Pharmacotherapies for diabetes management: an update for the practicing clinician

Over the past several years, the pharmacologic options for the management of glycemic control have tremendously expanded. Whereas prior to the introduction of metformin therapy in 1995 the only alternatives were human insulin therapies and sulfonylurea drugs, we now have the option of using several different classes of oral antidiabetic drugs, injectable non-insulin therapies, and insulin analogs. In this article we present a functional classification of glycemic therapies available for the treatment of diabetes in an attempt to provide the clinician with a practical framework which optimize blood glucose management. Patients with diabetes, especially type 2 diabetes, are often managed with a wide variety of injectable and non-injectable options in the attempt to improve glycemic control and glycemic variability, minimize hypoglycemia (as well as weight gain) and prevent both micro- and macrovascular complications. We specifically focus on novel therapies and present macrovascular complications. We specifically focus on novel therapies and present information about their efficacy and safety, as well as potential contraindications. The last section of this paper will present some suggestions for how to manage glycemia in the in-patient setting, including the use of rapid and long-acting insulin preparations to cover fasting and nutritional needs, as well as the proper use of insulin scales.     

Perioperative challenges in management of diabetic patients undergoing non-cardiac surgery

Prediabetes and diabetes are important disease processes which have several perioperative implications. About one third of the United States population is considered to have prediabetes. The prevalence in surgical patients is even higher. This is due to the associated micro and macrovascular complications of diabetes that result in the need for subsequent surgical procedures. A careful preoperative evaluation of diabetic patients and patients at risk for prediabetes is essential to reduce perioperative mortality and morbidity. This preoperative evaluation involves an optimization of preoperative comorbidities. It also includes optimization of antidiabetic medication regimens, as the avoidance of unintentional hypoglycemic and hyperglycemic episodes during the perioperative period is crucial. The focus of the perioperative management is to ensure euglycemia and thus improve postoperative outcomes. Therefore, prolonged preoperative fasting should be avoided and close monitoring of blood glucose should be initiated and continued throughout surgery. This can be accomplished with either analysis in blood gas samples, venous phlebotomy or point-of-care testing. Although capillary and arterial whole blood glucose do not meet standard guidelines for glucose testing, they can still be used to guide insulin dosing in the operating room. Intraoperative glycemic control goals may vary slightly in different protocols but overall the guidelines suggest a glucose range in the operating room should be between 140 mg/dL to 180 mg/dL. When hyperglycemia is detected in the operating room, blood glucose management may be initiated with subcutaneous rapid-acting insulin, with intravenous infusion or boluses of regular insulin. Fluid and electrolyte management are other perioperative challenges. Notably diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic state are the two most serious acute metabolic complications of diabetes that must be recognized early and treated.     

Chronic kidney disease in the general population

End-stage kidney disease (ESKD), defined as the need for dialysis, receipt of a transplant, or death from chronic kidney failure, generally affects fewer than 1% of the population. However ESKD is the end result of chronic kidney disease (CKD), a widely prevalent but often silent condition with elevated risks of cardiovascular morbidity and mortality and a range of metabolic complications. A recently devised classification of CKD has facilitated prevalence estimates that reveal an "iceberg" of CKD in the community, of which dialysis and transplant patients are the tip. Hypertension, smoking, hypercholesterolemia, and obesity, currently among the World Health Organization's (WHO's) top 10 global health risks, are strongly associated with CKD. The factors, together with increasing diabetes prevalence and an aging population, will result in significant global increases in CKD and ESKD patients. Treatments now available effectively reduce the rate of progression of CKD and the extent of comorbid conditions and complications. The challenges are (1) to intervene effectively to reduce the excess burden of cardiovascular morbidity and mortality associated with CKD, (2) to identify those at greatest risk for ESKD and intervene effectively to prevent progression of early CKD, and (3) to ultimately introduce cost-effective primary prevention to reduce the overall burden of CKD. The vast majority of the global CKD burden will be in developing countries, and policy responses must be both practical and sustainable in these settings.     

