Diabetes is a major cause of end-stage kidney disease (ESKD). Glycemic management is challenging in this population, and A1C, commonly used for monitoring glycemic control, is unreliable. Continuous glucose monitoring indices can be used for glycemic monitoring in people with ESKD. Dipeptidyl peptidase 4 inhibitors, incretin mimetic agents (glucagon-like peptide 1 and glucose-dependent insulinotropic peptide receptor agonists), and insulin using an automated insulin delivery system are preferred to manage diabetes in people with ESKD on hemodialysis.

Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.

Nateglinide is a meglitinide used for the treatment of type 2 diabetes mellitus. Individual studies demonstrated the association of CYP2C9, SLCO1B1, and MTNR1B variants with the safety and efficacy of nateglinide. The current study aimed to develop a pharmacogenomic algorithm to optimize nateglinide therapy.

Multiple linear regression (MLR) and classification and regression tree (CART) were used to develop a pharmacogenomic algorithm for nateglinide dosing based on the published nateglinide pharmacokinetic data on the area under the curve data (AUC) and C_max (n = 143). CYP2C9 metabolizer phenotype, SLCO1B1, MTNR1B genotypes, and CYP2C9 inhibitor usage were used as the input variables. The results and associations were further confirmed by meta-analysis and in silico studies.

The MLR models of AUC and C_max explain 87.4% and 59% variability in nateglinide pharmacokinetics. The Bland and Altman analysis of the nateglinide dose predicted by these two MLR models showed a bias of ± 26.28 mg/meal. The CART algorithm was proposed based on these findings. This model is further justified by the meta-analysis showing increased AUCs in CYP2C9 intermediate metabolizers and SLCOB1 TC and CC genotypes compared to the wild genotypes. The increased AUC in SLCO1B1 mutants is due to decreased binding affinity of nateglinide to the mutant affecting the influx of nateglinide into hepatocytes. MTNR1B rs10830963 G-allele-mediated poor response to nateglinide is attributed to increased transcriptional factor binding causing decreased insulin secretion.

CYP2C9, SLCO1B1, and MTNR1B genotyping help in optimizing nateglinide therapy based on this algorithm and ensuring safety and efficacy.

In October 2020, KDIGO (Kidney Disease: Improving Global Outcomes) published its first clinical practice guideline directed specifically to the care of patients with diabetes and chronic kidney disease (CKD). This commentary presents the views of the KDOQI (Kidney Disease Outcomes Quality Initiative) work group for diabetes in CKD, convened by the National Kidney Foundation to provide an independent expert perspective on the new guideline. The KDOQI work group believes that the KDIGO guideline takes a major step forward in clarifying glycemic targets and use of specific antihyperglycemic agents in diabetes and CKD. The purpose of this commentary is to carry forward the conversation regarding optimization of care for patients with diabetes and CKD. Recent developments for prevention of CKD progression and cardiovascular events in people with diabetes and CKD, particularly related to sodium/glucose cotransporter 2 (SGLT2) inhibitors, have filled a longstanding gap in nephrology's approach to the care of persons with diabetes and CKD. The multifaceted benefits of SGLT2 inhibitors have facilitated interactions between nephrology, cardiology, endocrinology, and primary care, underscoring the need for innovative approaches to multidisciplinary care in these patients. We now have more interventions to slow kidney disease progression and prevent or delay kidney failure in patients with diabetes and kidney disease, but methods to streamline their implementation and overcome barriers in access to care, particularly cost, are essential to ensuring all patients may benefit.

Diabetes mellitus is the commonest cause of end-stage kidney failure worldwide and is a proven and significant risk factor for the development of cardiovascular disease. Renal impairment has a significant impact on the physiology of glucose homeostasis as it reduces tissue sensitivity to insulin and reduces insulin clearance. Renal replacement therapy itself affects glucose control: peritoneal dialysis may induce hyperglycaemia due to glucose-rich dialysate and haemodialysis often causes hypoglycaemia due to the relatively low concentration of glucose in the dialysate. Autonomic neuropathy which is common in chronic kidney disease (CKD) and diabetes increases the risk for asymptomatic hypoglycaemia. Pharmacological options for improving glycaemic control are limited due to alterations to drug metabolism. Impaired glucose tolerance and diabetes are also common in the post-kidney-transplant setting and increase the risk of graft failure and mortality. This review seeks to summarise the literature and tackle the intricacies of glycaemic management in patients with CKD who are either on maintenance haemodialysis or have received a kidney transplant. It outlines changes to glycaemic targets, monitoring of glycaemic control, the use of oral hypoglycaemic agents, the management of severe hyperglycaemia in dialysis and kidney transplantation patients.

