MOST ORAL DIABETES DRUGS ARE CONTRAINDICATED IN ESRD
Sulfonylureas
Sulfonylureas reduce blood glucose by stimulating the pancreatic beta cells to increase insulin secretion.
Sulfonylureas have a wide volume of distribution and are highly protein-bound,20 but only the unbound drug exerts a clinical effect. Because of protein binding, dialysis cannot effectively clear elevated levels of sulfonylurea drugs. Furthermore, many ESRD patients take drugs such as salicylates, sulfonamides, vitamin K antagonists, beta-blockers, and fibric acid derivatives, which may displace sulfonylureas from albumin, thus increasing the risk of severe hypoglycemia.
The first-generation sulfonylureas—chlorpropamide (Diabinese), acetohexamide (Dymelor), tolbutamide (Orinase), and tolazamide (Tolinase)—are almost exclusively excreted by the kidney and are therefore contraindicated in ESRD.21 Second-generation agents include glipizide (Glucotrol), glimepiride (Amaryl), glyburide (Micronase), and gliclazide (not available in the United States). Although these drugs are metabolized in the liver, their active metabolites are excreted in the urine, and so they should be avoided in ESRD.22
The only sulfonylurea recommended in ESRD is glipizide, which is also metabolized in the liver but has inactive or weakly active metabolites excreted in the urine. The suggested dose of glipizide is 2.5 to 10 mg/day. In ESRD, sustained-release forms should be avoided because of concerns of hypoglycemia.23
Meglitinides
The meglitinides repaglinide (Prandin) and nateglinide (Starlix) are insulin secretagogues that stimulate pancreatic beta cells. Like the sulfonylureas, nateglinide is hepatically metabolized, with renal excretion of active metabolites. Repaglinide, in contrast, is almost completely converted to inactive metabolites in the liver, and less than 10% is excreted by the kidneys.24,25 The meglitinides still pose a risk of hypoglycemia, especially in ESRD, and hence are not recommended for patients on hemodialysis.24,25
Biguanides
Metformin (Glucophage) is a biguanide that reduces hepatic gluconeogenesis and glucose output. It is excreted essentially unchanged in the urine and is therefore contraindicated in patients with renal disease due to the risks of bioaccumulation and lactic acidosis.22
Thiazolidinediones
The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) are highly potent, selective agonists that work by binding to and activating a nuclear transcription factor, specifically, peroxisome proliferator-activated receptor gamma (PPAR-gamma). These drugs do not bioaccumulate in renal failure and so do not need dosing adjustments.26
The main adverse effect of these agents is edema, especially when they are combined with insulin therapy. Because of this effect, a joint statement of the American Diabetes Association and the American Heart Association recommends avoiding thiazolidinediones in patients in New York Heart Association (NYHA) class III or IV heart failure.27 Furthermore, caution is required in patients in compensated heart failure (NYHA class I or II) or in those at risk of heart failure, such as patients with previous myocardial infarction or angina, hypertension, left ventricular hypertrophy, significant aortic or mitral valve disease, age greater than 70 years, or diabetes for more than 10 years.27
In summary, although ESRD and dialysis do not affect the metabolism of thiazolidinediones, these agents are not recommended in ESRD because of the associated risk of fluid accumulation and precipitation of heart failure.
Alpha-glucosidase inhibitors
The alpha-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) slow carbohydrate absorption from the intestine. The levels of these drugs and their active metabolites are higher in renal failure,22 and since data are scarce on the use of these drugs in ESRD, they are contraindicated in ESRD.
GLP-1 ANALOGUES AND ‘GLIPTINS,’ NEW CLASSES OF DRUGS
Glucagon-like peptide-1 (GLP-1) stimulates glucose-dependent insulin release from pancreatic beta cells and inhibits inappropriate postprandial glucagon release. It also slows gastric emptying and reduces food intake. Dipeptidyl peptidase IV (DPP-IV) is an active ubiquitous enzyme that deactivates a variety of bioactive peptides, including GLP-1.
Exenatide (Byetta) is a naturally occurring GLP-1 analogue that is resistant to degradation by DPP-IV and has a longer half-life. Given subcutaneously, exenatide undergoes minimal systemic metabolism and is excreted in the urine.
No dose adjustment is required if the glomerular filtration rate (GFR) is greater than 30 mL/min, but exenatide is contraindicated in patients undergoing hemodialysis or in patients who have a GFR less than 30 mL/min (Table 1).
Sitagliptin (Januvia) is a DPP-IV inhibitor, or “gliptin,” that can be used as initial pharmacologic therapy for type 2 diabetes, as a second agent in those who do not respond to a single agent such as a sulfonylurea,28 metformin,29–31 or a thiazolidinedione,32 and as an additional agent when dual therapy with metformin and a sulfonylurea does not provide adequate glycemic control.28 Sitagliptin is not extensively metabolized and is mainly excreted in the urine.
The usual dose of sitagliptin is 100 mg orally once daily, with reduction to 50 mg for patients with a GFR of 30 to 50 mL/min, and 25 mg for patients with a GFR less than 30 mL/min.33 Sitagliptin may be used at doses of 25 mg daily in ESRD, irrespective of dialysis timing (Table 1).
Other drugs of this class are being developed. Saxagliptin (Onglyza) was recently approved by the US Food and Drug Administration and can be used at a dosage of 2.5 mg daily after dialysis.
Sitagliptin has been associated with gastrointestinal adverse effects. Anaphylaxis, angioedema, and Steven-Johnson syndrome have been reported. The risk of hypoglycemia increases when sitagliptin is used with sulfonylureas.