Counteraction of type 1 diabetic alterations by engineering skeletal muscle to produce insulin: insights from transgenic mice

Insulin replacement therapy in type 1 diabetes is imperfect because proper glycemic control is not always achieved. Most patients develop microvascular, macrovascular, and neurological complications, which increase with the degree of hyperglycemia. Engineered muscle cells continuously secreting basal levels of insulin might be used to improve the efficacy of insulin treatment. Here we examined the control of glucose homeostasis in healthy and diabetic transgenic mice constitutively expressing mature human insulin in skeletal muscle. Fed transgenic mice were normoglycemic and normoinsulinemic and, after an intraperitoneal glucose tolerance test, showed increased glucose disposal. When treated with streptozotocin (STZ), transgenic mice showed increased insulinemia and reduced hyperglycemia when fed and normoglycemia and normoinsulinemia when fasted. Injection of low doses of soluble insulin restored normoglycemia in fed STZ-treated transgenic mice, while STZ-treated controls remained highly hyperglycemic, indicating that diabetic transgenic mice were more sensitive to the hypoglycemic effects of insulin. Furthermore, STZ-treated transgenic mice presented normalization of both skeletal muscle and liver glucose metabolism. These results indicate that skeletal muscle may be a key target tissue for insulin production and suggest that muscle cells secreting basal levels of insulin, in conjunction with insulin therapy, may permit tight regulation of glycemia.     

Pancreas transplantation in humans with diabetes mellitus

Pancreas transplantation, when successful, is a reproducibly effective method to normalize glycemia without the use of exogenous insulin treatment in patients with diabetes mellitus. Success rates for combined pancreas and kidney transplantation are approximately 70%, and patient survival rates are approximately 90% 1 yr postoperatively. Metabolic benefits of this procedure include normalization of levels of fasting plasma glucose and HbA1C. Glucose-induced insulin secretion and intravenous glucose tolerance are normalized. Improvements are also observed in glucose recovery after insulin-induced hypoglycemia and in glucagon secretion during hypoglycemia. Pancreas transplantation is also associated with normalization of kidney structure and both motor and sensory nerve function. However, no benefits have been observed with regard to pancreatic polypeptide secretion, kidney function, and the retinal pathology of diabetes mellitus. Pancreas transplantation has reached a point in its history where the operative technique and its ancillary medical therapy have been optimized. Improvement in the rates of success, morbidity, and mortality will probably depend on improvement in immunosuppressive drugs and the physical condition of the recipients themselves. The time is at hand when we need to carefully consider whether it is ethical and advisable to make pancreas transplantation available to individuals who have fewer chronic complications of diabetes mellitus. Future studies of pancreas transplantation must incorporate more rigid experimental controls than have been used in the past to better assess the relative merits of this procedure.     

Unnecessary Renal Replacement Therapy for Acute Kidney Injury is Harmful for Renal Recovery

The use of renal replacement therapy (RRT) for severe acute kidney injury (AKI) is frequently necessary in the face of life‐threatening complications; however, there is wide practice variation with respect to triggers for RRT initiation. Recent evidence suggests that RRT may be independently associated with impaired recovery following AKI. There are plausible mechanistic reasons why RRT may be harmful and this concept is supported by ancillary evidence in the form of studies that have assessed the impact of different modalities of RRT for AKI as well as some of the literature pertaining to initiation of chronic hemodialysis in end‐stage kidney disease patients (ESKD). As such, avoiding unnecessary RRT (URRT) is a desirable goal. There is emerging evidence of strategies that may be effective to help limit URRT. These strategies primarily involve early identification of AKI and limiting iatrogenic harm once AKI is established. Further research into defining and preventing URRT may help improve the consistently poor outcomes following severe AKI with respect to development of chronic kidney disease and ESKD.     

