Optimization of guideline-directed medical therapies in patients with diabetes and chronic kidney disease.

Diabetes is the leading cause of chronic kidney disease (CKD) and kidney failure worldwide. CKD frequently coexists with heart failure and atherosclerotic cardiovascular disease in the broader context of cardio-kidney-metabolic syndrome. Diabetes and CKD are associated with increased risk of all-cause and cardiovascular death as well as decreased quality of life. The role of metabolic and hemodynamic abnormalities has long been recognized as an important contributor to the pathogenesis and progression of CKD in diabetes, while a more recent and growing body of evidence supports activation of both systemic and local inflammation as important contributors. Current guidelines recommend therapies targeting pathomechanisms of CKD in addition to management of traditional risk factors such as hyperglycemia and hypertension. Sodium-glucose cotransporter-2 inhibitors are recommended for treatment of patients with CKD and type 2 diabetes (T2D) if eGFR is ≥20 ml/min/173 m2 on a background of renin-angiotensin system inhibition. For patients with T2D, CKD, and atherosclerotic cardiovascular disease, a glucagon-like peptide-1 receptor agonist is recommended as additional risk-based therapy. A non-steroidal mineralocorticoid receptor antagonist is also recommended as additional risk-based therapy for persistent albuminuria in patients with T2D already treated with renin-angiotensin system inhibition. Implementation of guideline-directed medical therapies is challenging in the face of rapidly accumulating knowledge, high cost of medications, and lack of infrastructure for optimal healthcare delivery. Furthermore, studies of new therapies have focused on T2D and CKD. Clinical trials are now planned to inform the role of these therapies in people with type 1 diabetes (T1D) and CKD.

Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease.

PURPOSE OF REVIEW: Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Development of DKD increases risks for cardiovascular events and death. Glucagon-like peptide-1 (GLP-1) receptor agonist have demonstrated improved cardiovascular and kidney outcomes in large-scale clinical trials. RECENT FINDING: GLP-1 and dual GLP-1/glucose-depending insulinotropic polypeptide (GIP) receptor agonists have robust glucose-lowering efficacy with low risk of hypoglycemia even in advanced stages of DKD. Initially approved as antihyperglycemic therapies, these agents also reduce blood pressure and body weight. Cardiovascular outcome and glycemic lowering trials have reported decreased risks of development and progression of DKD and atherosclerotic cardiovascular events for GLP-1 receptor agonists. Kidney and cardiovascular protection is mediated partly, but not entirely, by lowering of glycemia, body weight, and blood pressure. Experimental data have identified modulation of the innate immune response as a biologically plausible mechanism underpinning kidney and cardiovascular effects. SUMMARY: An influx of incretin-based therapies has changed the landscape of DKD treatment. GLP-1 receptor agonist use is endorsed by all major guideline forming organizations. Ongoing clinical trials and mechanistic studies with GLP-1 and dual GLP-1/GIP receptor agonists will further define the roles and pathways for these agents in the treatment of DKD.

Geriatric Syndromes in Older Adults with Diabetes.

Over one-quarter of adults ≥65 years old have diabetes in the United States. Guidelines recommend individualization of glycemic targets in older adults with diabetes as well as implementing treatment strategies that minimize risk for hypoglycemia. Patient-centered management decisions should be informed by comorbidities, the individual's capacity for self-care, and the presence of key geriatric syndromes that may impact self-management and patient safety. Key geriatric syndromes include cognitive impairment, depression, functional impairments (eg, vision, hearing, and mobility challenges), falls and fractures, polypharmacy, and urinary incontinence. Screening for geriatric syndromes in older adults is recommended to inform treatment strategies and optimize outcomes.

Incretin Therapies for Patients with Type 2 Diabetes and Chronic Kidney Disease.

Since the early 2000s, an influx of novel glucose-lowering agents has changed the therapeutic landscape for treatment of diabetes and diabetes-related complications. Glucagon-like peptide-1 (GLP-1) receptor agonists represent an important therapeutic class for the management of type 2 diabetes (T2D), demonstrating benefits beyond glycemic control, including lowering of blood pressure and body weight, and importantly, decreased risk of development of new or worsening chronic kidney disease (CKD) and reduced rates of atherosclerotic cardiovascular events. Plausible non-glycemic mechanisms that benefit the heart and kidneys with GLP-1 receptor agonists include anti-inflammatory and antioxidant effects. Further supporting their use in CKD, the glycemic benefits of GLP-1 receptor agonists are preserved in moderate-to-severe CKD. Considering current evidence, major guideline-forming organizations recommend the use of GLP-1 receptor agonists in cases of T2D and CKD, especially in those with obesity and/or in those with high cardiovascular risk or established heart disease. Evidence continues to build that supports benefits to the heart and kidneys of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. Ongoing outcome and mechanistic studies will continue to inform our understanding of the role of GLP-1 and dual GLP-1/GIP receptor agonists in diverse patient populations with kidney disease.

Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence.

As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.

Postoperative delirium in Parkinson's disease patients following deep brain stimulation surgery.

