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Management of Hyperglycemia in Patients with Chronic Kidney Disease

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Management of Hyperglycemia in Patients with Chronic Kidney Disease REVIEW JNEPHROL 2013; 26(4): 629- 635 DOI: 10.5301/jn.5000248 Management of hyperglycemia in patients with chronic kidney disease Patrícia Aires Neto, Henrique Vieira Gomes, Nephrology Department, Coimbra University Hospitals, Mário Campos Coimbra - Portugal Nephrology Department, Coimbra University Hospitals, Coimbra - Portugal Nephrology Department, Coimbra University Hospitals, Coimbra - Portugal UK Prospective Diabetes Study (UKPDS) (2) and Kumamoto ABSTRACT studies (3) regarding patients with type 2 diabetes mellitus. Diabetes currently accounts for approximately 45% of The randomized STENO-2 study (4) was designed to as- cases of end-stage renal failure in patients undergo- sess the effects of intensive multifactorial therapy (a low-fat ing hemodialysis. Several observational studies have diet, the use of angiotensin-converting enzyme [ACE] inhibi- identified a positive correlation between measures of tors, vitamins C and E, and aspirin as secondary preven- glycemic control and cardiovascular and microvascu- tative measures) and antidiabetic drug therapy in patients lar benefits. Several randomized prospective studies with type 2 diabetes mellitus and microalbuminuria, with have been conducted to quantify the impact of strict a therapeutic target of glycated hemoglobin (HbA1c) below glycemic control on morbidity and mortality. These 6.5%. The results showed that the patients in the intensive studies have consistently demonstrated an associa- treatment group displayed delayed progression to nephrop- tion between strict glycemic control and a reduction athy, retinopathy and diabetic autonomic neuropathy. The in microvascular events, but these results contrast ADVANCE (5) study corroborated the known benefit associ- with the lack of consistent results regarding macro- vascular events. Treating diabetes has always been ated with stricter glycemic control (defined by a target value below 6.5%) based on the positive impact of limit- challenging. This challenge is increased in chronic of HbA1c kidney disease, due to changes in the pharmacoki- ing the onset and evolution of nephropathy in type 2 diabe- netics and pharmacodynamics of insulin and most tes mellitus. oral antidiabetic agents. The available pharmacother- Uremia alone alters absorption by delaying gastric emp- apeutic arsenal for treating type 2 diabetes mellitus tying and limiting the absorptive phase with respect to currently involves approximately 6 different pharma- intestinal wall edema. Delayed gastric emptying can be cological classes of oral antidiabetic agents and dif- reversibly aggravated by hyperglycemia (6), or it can result ferent modalities of insulin therapy. from gastroparesis in the context of diabetic autonomic neuropathy (7). Key words: Chronic kidney disease, Diabetes mellitus, Drug distribution can be impaired by quantitative changes Treatment (hypoalbuminemia – nephrotic syndrome) or qualitative changes (drug displacement by accumulated acids or ure- mia-induced changes in albumin’s tertiary and quaternary INTRODUCTION structures). These changes have particularly important im- plications in the presence of high levels of plasma protein The optimization of glycemic control in diabetes mellitus binding, which is seen with oral antidiabetics (8). delays the onset of microvascular complications such as Because no significant pharmacokinetic changes have been microalbuminuria and alleviates the decline in glomeru- observed with the use of oral antidiabetics in chronic kidney lar filtration rate (GFR). These results were demonstrated disease (CKD) stages 1 and 2, the use of these drugs is con- in the Diabetes Diabetes Control and Complications Trial / sidered safe (9). The treatment of type 2 diabetes mellitus can Epidemiology of Diabetes (DCCT/EDIC) (1) study which was follow the current recommendations of the American Diabe- conducted in patients with type 1 diabetes mellitus and the tes Association (ADA), which were made in early 2012 (10). © 2013 Società Italiana di Nefrologia - ISSN 1121-8428 629 Neto et al: Glycemic control in CKD Insulin degradation is only markedly impaired in severe MONITORING GLYCEMIC CONTROL renal dysfunction, when the GFR decreases to values below 15-20 ml/min; until this stage, decreased insulin Serial measurements of HbA1c facilitate the monitoring of degradation is compensated for by tubular secretion. the effectiveness of antidiabetic therapy; however, there Uremia reduces insulin degradation by the liver, but this are some concerns and interference may arise regarding condition can be reversed by instituting renal replace- their dosage determinations in renal failure. Hemoglobin ment therapy (18). carbamylation, which