Application of sulfonylureas in diabetic patients with chronic kidney disease

The number of people living with diabetes (DM) worldwide is increasing every year, and about 34 million children and adults in the United States currently have diabetes, which is common in kidney failure
.
It is important to
understand the safe use of hypoglycemic medications in patients with chronic kidney disease (CKD) to maintain necessary glycemic control, reduce hypoglycemia, and optimize heart and kidney disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in people with diabetes, and CKD further increases the overall risk of CVD in patients
.
Therefore, clinicians should focus not only on glycaemic control, but also on other cardiovascular risk factors such as weight, diet/nutrition, and exercise
.
It is important
to develop personalized blood glucose markers for patients to maintain blood glucose levels, reduce the occurrence and progression of complications, and avoid hypoglycemia.

CKD alters the relationship between blood glucose levels and long-term control indicators, such as glycated hemoglobin
.
As CKD progresses, medications used to treat diabetes may need to be dosed
.
Some drugs have special characteristics
for people with CKD.
Insulin and sulfonylureas increase the risk of hypoglycemia, some glucagon-like peptide 1 receptor agonists reduce the risk of CVD outcomes, and most sodium/glucose cotransporter 2 inhibitors reduce the risk of
CKD and CVD outcomes.
Therefore, for individual patients, changes in drug type and dose may require ongoing attention
as CKD progresses.

Blood sugar control has been shown to slow the progression of
cardiovascular disease and chronic kidney disease.
The American Diabetes Association (ADA) recommends a glycated hemoglobin target of ≤7%
for nonpregnant adults.
The American Diabetes Association (ADA) supports a more lenient target (<8%) for specific patients, such as those with a short life expectancy, a history of severe hypoglycemia, extensive comorbidities, and late complications<b21>.
The American Association of Clinical Endocrinologists (AACE) recommends that glycosylated hemoglobin (HbA1c) should be controlled at ≤6.
5% for healthy patients at low risk of hypoglycemia, but they acknowledge that these goals need to vary
from person to person.

Guides the influencing factors of an individual's HbA1c control target decision-making

Patients with CKD are at increased risk of hypoglycemia after insulin use, especially in the elderly, potentially frail, and osteodystrophy, because falls caused by hypoglycemia can easily lead to serious fractures, so careful monitoring of blood glucose when taking insulin requires careful blood glucose monitoring to safely adjust insulin dose, reduce the risk of hypoglycemia, and achieve glycemic control goals
.

The representative drugs that are easy to cause hypoglycemia among oral hypoglycemic drugs are sulfonylureas
.
Sulfonylureas increase insulin secretion, and currently used sulfonylureas are glipizide, glimepiride, glibenclamide, and glilazide (the latter is not available in the US).

Sulfonylureas reduce glycated hemoglobin by an average of 1.
0% to 2.
0% and are prone to hypoglycemia, especially glibenclamide and chloropropionamide (sometimes still in use as first-generation drugs).

When CKD is combined, the risk of hypoglycemia is increased
due to a decrease in the clearance of sulfonylureas and their metabolites decreases as GFR decreases.

For specific applications, it is recommended that when eGFRs < 60 mL/min/1.
73^m2, glibenclamide can significantly increase the risk of hypoglycemia, and glimepiride can modestly increase the risk of
hypoglycemia.
When eGFR < 60 mL/min/1.
73^m2, glibenclamide
should not be used.
Glimepiride should be used with caution if eGFR < 60 mL/min/1.
73 m2, and discontinued if eGFR < 30 mL/min/1.
73^m2
。 Glipizide and gliclazide do not have an active metabolite cleared by the kidneys, so dose adjustment is not required, however, caution is still required, and when the eGFR < 40 mL/min/1.
73^m2, the use of gliclazide
is not recommended.

Dose adjustment of diabetes drugs in patients with CKD

For patients who already need hemodialysis, it is known that the glycemic response during hemodialysis is very variable and unpredictable, so frequent dose
adjustments may be required.
In peritoneal dialysis (PD), large amounts of glucose in the dialysate may cause significant hyperglycemia
.
In patients receiving ongoing PD, a standard basal/injectable insulin regimen is best
.
In patients receiving nocturnal cyclic PD, a fixed combination of mixed insulin, such as 70/30 or 75/25 insulin, usually better covers the increased glucose load
at the onset of PD.
In order to properly adjust the dose of insulin, it is necessary to inform the patient's endocrinologist about changes in the concentration of glucose in the dialysate, since more or less fluid
is needed.

Overall, close communication and communication between primary care clinicians, nephrologists, diabetes doctors, cardiologists, diabetes and kidney disease educators is important
in deciding how and when to use hypoglycemic agents.
Insulin and sulfonylureas with strong hypoglycemic efficacy should also be used
as appropriate on a clinical basis.

References:

1.
Hahr AJ, Molitch ME.
Management of Diabetes Mellitus in Patients With CKD: Core Curriculum 2022.
Am J Kidney Dis.
2022 May; 79(5):728-736.
doi: 10.
1053/j.
ajkd.
2021.
05.
023.
Epub 2021 Sep 30.
PMID: 34600745.

2.
Lo C, Toyama T, Wang Y, et al.
Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease.
Cochrane Database Syst Rev.
2018 Sep 24; 9(9):CD011798.
doi: 10.
1002/14651858.
CD011798.
pub2.

3.
Tong L, Adler S.
Glycemic control of type 2 diabetes mellitus across stages of renal impairment: information for primary care providers.
Postgrad Med.
2018 May; 130(4):381-393.
doi: 10.
1080/00325481.
2018.
1457397.