Management of type 2 diabetes mellitus in chronic kidney disease

Keywords: :

• Chronic kidney disease
• DPP-4 inhibitors
• Glycemic control
• Linagliptin

Chronic kidney disease (CKD) is a common complication of type 2 diabetes mellitus, with the latter being the main cause of end stage renal disease, which often requires renal replacement therapy1^,2. Increased life expectancy and higher type 2 diabetes mellitus incidence lead to an increase in the number of diabetic patients with CKD. The management of hyperglycemia in type 2 diabetic patients with CKD should be aimed at the use of drugs associated with the lowest possible risk of hypoglycemia3^,4. Hypoglycemia, in fact, is a common, unpredictable and potentially dangerous side effect of anti-diabetic treatment, and it should be avoided. Hypoglycemic episodes may involve neurogenic symptoms such as palpitations, tremor, hunger, and sweating, as well as neuroglycopenic symptoms including behavioral changes, difficulty thinking, confusion, and possibly seizure, coma, and even death5. Treatment with oral anti-diabetic drugs in the initial stages of CKD is relatively safe; however, in advanced stages of CKD, commonly observed in the elderly population, the risk of hypoglycemia increases. According to American Diabetes Association guidelines6, metformin is the first line drug and the drug of choice in the treatment of type 2 diabetes mellitus. However, one of its biggest limitations is that it is mainly eliminated throughout the kidneys and, therefore, it is accumulated in the case of renal failure, with the resulting risk of lactic acidosis according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines7. For this reason, metformin use should be avoided when glomerular filtration rate (GFR) goes <60 ml/min. Sulfonylureas and meglitinides, instead, stimulate endogenous insulin secretion by pancreatic β-cells. Glipizide and gliclazide are recommended in patients with advanced CKD, kidney transplants or those on dialysis, since they do not require dose adjustment, because they are metabolized to inactive compounds7. However, since sulfonylureas are potent hypoglycemic agents, they can produce severe and prolonged hypoglycemia, especially in cases of a reduced GFR, due to their long half-life and the elimination throughout the kidneys either of the unchanged drug or its active metabolites. On the other hand, α-glucosidase inhibitors reduce post-prandial glycemia delaying the conversion of complex carbohydrates to monosaccharides in the intestines. Miglitol is absorbed in the intestines and is not metabolized, but rather eliminated unchanged in urine; however, acarbose is metabolized in the gastrointestinal mucosa, its absorption is low and its elimination throughout the kidneys is <2%. Its use is advised against in advanced stages of CKD (GFR <25 ml/min or serum creatinine >2 mg/dl), and in dialysis8.

Pioglitazone, instead, increases peripheral sensitivity to insulin throughout activation of the peroxisome proliferator-activated receptor-γ9. Pioglitazone has the advantage of not causing hypoglycemia and being potentially beneficial in secondary prevention due to its anti-inflammatory and anti-atherogenic effects10. Given its essentially hepatic metabolism, pioglitazone can be safely used in CKD.

In recent years, the new class of incretins has been developed as an additional option for the treatment of type 2 diabetes mellitus. Incretins are secreted by intestinal L-cells, mainly in response to food intake; the most important incretin, glucagon-like peptide-1 (GLP-1) has several actions including stimulation of insulin secretion and reduction of glucagon secretion, both in a glucose-dependent manner, resulting in a reduced hepatic glucose production, delayed gastric emptying, and increased sense of satiety11–13. GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), that limits GLP-1 time of action in the blood14. Actually two classes of drugs based on the incretin system are available: GLP-1 receptor agonists such as exenatide, liraglutide, and lixisenatide that are resistant to DPP-4 cleavage15, and DPP-4 inhibitors, that delay endogenous degradation of GLP-1, including sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin16. Dipeptidyl peptidase-4 inhibitors have been widely used, because of their efficacy in reducing glycated hemoglobin, and their low risk of hypoglycemia16. Different studies have demonstrated the efficacy and safety of these drugs in CKD17. However, each DPP-4 inhibitor has its own specific properties, and for this reason, recommendations for their use in CKD are different (Table 1). Sitagliptin is mostly eliminated unchanged in the urine and can be used with appropriate dose reduction as renal function declines18. The normal dose, 100 mg once daily, should be reduced to 50 mg once daily for patients with moderate renal impairment (GFR ≥30 to <50 ml/min). In severe renal impairment (GFR <30 ml/min) or end-stage renal disease requiring dialysis, the dose should be further reduced to 25 mg once daily.