Diabetes mellitus is the leading cause of end-stage renal disease, and uncontrolled hyperglycemia is directly related to the increased mortality in this setting. As kidney function decreases, it becomes more challenging to control blood glucose since the risk of hypoglycemia increases. Decreased appetite, changes in glycaemia homeostasis, along with reduced renal excretion of anti-hyperglycemic drugs tend to facilitate the occurrence of hypoglycemia, despite the paradoxical occurrence of insulin resistance in advanced kidney disease. Thus, in patients using insulin and/or oral anti-hyperglycemic agents, dynamic adjustments with drug dose reduction or drug switching are often necessary. Furthermore, in addition to consider these pharmacokinetics alterations, it is of utmost importance to choose drugs with proven cardio-renal benefits in this setting, such as sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists. In this review, we summarize the indications and contraindications, titration of doses and side effects of the available anti-hyperglycemic agents in the presence of advanced diabetic kidney disease (DKD) and dialysis, highlighting the risks and benefits of the different agents. Additionally, basic renal function assessment and monitoring of glycemic control in DKD will be evaluated in order to guide the use of drugs and define the glycemic targets to be achieved.

The objective is to formulate clinical practice guidelines for the treatment of diabetes in older adults.

Diabetes, particularly type 2, is becoming more prevalent in the general population, especially in individuals over the age of 65 years. The underlying pathophysiology of the disease in these patients is exacerbated by the direct effects of aging on metabolic regulation. Similarly, aging effects interact with diabetes to accelerate the progression of many common diabetes complications. Each section in this guideline covers all aspects of the etiology and available evidence, primarily from controlled trials, on therapeutic options and outcomes in this population. The goal is to give guidance to practicing health care providers that will benefit patients with diabetes (both type 1 and type 2), paying particular attention to avoiding unnecessary and/or harmful adverse effects.

Diabetes is highly and increasingly prevalent in the dialysis population and negatively impacts both quality and quantity of life. Nevertheless, the best approach to these patients is still debatable. The question of whether the management of diabetes should be different in dialysis patients does not have a clear yes or no answer but is divided into too many sub-issues that should be carefully considered. In this review, lifestyle, cardiovascular risk, and hyperglycemia management are explored, emphasizing the possible pros and cons of a similar approach to diabetes in dialysis patients compared to the general population.

The safety of short-acting meglitinides in diabetic patients with advanced chronic kidney disease (CKD) has not been widely reported. Diabetic patients with advanced CKD who had a serum creatinine level of > 6 mg/dL a hematocrit level of ≦ 28% and received erythropoiesis-stimulating agent treatment between 2000 and 2010, were included in this nationwide study in Taiwan. The outcomes of interest were defined as hypoglycemia and long-term mortality. The risks of hypoglycemia and death were analyzed using Cox proportional hazards models, with end-stage renal disease and anti-diabetic drugs as time-dependent variables. Fresh users and matched non-users of meglitinides (both n = 2,793) were analyzed. The use of meglitinides increased the risk of hypoglycemia (HR, 1.94, p<0.001), as did other anti-diabetic agents. Concomitant use of meglitinide and insuilin will incresase the hypoglycemic risk. (HR, 1.69, p=0.018) Moreover, it was not the use of meglitinides, but the presence of hypoglycemia that predicted mortality. The function curve showed an insignificant trend towards increased hypoglycemic risk in patients aged > 62 and ≤ 33 years from the generalized additive model. This study suggests that the use of short-acting meglitinides could be associated with increased risk of hypoglycemia in diabetic patients with advanced CKD, especially in patients aged > 62 and ≤ 33 years. Meglitinide combined with insulin will increase hypoglycemia in patients with advanced CKD.

Oral anti-diabetic drugs (OADs) are leading option for treatment of type 2 diabetes (T2D). However, availability of OADs are limited in the presence of renal impairment (RI).

In this study, we examined the efficacy of repaglinide, which is mainly metabolized and excreted via non-renal route, in patients with T2D and severe RI that consists mainly of chronic kidney disease (CKD) stage 4.