Utility of different glycemic control metrics for optimizing management of diabetes

The benchmark for assessing quality of long-term glycemic control and adjustment of therapy is currently glycated hemoglobin(Hb A1c). Despite its importance as an indicator for the development of diabeticcomplications, recent studies have revealed that this metric has some limitations; it conveys a rather complex message, which has to be taken into consideration for diabetes screening and treatment. On the basis of recent clinical trials, the relationship between Hb A1 c and cardiovascular outcomes in long-standing diabetes has been called into question. It becomes obvious that other surrogate and biomarkers are needed to better predict cardiovascular diabetes complications and assess efficiency of therapy. Glycated albumin, fructosamin, and 1,5-anhydroglucitol have received growing interest as alternative markers of glycemic control. In addition to measures of hyperglycemia, advanced glucose monitoring methods became available. An indispensible adjunct to Hb A1 c in routine diabetes care is selfmonitoring of blood glucose. This monitoring method is now widely used, as it provides immediate feedback to patients on short-term changes, involving fasting, preprandial, and postprandial glucose levels. Beyond the traditional metrics, glycemic variability has been identified as a predictor of hypoglycemia, and it might also be implicated in the pathogenesis of vascular diabetes complications. Assessment of glycemic variability is thus important, but exact quantification requires frequently sampled glucose measurements. In order to optimize diabetes treatment, there is a need for both key metrics of glycemic control on a day-to-day basis and for more advanced, user-friendly monitoring methods. In addition to traditional discontinuous glucose testing, continuous glucose sensing has become a useful tool to reveal insufficient glycemic management. This new technology is particularly effective in patients with complicated diabetes and provides the opportunity to characterize glucose dynamics. Several continuous glucose monitoring(CGM) systems, which have shown usefulness in clinical practice, are presently on the market. They can broadly be divided into systems providing retrospective or real-time information on glucose patterns. The widespread clinical application of CGM is still hampered by the lack of generallyaccepted measures for assessment of glucose profiles and standardized reporting of glucose data. In this article, we will discuss advantages and limitations of various metrics for glycemic control as well as possibilities for evaluation of glucose data with the special focus on glycemic variability and application of CGM to improve individual diabetes management.     

Insulin therapy for maximal glycemic control in type 2 diabetes mellitus

Type 2 diabetes mellitus is on the rise, yet glycemic control continues to elude patients-and their physicians. During the past decade, the use of insulin monotherapy has decreased while the use of oral antidiabetic agents (either alone or in combination with insulin injections) has increased. The continued prevalence of the disorder, changes in prescribing patterns, and recent data indicating that only one third of patients with type 2 diabetes mellitus achieve glycemic control underscore the need for physicians to reevaluate the clinical management of this now common disorder. Insulin analogs provide flexibility in the delivery of insulin therapy for this population. Although potential barriers and complications to initiation exist, patients should understand that achieving and maintaining glycemic control reduces the risk of long-term complications as a result of type 2 diabetes mellitus. Physicians are encouraged to actively identify and address patient concerns about this treatment modality.     

When ESKD complicates disease management: GI bleeding and other GI illnesses

The presentation of gastrointestinal (GI) illnesses is similar in patients with end-stage kidney disease (ESKD) and in the general population. However, there are several instances where kidney failure and renal replacement therapy (RRT) can affect the course of the disease and its management. In this section, we will focus on unique factors of GI illnesses that should be considered in the ESKD population with and without residual kidney function (RKF). We will also discuss the role of RRT modalities in the occurrence and treatment of GI disease.     

Decrease in the number of neonatal islets required for successful transplantation by strict metabolic control of diabetic rats

We have investigated the influence of glycemic control on the number of transplanted neonatal islets needed to cure streptozotocin (STZ)-diabetic rats. Intrasplenic transplantation of 1000 neonatal islets to a group of STZ-diabetic rats with poor glycemic control cured only 30% of the rats. In a second group, insulin at doses of 10-15 U/day given for 5 days after transplantation improved the cure rate to 72%. Normalization of blood glucose by a previous transplant to the kidney capsule produced cure in 100% of the rats. The above results were obtained despite the fact that isolated adult islets, when compared with neonatal islets, were larger, contained more protein and DNA--and, in response to glucose stimulation, released more insulin than neonatal islets. These experiments show that neonatal islets are an excellent source of endocrine replacement tissue when transplanted intrasplenically, and that the number of islets needed to cure experimental diabetes is significantly reduced by normalization of the metabolic milieu in the recipient.     