occurs in uremia and metabolic aci- Increased insulin secretion can be observed under nor- dosis, can be associated with false HbA1c elevations (11). mal conditions with the purpose of normalizing plasma In contrast to the shortened lifespan of red blood cells, ac- glucose. Reduced insulin pancreatic secretion (which is celerated erythropoiesis due to the use of erythropoiesis- apparently related to metabolic acidosis) with secondary stimulating agents and frequent transfusions is associated hyperparathyroidism is usually observed in CKD and in- with falsely normalized HbA1c levels (11). Regardless of terferes with the ability of pancreatic beta cells to secrete the limitations of measuring HbA1c, this method is consid- insulin (19). ered to be useful for monitoring glycemic control in renal failure. MANAGEMENT OF HYPERGLYCEMIA IN Glycemic control should be considered adequate in dia- PATIENTS WITH DIABETES AND CKD betic patients undergoing hemodialysis when their fast- ing blood glucose levels are below 140 mg/dL, their postprandial blood glucose is below 200 mg/dl and their Use of insulin HbA1c values fall between 6% and 7% for type 1 diabe- tes mellitus and between 7% and 8% for type 2 diabetes Prandial insulin preparations obtained through recombinant mellitus (12). DNA techniques are currently available, and they are divided Shurraw et al carried out a retrospective cohort study with into short-acting human insulin (regular) and fast-acting in- 1,484 patients to determine whether worse glycemic control sulin analogues (insulin lispro, aspart and glulisine). Interme- as measured using serum glucose and HbA1c level was inde- diate-acting insulin (human) and long-acting analogues are pendently associated with higher mortality in these patients. available as basal insulin. They found that higher casual glucose and HbA1c levels Studies of insulin therapy in different stages of CKD are were not associated with mortality in patients undergoing quite limited (20). However, given the risk for hypoglyce- hemodialysis (13). mia that is simultaneously accompanied by an increase in Recognizing the paucity and inconsistency of the data, pub- insulin resistance, fast-acting and long-acting analogues lished guidelines for glycemic control in dialysis patients are are preferred (21). Rave et al (22) conducted a study on classified as “weak” in their evidence base and caution cli- a small population of type 1 diabetic patients with and nicians regarding the risk of hypoglycemia when following without diabetic nephropathy and with and without renal guidelines developed for the general population. failure, and they compared the differences in pharmaco- kinetics and pharmacodynamics between regular insulin ABNORMALITIES IN CARBOHYDRATE AND and insulin lispro. The authors concluded that plasma in- sulin levels are higher and the metabolic response to reg- INSULIN METABOLISM IN CKD ular insulin is lower in patients with diabetic nephropathy The kidney plays a central role in insulin clearance; 60% and renal failure. This result is in contrast to the stability of renal insulin clearance depends on glomerular filtration, and safety of insulin lispro with respect to its pharmacoki- and the remainder depends on secretion from peritubular netic and pharmacodynamic properties in the same popu- capillaries (14-17). Less than 1% of intact insulin is found lation. Aisenpreis et al (23) demonstrated that the pulsatile in urine. pharmacokinetic profile of insulin lispro may facilitate the The liver is responsible for eliminating 50% of the portal correction of hyperglycemia and may reduce the risk of insulin, and a significantly relevant first-pass effect exists. hypoglycemic events, which is particularly important for Insulin that is administered parenterally or subcutaneously the type 1 and 2 diabetic population undergoing hemo- is primarily eliminated by the kidney. This aspect is particu- dialysis. larly relevant to the diabetic population experiencing renal Toyoda et al (24) demonstrated that in 14 hemodialysis un- failure while receiving insulin therapy (18). dergoing patients who were being treated with neutral prot- 630 © 2013 Società Italiana di Nefrologia - ISSN 1121-8428 JNEPHROL 2013; 26(4): 629- 635 amine Hagedorn (NPH) based basal-bolus insulin therapy, maximum glimepiride dose for patients with GFRs be- regular insulin, NPH insulin or premixed insulin and who were tween 20 and 50 ml/min is 2-4 mg (50% of the dose when switched to glargine, an improvement in quality of life and a compared with that for patients with GFRs greater than reduction in frequency of hypoglycemic episodes occurred. 50 ml/min). Patients with GFRs less than 20 ml/min require Dose adjustments may be necessary based on the degree a dosage of only 1 mg/day (31). According to the KDOQI’s of kidney dysfunction: There is no need to perform dose
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