Oral hypoglycaemic choice in chronic kidney disease

What it is

This is the decision of which diabetes agent may be used as kidney function falls. It turns on the estimated glomerular filtration rate rather than on the serum creatinine level, because the eGFR equation includes age, sex, race, and other parameters.

How it is treated

Metformin is recommended as first-line therapy as long as there are no contraindications, and it is used in type 2 diabetes to reduce microvascular complications, assist in weight management, reduce the risk of cardiovascular events, and reduce the risk of mortality. Until recently metformin was contraindicated for patients with renal dysfunction suggested by a creatinine level of 1.5 mg/dL for men and 1.4 mg/dL for women, but available evidence now supports the use of metformin in individuals with mild to moderate chronic renal disease defined by the eGFR. Patients with an eGFR between 45 and 60 mL/min/1.73 m2, that is chronic mild kidney disease, are now permitted to take metformin. Metformin should not be used in patients with an eGFR below 45 mL/min/1.73 m2, which is moderate kidney disease. Patients who are intolerant of metformin are unlikely to be successful with a third trial of that agent, and empagliflozin, an SGLT2 inhibitor, is considered a second-line choice for them; empagliflozin has also been associated with secondary prevention of cardiovascular disease. Among the GLP-1 receptor agonists, which are liraglutide, exenatide and dulaglutide, only liraglutide has been shown to lower the risk of recurrent cardiovascular events and has received FDA approval for this indication, while glipizide, rosiglitazone and sitagliptin have not been associated with improved cardiovascular outcomes. For the target, a healthy person with a reasonable life expectancy should have a hemoglobin A1c goal below 7%; if the hemoglobin A1c is not at the goal or is 9% or more, then adding another agent to metformin is recommended, and basal insulin at 10 units/day is an acceptable choice, with diet, exercise and home monitoring of blood glucose recommended in addition.

The classes each have a named example to hang them on: gliclazide and glibenclamide for the sulfonylureas, sitagliptin for the DPP-4 inhibitors, exenatide and dulaglutide for the GLP-1 receptor agonists, and dapagliflozin and canagliflozin for the SGLT2 inhibitors. Set out by mechanism and by main side effect, metformin increases insulin sensitivity and decreases hepatic gluconeogenesis, with gastrointestinal upset and lactic acidosis; sulfonylureas stimulate pancreatic beta cells to secrete insulin, with hypoglycaemia, weight gain and hyponatraemia; thiazolidinediones activate the PPAR-gamma receptor in adipocytes, with weight gain and fluid retention, pioglitazone being the only one currently available; DPP-4 inhibitors increase incretin levels which inhibit glucagon secretion, generally well tolerated but with an increased risk of pancreatitis; SGLT-2 inhibitors inhibit reabsorption of glucose in the kidney, with urinary tract infection as the main side effect; and GLP-1 agonists are incretin mimetics which inhibit glucagon secretion, given subcutaneously, with nausea, vomiting and pancreatitis. The last two typically result in weight loss.

An acute illness changes the list again, and the sick day rules say which drugs are held. In diabetes: hold metformin, sulfonylureas and SGLT2 inhibitors; insulin is not held, and the patient checks the glucose regularly, continues to take the insulin, takes enough carbs and drinks enough fluids, with care if the glucose is too high. Chronic steroids move the other way: the usual daily dose is doubled for a mild to moderate illness, and the patient must notify the doctor or surgeon if admitted with a severe illness, when a stress dose is usually given.

The second-line agent is chosen by the comorbidity. In atherosclerotic cardiovascular disease a GLP-1 receptor agonist such as liraglutide, or an SGLT2 inhibitor such as empagliflozin, is chosen for proven cardiovascular benefit. In heart failure an SGLT2 inhibitor reduces hospitalizations and cardiovascular mortality. In chronic kidney disease an SGLT2 inhibitor slows progression of the disease. Where hypoglycemia must be avoided, a DPP-4 inhibitor, a GLP-1 receptor agonist or an SGLT2 inhibitor has a safe profile. Where weight loss is desired, a GLP-1 receptor agonist or an SGLT2 inhibitor promotes it, and where cost is a concern a sulfonylurea such as gliclazide, or metformin, is inexpensive and effective.