Diabetes Drugs Account for Renal Impairment

Case

A 68-year-old female with a history of type 2 diabetes mellitus (DM), hypertension, and chronic kidney disease presents to the clinic complaining of increasing hypoglycemic events. Recent laboratory findings include an A1c level of 6.8% (American Diabetes Association goal, lower than 7%) and worsening renal function, with a serum creatinine (SCr) level of 2.1 mg/dL (previously, 1.6 mg/dL; normal range: 0.6 to 1.1 mg/dL) and an estimated glomerular filtration rate (eGFR) of 28 mL/min (previously, 40 mL/min). Current medications include glyburide, 5 mg/d; lisinopril, 20 mg/d; amlodipine, 10 mg/d; aspirin, 81 mg/d; and atorvastatin, 20 mg/d.

Discussion

The prevalence of type 2 DM is increasing worldwide, making it imperative that safe and efficacious medications are available to manage this disorder. However, DM management often is complicated by the presence of comorbid conditions and increasing age.

Moderate to severe renal impairment (defined as eGFR lower than 60mL/min) occurs in about 20% to 30% of patients with DM, and it presents specific difficulties for the clinician and the patient.¹ Changes in renal function affect most DM medications; therefore, the clinician must be aware of the doses and contraindications associated with reduced clearance as well as adverse effects associated with their use, especially in renal impairment.

Patients with DM and renal impairment are at increased risk for hypoglycemia and even death.² This increased risk is in large part caused by the reduced clearance of insulin as well as most medications that are available to manage DM. As seen in the case above, this risk is a serious concern in patients with chronic kidney disease, one that can complicate treatment.

Metformin, most often the first-line agent in the treatment of patients with DM, has particular concerns in renal impairment. The drug is renally eliminated, and although lactic acidosis is rare, the risk is increased in patients with decreased renal function. Current prescribing guidelines list an SCr level of 1.5 mg/dL or higher in men or 1.4 mg/dL or higher in women as a contraindication to its use,³ although this is controversial. Other data suggest that the use of metformin may be continued until the eGFR falls below 30 mL/min, with a dose reduction occurring when the eGFR falls below 45 mL/min.⁴

Sulfonylureas, a common second-line option, are associated with a higher risk of hypoglycemia than metformin and other oral therapies. These agents also exhibit decreased elimination in the setting of renal impairment and therefore place the patient at greater risk for hypoglycemia with decreased clearance of the drug. This risk is of particular concern with glyburide, as seen in the case above, because of a prolonged duration of action and active metabolites; therefore, the use of this drug should be avoided, especially in older patients and those with renal impairment. Other sulfonylureas (glimepiride and glipizide) require dosage adjustment for patients with severe renal impairment and should be used with caution in patients with kidney disease because they can increase the risk of hypoglycemia.¹

Because the thiazolidinedione pioglitazone is not eliminated renally, there are no dosing restrictions in this population. However, fluid retention and edema are common adverse effects of this medication.¹ They may be of concern and limit its use, especially in patients with kidney disease.

The incretin agents are one of the newest classes of medications for the management of DM. They include the dipeptidyl peptidase-4 (DPP-4) inhibitors as well as the glucagon-like peptide-1 (GLP-1) agonists exenatide and liraglutide.

GLP-1 increases the glucose-dependent stimulation of insulin and suppression of glucagon secretion, and it has other beneficial effects, such as delaying gastric emptying and increasing satiety. The GLP-1 agonist exenatide is contraindicated in severe renal impairment (creatinine clearance [CrCl] less than 30 mL/min), and because this drug can cause nausea and vomiting, caution is advised in patients with moderate renal impairment-worsening renal function has been noted with hypovolemia.⁵ Although no dosage adjustment is needed with liraglutide, there are limited data regarding its use in severe renal impairment. In addition, warnings similar to those with exenatide regarding the potential for worsening renal function require the drug be used with caution, especially in patients with kidney disease.⁶

DPP-4 inhibitors meanwhile have garnered increased interest, especially for use in older patients and in patients with kidney disease. The agents in this class, which include sitagliptin, saxagliptin, alogliptin, and linagliptin, inhibit the breakdown of endogenous GLP-1 and can be used for initial monotherapy for patients with DM; they have been studied in combination with metformin, sulfonylureas, and pioglitazone. Although they lower the A1c level only modestly, they generally are well tolerated by most patients who have little or no hypoglycemia.¹ This minimal risk of hypoglycemia is especially intriguing in the setting of kidney disease because decreased clearance of the drug, resulting in higher drug levels, should not result in an increased risk of hypoglycemia.

Although the risks with DPP-4 inhibitors are minimal, 3 of the available drugs do need dose reduction in moderate-severe renal insufficiency. Sitagliptin is available in 100-mg tablets taken once daily with a dose reduction to 50 mg/d, with a CrCl of 30 to 49 mL/min, and a dose of 25 mg/d, with a CrCl lower than 30 mL/min.⁷ Saxagliptin, typically dosed at 5 mg/d, also requires a dosage reduction to 2.5 mg/d in patients with a CrCl lower than 50mL/min.⁸ Alogliptin, the newest agent, requires adjustment when the CrCl falls below 60mL/min and then again when less than 30 mL/min.⁹ Linagliptin, also dosed at 5 mg/d, requires no dosage adjustment with renal impairment and has been shown to be safe and effective even in severe renal impairment (eGFR less than 30 mL/min).^10,11 The patient in the case above may benefit from a switch to a DPP-4 inhibitor, such as linagliptin, to maintain glycemic control while reducing the risk of hypoglycemia.

Conclusions

Chronic kidney disease is common in patients with type 2 DM and can complicate the treatment of these patients, especially when available noninsulin therapies are considered. Clinicians should be aware of the concerns and consequences associated with current type 2 DM therapies when they are used in patients with renal impairment and, when appropriate, consider discontinuation or dose reduction. The DPP-4 inhibitors may be a safe and effective alternative in these patients, especially linagliptin, which requires no dosage adjustment in patients with kidney disease.

References:

1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). [Erratum in: Diabetes Care. 2013;36:490.] Diabetes Care. 2012;35:1364-1379.

2. Moen MF, Zhan M, Hsu VD, et al. Frequency of hypoglycemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:1121-1127.

3. Package insert – Metformin.

4. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care. 2011;34:1431-1437.

5. Package insert – Exenatide.

6. Package insert – Liraglutide.

7. Package insert – Sitagliptin.

8. Package insert – Saxagliptin.

9.  Package Insert – Alogliptin.

10. Package insert – Linagliptin.

11. McGill JB, Sloan L, Newman J, et al. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care. 2013;36:237-244.