of transaminases and
histological improvement.
 Associated with reduced risk of hepatocellular carcinoma.
Thiazolidinedione  Poorly studied in patients with chronic liver disease.
 Should be used with careful monitoring in patients with serum
transaminases 2.5 times normal. It should be discontinued if
serum transaminases remain high or increased.
 Avoid its use in Child-Pugh stage C cirrhosis.
Sulfonylurea  Higher risk of severe hypoglycemia in chronic liver disease
 Its use may be limited in alcoholic individuals due to damage of
beta cells of pancreatic islets.
 Its pharmacodynamic features have not been evaluated in
patients with chronic liver disease.
 Glibenclamide and gliclazide has been reported to cause
hepatotoxicity. Therefore, they are not recommended in severe
hepatic impairment.
 Meglitinide  Repaglinide is contraindicated in patients with advanced liver
insufficiency because its rate of elimination is significantly
reduced in chronic liver disease.
 Nateglinide is expected to be safer because its pharmacodynamic
is not altered in chronic liver disease.
SGLT-2 inhibitor  Administration of dapagliflozin to cirrhotic patient should be
individually assessed because long-term safety profile and
efficacy has not been specifically studied in this population.
 Canagliflozin and empaglizflozin are well tolerated in patients
with mild and moderate liver impairment. However, there is no
study of their chronic use in patients with severe liver impairment
(Child-Pugh stage C group).

Oral Antidiabetics in Chronic Kidney Disease

According to International Diabetes Federation guideline in 2017, most oral antidiabetics are
contraindicated in severe chronic kidney disease (CKD). See Table 2 for further information.2

Table 2. Oral antidiabetic in chronic kidney disease2

CKD stage 3A and 3B CKD stage 4 and 5

Metformin Reduce dose in stage 3A, Contraindicated
contraindicated in stage 3B
Sulfonylurea Caution higher risk of Contraindicated, except
hypoglycemia glipizide and gliclazide
Glinides Caution higher risk of Contraindicated
hypoglycemia
Pioglitazone Neutral Neutral
Alpha-glucosidase Neutral Contraindicated
inhibitors
DPP-4 inhibitors Neutral, but must reduce Neutral, but must reduce
dose, except linagliptin dose, except linagliptin
SGLT-2 inhibitors Contraindicated in stage 3B Contraindicated

Oral Antidiabetics in Cerebrovascular Disease

When considering antidiabetic treatment in stroke patients, three different situations must be
considered: preadmission use of antidiabetic drugs; antidiabetic drugs use after acute stroke; and
antidiabetic drug use in patients with anamnestic stroke.3

In a Danish follow-up study of 4,817 patients hospitalized with ischemic stroke, the preadmission
uses of metformin, insulin, and patients without antidiabetic pharmacotherapy had a lower 30-
day mortality compared with users of sulfonylurea. However, no significant differences were
observed in 1-year mortality rates.3
Hyperglycemia during acute stroke associated with poor outcome. Therefore, antidiabetics are
needed in acute stroke. However, there is no certain recommendation on oral antidiabetic use
during stroke. Insulin is more preferred in acute stroke setting. Furthermore, metformin is
contraindicated in patients within 2 weeks after stroke.

No data of antidiabetic drug use in patients with anamnestic stroke.

Oral Antidiabetics in Cardiovascular Disease

In 2007, a meta-analysis found an association between rosiglitazone use and increased risk of
myocardial infarction. This finding arouses a concern of antidiabetic cardiovascular safety. Large
scale clinical trials of antidiabetic cardiovascular safety profiles had been conducted. Antidiabetics
that has been tested include pioglitazone, DPP-4 inhibitors, GLP-1 agonist, and SGLT-2 inhibitors.
All of those drugs are proved to safe in primary endpoint (composite of death from cardiovascular
causes, non-fatal myocardial infarction, and non-fatal stroke).4

While pioglitazone and SGLT-2 inhibitor showed to reduce primary endpoint, DPP-4 inhibitors
were not proved to be beneficial for cardiovascular outcomes. Moreover, saxagliptin, alogliptin,
and vildagliptin showed to increase risk of hospitalization for heart failure. This disadvantage does
not apply to all class of DPP-4 inhibitors, because sitagliptin did not exhibit similar risk.4

Conclusion
Clinician should exercise caution when giving oral antidiabetics to patients with specific
conditions, whether it is chronic liver disease, chronic kidney disease, cerebrovascular disease, or
cardiovascular disease.

Keywords
oral antidiabetics; chronic liver disease; chronic kidney disease, cerebrovascular disease,
cardiovascular disease

References
1. Garcia-Compean D, Gonzalez-Gonzales JA, Lavalle-Gonzalez FJ, Gonzalez-Moreno EI,
Maldonado-Garza HJ, Villarreal-Perez JZ. The treatment of diabetes mellitus of patients with
chronic liver disease. Ann Hepatol. 2015;14(6):780-8.
2. International Diabetes Federation. IDF clinical practice recommendations for managing type 2
diabetes in primary care. Belgium: International Diabetes Federation; 2017.
3. Tschope D, Hanefeld M, Meier JJ, Gitt AK, Halle M, Bramlage P, et al. The role of co-morbidity
in the selection of antidiabetic pharmacotherapy in type-2 diabetes. Cardiovascular Diabetol.
2013;12:62.
4. Bae JC. Diabetes drugs and cardiovascular safety. Endocrinol Metab. 2016;31:239-44.