Table 1. DPP-4 inhibitor dosing adjustments in chronic kidney disease.

DPP-4 inhibitors	Severe CKD	Moderate CKD	Mild CKD
Sitagliptin	25 mg/day	50 mg/day	100 mg/day
Vildagliptin	50 mg/day	50 mg/day	100 mg/day
Saxagliptin	2.5 mg/day	2.5 mg/day	5 mg/day
Linagliptin	5 mg/day	5 mg/day	5 mg/day
Alogliptin	6.25 mg/day	12.5 mg/day	25 mg/day

CKD: chronic kidney disease.

Vildagliptin is metabolized mostly in the kidneys to inactive metabolites that are eliminated renally19. In patients with moderate or severe renal impairment, it is recommended that the normal daily dose, 50 mg twice daily, be reduced to 50 mg once daily, and that particular caution be applied if giving to patients with end-stage renal disease or those receiving dialysis.

Saxagliptin is mainly metabolized in the liver to an active metabolite that is eliminated in the urine20. For this reason, the normal dose of 5 mg once daily should be reduced to 2.5 mg, once daily, in patients with moderate or severe renal impairment and excluded for patients with end-stage renal disease that requires hemodialysis.

The proportion of alogliptin excreted unchanged in the urine is 60-70%. For this reason, the normal dose of 25 mg once daily should be reduced to 12.5 mg once daily in patients with moderate renal impairment (GFR ≥30 to ≤50 mL/min), and to 6.25 mg once daily in patients with severe renal impairment (GFR <30 mL/min) or end-stage renal disease requiring dialysis21.

Due to its hepatic metabolism, linagliptin is the only gliptin that does not require a dose adjustment in CKD22. Linagliptin can be used in patients with any degree of renal insufficiency without dose adjustment. Phase 3 studies have demonstrated the efficacy and safety of linagliptin as monotherapy and in combination with other oral anti-diabetes drugs and/or insulin23. In this regard, the pooled analysis conducted by Zeng et al.24 confirmed that linagliptin provides clinically meaningful and statistically significant reductions in glycated hemoglobin in patients with inadequately controlled type 2 diabetes mellitus. Linagliptin was well tolerated, with no meaningful changes in body weight and little risk for hypoglycemic episodes except when co-administered with a sulfonylurea; no new safety concerns emerged. Linagliptin also proved to be safe in patients with severe CKD. A study conducted by McGill et al. showed that linagliptin is a safe and effective glucose-lowering treatment in type 2 diabetic patients with moderate-to-severe renal impairment for whom sulfonylurea treatment is no longer sufficient25.

Regarding GLP-1 agonists, exenatide, liraglutide and lixisenatide are not recommended for use in patients with end-stage renal disease or severe renal impairment (GFR <30 ml/min). The clinical experience in patients with moderate renal impairment is very limited15.

Finally, insulin should also be used with caution in patients with CKD, because CKD is associated with insulin resistance and, in advanced CKD, decreased insulin degradation. The latter can lead to a marked decrease in insulin requirement or even the cessation of insulin therapy in patients with type 2 diabetes. Because of the uncertainty in predicting insulin requirements, individualized therapy is essential among patients who have advanced CKD or are initiating dialysis26.

In conclusion, in patients with moderate to severe CKD, the only drugs we can use without dose adjustment are pioglitazone and linagliptin, other drugs should be avoided or used with caution, reducing the daily dose. This should be considered in clinical practice, to avoid complications in already frail patients.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

P.M. and G.D. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.