This was an open label, single arm, interventional study by repaglinide monotherapy. The primary efficacy end point was HbA1c change from baseline to week 12.

Repaglinide treatment significantly reduced HbA1c levels from 7.7 ± 0.7% to 6.1 ± 0.3% (p<0.001) in 9 patients with severe RI (mean estimated glomerular filtration rate was 26.4 ± 7.5 mL/min/1.73m²). Focusing on 4 patients who received DPP-4 inhibitor monotherapy at enrolment, switching to repaglinide also significantly improved HbA1c levels. No hypoglycemic symptoms or severe hypoglycemia was reported in patients who completed the period of 12 weeks.

We demonstrated the efficacy of repaglinide in patients with T2D and severe RI. In case that DPP-4 inhibitors are not enough to achieve targeted range of glycemic control, repaglinide is another good candidate.

This review focuses on hypoglycemia in patients with end-stage renal disease (ESRD). It discusses the pathophysiology of glucose metabolism in the kidney, the impact of dialysis on glucose and insulin metabolism, and the challenges of glucose monitoring in ESRD. The clinical relevance of these changes is reviewed in relation to altered blood glucose targets and modification of antidiabetes therapy to prevent hypoglycemia. Based on current data and guidelines, recommendations for the outpatient and inpatient setting are provided for diabetes management in ESRD.

PubMed, OVID, and Google Scholar were searched to identify related articles through May 2016 using the following keywords: "glucose metabolism," "kidney," "diabetes," "hypoglycemia," "ESRD," and "insulin" in various combinations for this review.

In ESRD, a combination of impaired insulin clearance, changes in glucose metabolism, and the dialysis process make patients vulnerable to low blood glucose levels. Hypoglycemia accounts for up to 3.6% of all ESRD-related admissions. At admission or during hospitalization, hypoglycemia in ESRD has a poor prognosis, with mortality rates reported at 30%. Several guidelines suggest a modified hemoglobin A1c (A1c) goal of 7 to 8.5% (53 to 69 mmol/mol) and an average blood glucose goal of 150 to 200 mg/dL. Noninsulin antidiabetes agents like dipeptidyl peptidase 4 inhibitors, repaglinide, and glipizide in appropriate doses and reduction of insulin doses up to 50% may help decrease hypoglycemia.

Patients with ESRD are at high risk for hypoglycemia. Increased awareness by providers regarding these risks and appropriate diabetes regimen adjustments can help minimize hypoglycemic events.

ADA = antidiabetes agent BG = blood glucose CKD = chronic kidney disease DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate ESRD = end-stage renal disease GFR = glomerular filtration rate HD = hemodialysis NPH = neutral protamine Hagedorn PD = peritoneal dialysis SA = short acting SU = sulfonylurea.

To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.

Diabetes and chronic kidney disease (CKD) are a high-stakes combination for cardiovascular disease. Patients with decreased kidney function and end-stage renal disease (ESRD) have increased risk of hypoglycemia when attaining better glycemic control, leading to higher risk of myocardial infarction (MI). For these patients, which kinds of anti-hyperglycemic agents would be associated with higher risk of MI is not clear.

We identified patients from a nation-wide database called Registry for Catastrophic Illness, which encompassed almost 100% of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Patients with diabetes and ESRD were selected as the study cohort. Propensity score adjustment and Cox's proportional hazards regression model were used to estimate the hazard ratios (HRs) for new-onset MI.

Among 15,161 patients, 39% received insulin, 40% received sulfonylureas, 18% received meglitinides and 3% received thiazolidinedione (TZD). After a median follow-up of 1,357 days, the incidence of MI was significant increase in patients taking sulfonylureas (HR = 1.523, 95% confidence interval [CI] = 1.331-1.744), meglitinides (HR = 1.251, 95% CI = 1.048-1.494) and TZD (HR = 1.515, 95% CI = 1.071-2.145) by using patients receiving insulin therapy as the reference group. The risk of MI remains higher in other three groups in subgroup analyses.

In conclusion, among diabetic patients with ESRD undergoing dialysis, the use of sulfonylureas, meglitinides and TZD are associated with higher risk of new-onset MI as compared with insulin.