Reversal of type 1 diabetes in mice by brown adipose tissue transplant

Current therapies for type 1 diabetes (T1D) involve insulin replacement or transplantation of insulin-secreting tissue, both of which suffer from numerous limitations and complications. Here, we show that subcutaneous transplants of embryonic brown adipose tissue (BAT) can correct T1D in streptozotocin-treated mice (both immune competent and immune deficient) with severely impaired glucose tolerance and significant loss of adipose tissue. BAT transplants result in euglycemia, normalized glucose tolerance, reduced tissue inflammation, and reversal of clinical diabetes markers such as polyuria, polydipsia, and polyphagia. These effects are independent of insulin but correlate with recovery of the animals' white adipose tissue. BAT transplants lead to significant increases in adiponectin and leptin, but with levels that are static and not responsive to glucose. Pharmacological blockade of the insulin receptor in BAT transplant mice leads to impaired glucose tolerance, similar to what is seen in nondiabetic animals, indicating that insulin receptor activity plays a role in the reversal of diabetes. One possible candidate for activating the insulin receptor is IGF-1, whose levels are also significantly elevated in BAT transplant mice. Thus, we propose that the combined action of multiple adipokines establishes a new equilibrium in the animal that allows for chronic glycemic control without insulin.     

Examination of Carbohydrate Metabolism Parameters After Simultaneous Pancreas-Kidney Transplantation

End-stage renal failure, a frequent complication of type 1 diabetes mellitus, requires renal replacement therapy. Our team examined the laboratory parameters of carbohydrate metabolism in 18 patients with type 1 diabetes at 10 to 89 months after simultaneous pancreas-kidney transplantation. We compared these results with those of 17 patients with type 1 diabetes who had formerly received kidney-alone transplantations, and were undergoing insulin treatment, as well as with those of 16 metabolically healthy controls. The hemoglobin A1c (HbA1c) and blood glucose levels of the pancreas-kidney transplant recipients were within the normal ranges, not differing significantly from those of the healthy controls. In contrast, the HbA1c and glucose levels were significantly elevated among kidney transplanted diabetic subjects. However, fasting and 2-hour insulin levels of pancreas-kidney transplant patients were significantly higher than those of the controls, indicating insulin resistance. According to these results, the insulin secretion by the pancreas graft sufficiently compensated for insulin resistance. Thus 10 to 89 months after successful pancreas-kidney transplantation, carbohydrate metabolism by type 1 diabetic patients was well controlled without antidiabetic therapy.     

Basal insulin gene expression significantly improves conventional insulin therapy in type 1 diabetic rats.

Although a conventional insulin regimen for type 1 diabetes with twice-daily insulin injections is effective in preventing postprandial blood glucose excursions, this treatment is limited by its inadequate control of fasting hyperglycemia. Alternatively, sustained basal hepatic insulin gene expression has been shown to result in fasting normoglycemia in type 1 diabetic rats, although the treated animals still exhibited moderate postprandial hyperglycemia. To test the hypothesis that basal hepatic insulin production can be used as an auxiliary treatment to conventional insulin therapy for achieving better glycemic control, streptozotocin-induced diabetic rats were treated with twice-daily insulin injections, basal hepatic insulin production, or both in combination. Diabetic rats treated by conventional insulin therapy still suffered from fasting hyperglycemia, but when complemented with basal hepatic insulin production, near-normoglycemia under both fed and fasting conditions was achieved without fasting hypoglycemia. In addition, the combination-treated animals showed significantly enhanced glucose tolerance and markedly improved profiles in lipid metabolism. Furthermore, the combination treatment reduced the elevated fructosamine, glycated hemoglobin, and advanced glycation end products concentrations to normal. These results provide a proof of concept for basal hepatic insulin production as an adjuvant treatment to conventional insulin therapy in type 1 diabetes.     