Patients who undergo solid organ transplantation may have preexisting diabetes mellitus (DM), develop new-onset DM after transplantation (NODAT), or have postoperative hyperglycemia that resolves shortly after surgery. Although insulin is usually used to control hyperglycemia in the hospital, following discharge most of the usual diabetes oral and parenteral medications can be used in treatment. However, when there are comorbidities such as impaired kidney or hepatic function, or heart disease, special precautions may be necessary. In addition, drug-drug interactions, such as drugs interacting with CYP3A4 enzyme pathway, require additional consideration because of possible interaction with immunosuppressive drug metabolism.

The purpose of this study was to evaluate the therapeutic options for diabetes treatment and their potential side effects, in addition to analyzing the risks and benefits of tight glycemic control in patients with diabetic kidney disease. For this review, a search was performed using several pre-defined keyword combinations and their equivalents: "diabetes kidney disease" and "renal failure" in combination with "diabetes treatment" and "oral antidiabetic drugs" or "oral hypoglycemic agents." The search was performed in PubMed, Endocrine Abstracts and the Cochrane Library from January 1980 up to January 2015. Diabetes treatment in patients with diabetic kidney disease is challenging, in part because of progression of renal failure-related changes in insulin signaling, glucose transport and metabolism, favoring both hyperglycemic peaks and hypoglycemia. Additionally, the decline in renal function impairs the clearance and metabolism of antidiabetic agents and insulin, frequently requiring reassessment of prescriptions. The management of hyperglycemia in patients with diabetic kidney disease is even more difficult, requiring adjustment of antidiabetic agents and insulin doses. The health team responsible for the follow-up of these patients should be vigilant and prepared to make such changes; however, unfortunately, there are few guidelines addressing the nuances of the management of this specific population.

Nowadays, diabetes mellitus (DM) and hypertension are considered as the most common causes of end-stage renal disease (ESRD). In this paper, other than presenting the role of DM in ESRD, glucose metabolism and the management of hyperglycemia in these patients are reviewed. Although in several large studies there was no significant relationship found between tight glycemic control and the survival of ESRD patients, it is recommended that glycemic control be considered as the main therapeutic goal in the treatment of these patients to prevent damage to other organs. Glycemic control is perfect when fasting blood sugar is less than 140 mg/dL, 1-h postprandial blood glucose is less than 200 mg/dL, and glycosylated hemoglobin (HbA1c) is 6-7 in patients with type 1 diabetes and 7-8 in patients with type 2 diabetes. Administration of metformin should be avoided in chronic renal failure (CRF) because of lactic acidosis, the potentially fatal complication of metformin, but glipizide and repaglinide seem to be good choices.

Glycemic control is essential to delay or prevent the onset of diabetic kidney disease. There are a number of glucose-lowering medications available but only a fraction of them can be used safely in chronic kidney disease and many of them need an adjustment in dosing. The ideal target hemoglobin A1c is approximately 7 % but this target is adjusted based on the needs of the patient. Diabetes control should be optimized for each individual patient, with measures to reduce diabetes-related complications and minimize adverse events. Overall care of diabetes necessitates attention to multiple aspects, including reducing the risk of cardiovascular disease, and often, multidisciplinary care is needed.

This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation.

Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched for literature published in English from January 1989 to May 2014 for diabetes mellitus, hypoglycemia, chronic kidney disease, and chronic renal insufficiency.

The presence of type 2 diabetes mellitus (T2DM) is a common risk factor for the development of chronic kidney disease, but appropriate glycemic control can slow the progression of kidney dysfunction in patients with T2DM. The kidney plays a role in insulin resistance and gluconeogenesis, therefore, impaired kidney function alters glucose dynamics compared with normal kidney function, thus affecting antihyperglycemic treatment strategies. Glycemic management is further complicated by reduced drug clearance and a greater risk of hypoglycemia with use of certain medications, notably the sulfonylureas. Of the classes of antihyperglycemic drugs discussed in this review, caution is advised when using some classes in patients with T2DM and kidney disease.

This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug's pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.

People with chronic kidney disease (CKD) of stages 3 - 5 (creatinine clearance < 60 ml/min) represent ≈ 25% of patients with type 2 diabetes mellitus (T2DM), but the problem is underrecognized or neglected in clinical practice. However, most oral antidiabetic agents have limitations in case of renal impairment (RI), either because they require a dose adjustment or because they are contraindicated for safety reasons.

The author performed an extensive literature search to analyze the influence of RI on the pharmacokinetics (PK) of glucose-lowering agents and the potential consequences for clinical practice.

As a result of PK interferences and for safety reasons, the daily dose should be reduced according to glomerular filtration rate (GFR) or even the drug is contraindicated in presence of severe CKD. This is the case for metformin (risk of lactic acidosis) and for many sulfonylureas (risk of hypoglycemia). At present, however, the exact GFR cutoff for metformin use is controversial. New antidiabetic agents are better tolerated in case of CKD, although clinical experience remains quite limited for most of them. The dose of DPP-4 inhibitors should be reduced (except for linagliptin), whereas both the efficacy and safety of SGLT2 inhibitors are questionable in presence of CKD.

New onset diabetes mellitus after transplant (NODAT) refers to the development of diabetes post-transplant in previously non-diabetic patients and is associated with increased rates of acute transplant rejection, infection, late cardiovascular events, and decreased survival. NODAT is primarily due to the immunosuppressive drug regimen but the standard predisposing risk factors for diabetes also pertain. NODAT is diagnosed by the standard ADA criteria, once prednisone doses are less than 10 mg per day and in the absence of acute illness. Sulfonylureas, metformin, DPP-4 inhibitors, GLP-1 agonists, and insulin can be used in treatment, but when there is impaired kidney or hepatic function, special precautions are necessary. In addition, those drugs interacting with P450 enzymes require additional consideration because of possible interaction with immunosuppressive drug metabolism.

Hyperglycemia management in chronic kidney disease (CKD) patients presents difficult challenges, partly due to the complexity involved in treating these patients, and partly due to lack of data supporting benefits of tight glycemic control. While hyperglycemia is central to the pathogenesis and management of diabetes, hypoglycemia and glucose variability also contribute to outcomes. Multiple agents with different mechanisms of action are now available; some can lower glucose levels without the risk of hypoglycemia. This article reviews metabolic changes present in kidney impairment/failure, current views about glycemic goals, and treatment options for the diabetic patient with CKD.

The 2012 update of the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guideline for Diabetes and Chronic Kidney Disease (CKD) is intended to assist the practitioner caring for patients with diabetes and CKD. Substantial high-quality new evidence has emerged since the original 2007 KDOQI guideline that could significantly change recommendations for clinical practice. As such, revisions of prior guidelines are offered that specifically address hemoglobin A(1c) (HbA(1c)) targets, treatments to lower low-density lipoprotein cholesterol (LDL-C) levels, and use of angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin receptor blocker (ARB) treatment in diabetic patients with and without albuminuria. Treatment approaches are addressed in each section and the stated guideline recommendations are based on systematic reviews of relevant trials. Appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Limitations of the evidence are discussed and specific suggestions are provided for future research.

The incidence and prevalence of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) continues to grow worldwide. ESRD causes significant morbidity and mortality and has enormous financial and personal costs.

Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched from 1989 to September 2009 to summarize current pharmacotherapy of ESRD-associated complications in adults receiving maintenance dialysis (hemodialysis or continuous ambulatory peritoneal dialysis). Current guidelines for the treatment of ESRD (e.g., NKF-K/DOQI, KDIGO, and the ERA-EDTA's European Renal Best Practice Guidelines) were included.

Commonly used pharmacological treatment strategies for chronic arterial hypertension, anemia, iron management, dyslipidemia, hyperglycemia, and for disturbances of bone and mineral metabolism, including hyperphosphatemia and secondary hyperparathyroidism in ESRD, are presented. In addition, the reader will learn that nonadherence to oral medication in ESRD can contribute significantly to excess morbidity and mortality of the dialysis population.

Improvements in pharmacotherapy of ESRD may be at least in part counteracted by continuously increasing age and comorbid disease of the dialysis population. Individualized and tailor-made pharmacological management of the ESRD patient remains a challenge for the future.

Diabetes mellitus is a leading cause of kidney disease worldwide. A large and expanding array of treatments for diabetes is available to improve glycemic control, including newer classes of drugs, such as thiazolidinediones and incretin-based therapies. The presence of impaired kidney function with reduced glomerular filtration rate should influence choices, dosing, and monitoring of hypoglycemic agents, as some agents require a dosing adjustment in patients with kidney disease and some are entirely contraindicated. This article reviews the clinical use of insulin and other antidiabetic therapies, focusing on pharmacokinetic properties and dosing in patients with advanced kidney disease.