High prevalence of colon adenomas in end‐stage kidney disease patients on hemodialysis undergoing renal transplant evaluation

The aim of this study was to determine whether patients with end‐stage kidney disease (ESKD) on hemodialysis (HD) undergoing kidney transplant evaluation are at higher risk for colonic neoplasia than the general population. This is a retrospective cohort study of patients with ESKD who underwent a first screening colonoscopy while undergoing kidney transplant evaluation. Data were collected on the prevalence of adenomatous polyps and advanced adenomas in 70 patients with ESKD and 70 controls, undergoing their first screening colonoscopy, matched for age, gender, and endoscopist. At the time of the colonoscopy, an average time on HD was 3.2 ± 2.9 yr. The prevalence of adenomatous polyps was significantly higher in ESKD on HD (54.3% vs. 32.9%, p = 0.008) than in controls. In a multivariate analysis controlling for other factors, ESKD on HD remained a risk factor for the presence of adenomas (OR 3.06, 95% CI 1.21, 7.73). No colonoscopy‐related complications were reported in the patients with ESKD on HD. We demonstrate a significantly higher prevalence of adenomatous polyps in patients with ESKD undergoing a first screening colonoscopy as part of kidney transplant evaluation. In addition, colonoscopy can be safely performed in this population.     

Type 2 diabetes mellitus and insulin resistance: Stroke prevention and management

Opinion statement Clinically recognized disorders of glucose metabolism include impaired fasting glucose, impaired glucose tolerance (both termed prediabetes), and diabetes mellitus. Type 2 diabetes mellitus affects 6% to 13% of adults in the United States. Among patients with recent stroke, 70% will have known diabetes, occult diabetes (detectable on an oral glucose tolerance test), or prediabetes. Type 2 diabetes mellitus is associated with a two- to six-fold increased risk for first or recurrent ischemic stroke. The mechanisms for the association are myriad and include the effects of hyperglycemia on vascular tissues and coagulation, and aberrations in blood pressure regulation, lipid metabolism, endothelial function, vascular inflammation, lipid metabolism, smooth muscle cell proliferation, and fibrinolysis. The most effective strategies to prevent stroke among people with diabetes include blood pressure control, antiplatelet therapy, and statin therapy. Tight glycemic control is recommended to prevent microvascular disease, but the effect on macrovascular disease, including stroke, has not been proven. Target blood pressure should be less than 130/80. Antiplatelet therapy may be accomplished with 81 to 325 mg of aspirin daily or 75 mg of clopidogrel daily. Statins should be given in dosages effective to reduce lowdensity lipoprotein cholesterol to less than 100 mg/dL. For glycemic control, first line therapy for most patients is metformin, starting at 500 mg daily. With time, most patients will need two or three oral medications from different classes and many eventually will require insulin therapy. Prevention of diabetes may be best accomplished by identifying those at risk and modifying diet, weight, and exercise habits. Screening for prediabetes and diabetes is appropriate for men and women older than 45 years and all individuals with vascular disease. Insulin resistance and impaired insulin secretion is the major underlying defect in type 2 diabetes mellitus. It also affects 50% of nondiabetic subjects with a recent ischemic stroke. Emerging evidence has linked insulin resistance to the pathophysiologic derangements in type 2 diabetes mellitus that accelerate atherosclerosis. Treatment of insulin resistance with weight loss, exercise, or medication can correct these derangements, and represents a promising approach to stroke prevention.     

Epidemiology of end-stage kidney disease

End-stage kidney disease (ESKD) is a common and morbid disease that affects patients’ quality and length of life, representing a large portion of health care expenditure in the United States. These patients commonly have associated diabetes and cardiovascular disease, with high rates of cardiovascular-related death. Management of ESKD requires renal replacement therapy via dialysis or transplantation. While transplantation provides the greatest improvement in survival and quality of life, the vast majority of patients are treated initially with hemodialysis. However, outcomes differ significantly among patient populations. Barriers in access to care have particularly affected at-risk populations, such as Black and Hispanic patients. These patients receive less pre-ESKD nephrology care, are less likely to initiate dialysis with a fistula, and wait longer for transplants—even in pediatric populations. Priorities for ESKD care moving into the future include increasing access to nephrology care in underprivileged populations, providing patient-centered care based on each patient’s “life plan,” and focusing on team-based approaches to ESKD care. This review explores ESKD from the perspective of epidemiology, costs, vascular access, patient-reported outcomes, racial disparities, and the impact of the COVID-19 crisis.     