Diabetic nephropathy is the leading cause of chronic renal disease and a major cause of cardiovascular mortality. Diabetic nephropathy has been categorized into stages: microalbuminuria and macroalbuminuria. The cut-off values of micro- and macroalbuminuria are arbitrary and their values have been questioned. Subjects in the upper-normal range of albuminuria seem to be at high risk of progression to micro- or macroalbuminuria and they also had a higher blood pressure than normoalbuminuric subjects in the lower normoalbuminuria range. Diabetic nephropathy screening is made by measuring albumin in spot urine. If abnormal, it should be confirmed in two out three samples collected in a three to six-months interval. Additionally, it is recommended that glomerular filtration rate be routinely estimated for appropriate screening of nephropathy, because some patients present a decreased glomerular filtration rate when urine albumin values are in the normal range. The two main risk factors for diabetic nephropathy are hyperglycemia and arterial hypertension, but the genetic susceptibility in both type 1 and type 2 diabetes is of great importance. Other risk factors are smoking, dyslipidemia, proteinuria, glomerular hyperfiltration and dietary factors. Nephropathy is pathologically characterized in individuals with type 1 diabetes by thickening of glomerular and tubular basal membranes, with progressive mesangial expansion (diffuse or nodular) leading to progressive reduction of glomerular filtration surface. Concurrent interstitial morphological alterations and hyalinization of afferent and efferent glomerular arterioles also occur. Podocytes abnormalities also appear to be involved in the glomerulosclerosis process. In patients with type 2 diabetes, renal lesions are heterogeneous and more complex than in individuals with type 1 diabetes. Treatment of diabetic nephropathy is based on a multiple risk factor approach, and the goal is retarding the development or progression of the disease and to decrease the subject's increased risk of cardiovascular disease. Achieving the best metabolic control, treating hypertension (<130/80 mmHg) and dyslipidemia (LDL cholesterol <100 mg/dl), using drugs that block the renin-angiotensin-aldosterone system, are effective strategies for preventing the development of microalbuminuria, delaying the progression to more advanced stages of nephropathy and reducing cardiovascular mortality in patients with diabetes.

Therapy for type 2 diabetes mellitus should aim to control not only fasting, but also postprandial glucose levels. Nateglinide, a d-phenylalanine derivative, restores postprandial early phase insulin secretion in a transient and glucose-sensitive manner without affecting basal insulin levels. As nateglinide is administered immediately before meals it provides greater lifestyle flexibility than agents that require patients to eat to avoid hypoglycemic events (e.g. long-acting sulfonylureas). In randomised, double-blind trials in patients with type 2 diabetes, nateglinide monotherapy (mealtime treatment of 120 mg three times daily) significantly improved long-term glycaemic control by significantly reducing glyated haemoglobin (HbA 1c) and preventing mealtime glucose spikes. The combination of nateglinide with insulin-sensitising agents, for example, metformin and thiazolidinediones, addresses the dual defects of loss of insulin secretion and insulin resistance to provide optimal management of type 2 diabetes, and more patients achieve HbA 1c goal with nateglinide combination therapy rather than with monotherapy with other oral agents. Nateglinide also restores early insulin secretion and reduces postprandial hyperglycaemia in prediabetic subjects with impaired glucose tolerance (IGT) and appears similarly effective in elderly and non-elderly populations with type 2 diabetes. It has an excellent safety and tolerability profile, with a low propensity to cause hypoglycaemia due to its transient, selective effect on early phase insulin secretion. Nateglinide as monotherapy or combination therapy is an effective option to reduce mealtime glucose in patients with type 2 diabetes. The results of ongoing research into its potential role in delaying progression to overt diabetes, and protecting against cardiovascular events, in prediabetic patients with IGT are awaited.

Diabetes mellitus is recognized as a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. There is a vast array of medications used to treat diabetes, including insulin and the sulfonylureas, as well as newer classes of drugs such as the thiazolidinediones and biguanides. In patients with reduced glomerular filtration rate (GFR), it is necessary to decrease the dosage of some of these drugs, while others are best avoided altogether. Accumulation of either the parent compound or its metabolites can result in symptomatic hypoglycemia, or in the case of metformin, significant lactic acidosis. In this article we will review the use of insulin and the various classes of oral medications used to treat type 2 diabetes mellitus, focusing on their pharmacokinetic properties and dosing in patients with advanced kidney disease.