Pathological consequences of C-peptide deficiency in insulin-dependent diabetes mellitus

Diabetes is associated with several complications such as retinopathy, nephropathy, neuropathy and cardiovascular diseases. Currently, insulin is the main used medication for management of insulin-dependentdiabetes mellitus(type-1 diabetes). In this metabolic syndrome, in addition to decrease of endogenous insulin, the plasma level of connecting peptide(C-peptide) is also reduced due to beta cell destruction. Studies in the past decade have shown that C-peptide is much more than a byproduct of insulin biosynthesis and possess different biological activities. Therefore, it may be possible that C-peptide deficiency be involved, at least in part, in the development of different complications of diabetes. It has been shown that a small level of remaining C-peptide is associated with significant metabolic benefit. The purpose of this review is to describe beneficial effects of C-peptide replacement on pathological features associated with insulin-dependent diabetes. Also, experimental and clinical findings on the effects of C-peptide on wholebody glucose utilization, adipose tissue metabolism and tissues blood flow are summarized and discussed. The hypoglycemic, antilipolytic and vasodilator effects of C-peptide suggest that it may contribute to fine-tuning of the tissues metabolism under different physiologic or pathologic conditions. Therefore, C-peptide replacement together with the classic insulin therapy may prevent, retard, or ameliorate diabetic complications in patients with type-1 diabetes.     

When ESKD complicates cancer screening and cancer treatment

End-stage kidney disease (ESKD) affects the recommended screening, incidence, treatment, and mortality of cancer. Cancer occurring in a patient with ESKD can influence candidacy for kidney transplantation as well as dialysis decision-making and cancer treatment. Certain cancers are more common among ESKD patients, notably, viral-mediated cancers that are associated with human papilloma or hepatitis viruses, and urothelial cancers associated with analgesic and Balkan nephropathies. Solid tumors are not believed to occur more frequently in ESKD patients. The presence of ESKD may confer a higher risk of post-surgical complications as well as mortality. The cost-effectiveness of cancer screening depends upon individual cancer risk and estimated overall survival. The high mortality associated with ESKD argues against routine cancer screening in dialysis patients. Cancer treatment in ESKD may be complicated by the need to avoid, adjust doses of and/or coordinate the timing of administration of imaging contrast, chemotherapy, and immunotherapy with dialysis treatments. There is a general dearth of information on the treatment of cancer in ESKD patients. These issues will be discussed, and some general guidelines presented based upon the current literature.     

Incorporating ethnic and cultural food preferences in the renal diet

Medical nutrition therapy (MNT), nutrition education, and counseling are essential components for effective management of end-stage kidney disease (ESKD). Patients with ESKD have to alter their diets and to implement new eating behaviors, sometimes irrespective of ethnic and cultural food preferences because of their high content of specific nutrients. Ethnic and cultural factors influence dietary adherence. Therefore, assessing cultural issues surrounding food and food preferences may help improve dietary adherence. A large percentage of the ESKD population in the United States is black and Hispanic, with cultural food preferences that are particularly high in potassium, phosphorus, and sodium. This article provides an overview of the role of culture and ethnicity in food habits and dietary adherence, a list of cultural and ethnic foods that should be examined and incorporated in the development of an appropriate renal diet meal plan for black and Hispanic Americans with ESKD, and practical recommendations for cross-cultural nutrition counseling. If MNT is to be effective in the medical management of patients from different cultural and ethnic backgrounds, it must incorporate more traditional and customary foods in the renal diet meal plan.