Deep brain stimulation (DBS) surgery is an effective treatment for patients with advanced Parkinson's disease. Delirium in hospitalized Parkinson's disease patients is common and often leads to prolonged hospital stays. This study reports on the incidence and etiology of postoperative delirium following DBS surgery. Patients (n=59) with advanced Parkinson's disease underwent bilateral (n=56) or unilateral (n=3) DBS electrode implant surgery, followed 1 week later with surgical placement of DBS generators. The development of delirium during either hospital stay was evaluated retrospectively from the hospital chart. Potential causes of delirium were evaluated, including history of delirium, opiate equivalents, medication administration delays and missed doses during hospitalization, and Parkinson's disease duration. Delirium following implantation of DBS electrodes was common (22% of patients). It was less commonly associated with generator placement (10%). A history of delirium, age, and disease duration were positive predictors of delirium. Opiate equivalent doses were negatively correlated with delirium. Missed Parkinson's medication doses (53% of patients) and delayed administration (81% of patients) were common, and had a slight relation with delirium. Delirium was not related to complexity of medication regimen or use of dementia medications. Despite the presence of delirium most patients still only required a single night in the hospital post-surgery (67%). Prolonged hospital stay was due not only to delirium but also severe off states and other medical issues. Recognition and expectant management of delirium is best accomplished in a multidisciplinary setting, including the patient's family and nursing, pharmacy and neurological surgery staff.

Clinical review of treatment options for select nonmotor symptoms of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with a host of nonmotor symptoms, including psychosis, cognitive impairment, depression, sleep disturbance, swallowing disorders, gastrointestinal symptoms, and autonomic dysfunction. The nonmotor symptoms of PD have the potential to be more debilitating than the motor features of the disorder. OBJECTIVE: The aim of this article was to review treatment options for the nonmotor manifestations of PD, including pharmacologic and nonpharmacologic interventions. METHODS: The PubMed and MEDLINE databases were searched for articles published in English between January 1966 and April 2010, using the terms Parkinson's disease, nonmotor, psychosis, hallucination, antipsychotic, cognitive impairment, dementia, depression, sleep disturbance, sleepiness, REM (rapid eye movement) sleep behavior disorder, dysphagia, swallowing disorder, sialorrhea, gastrointestinal, constipation, autonomic dysfunction, orthostatic hypotension, gastroparesis, erectile dysfunction, sexual dysfunction, and urinary dysfunction. Articles were selected for review if they were randomized controlled trials (RCTs), meta-analyses, or evidence-based reviews of treatment of patients with PD, and/or expert opinion regarding the treatment of nonmotor symptoms of PD. RESULTS: A total of 148 articles, including RCTs, meta-analyses, and evidence-based reviews, were included in this review. The treatment of hallucinations or psychosis in PD should include a stepwise reduction in medications for motor symptoms, followed by the use of quetiapine or clozapine. Dementia may be treated with acetylcholinesterase inhibitors. Evidence is lacking concerning the optimal pharmacologic treatment for depression in PD, with expert opinions indicating selective serotonin reuptake inhibitors as the antidepressants of choice. However, the largest study to date found nortriptyline therapy to be efficacious compared with placebo, whereas paroxetine controlled release was not. A variety of sleep disturbances may plague a person with PD, and treatment must be individualized to the patient's specific sleep disturbance pattern and contributing factors. Swallowing disorders may lead to aspiration and pneumonia, and patients with dysphagia should be referred to a speech therapist for further evaluation and treatment. Orthostasis may be treated with nonpharmacologic interventions as well as pharmacologic treatments (eg, fludrocortisone, midodrine, indomethacin). Other autonomic symptoms are managed in a manner similar to that in patients without PD, although careful attention must be aimed at avoiding dopamine-blocking therapies in the treatment of gastrointestinal dysfunction and gastroparesis. CONCLUSIONS: Various pharmacologic and nonpharmacologic strategies are available for the management of the nonmotor symptoms of PD. The challenges associated with nonmotor symptoms must not be forgotten in light of the motor symptoms of PD, and treatment of nonmotor symptoms should be encouraged.

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Type 2 diabetes mellitus traditionally has been characterized by insulin resistance and beta-cell dysfunction, leading to hyperglycemia and eventual micro- and macrovascular complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of drugs available for the management of type 2 diabetes. In order to provide a comprehensive evaluation and comparison of the pharmacology, pharmacokinetics, efficacy, and safety of the DPP-4 inhibitors-sitagliptin, vildagliptin, saxagliptin, and alogliptin-in the treatment of type 2 diabetes, we conducted a MEDLINE search (1966-July 2009) for pertinent English-language articles. Abstracts of the annual meetings of the American Diabetes Association and European Association for the Study of Diabetes from 2005-2009 were also searched. As a drug class, the DPP-4 inhibitors have become widely accepted in clinical practice because of their low risk of hypoglycemia, favorable adverse-effect profile, and once-daily dosing. They are weight neutral (do not cause weight gain or loss) and appear to decrease beta-cell apoptosis and increase beta-cell survival. Because clinical studies directly comparing agents from this class have not, to our knowledge, been conducted, making comparisons in terms of efficacy and safety will become difficult for clinicians as more agents become available. Based on information from preclinical, clinical, and postmarketing data, there does not appear to be a compelling advantage of one DPP-4 inhibitor over another in terms of efficacy, safety, or ease of clinical use. Although theoretical advantages exist for agents with a higher specificity for DPP-4 inhibition versus inhibition of other isoenzymes associated with toxicity, comparative studies and/or increased clinical experience with this class of drug will determine the clinical advantages, if any, of one agent over another.

Ethnicity/race, use of pharmacotherapy, scope of physician-ordered cholesterol screening, and provision of diet/nutrition or exercise counseling during US office-based visits by patients with hyperlipidemia.

BACKGROUND: Elevation of serum cholesterol, or hyperlipidemia, is recognized as one of the major modifiable risk factors in the development of atherosclerosis and cardiovascular disease. On a US population basis, there has been a downward trend in total- and LDL-cholesterol levels, and an increase in cholesterol screening. Nevertheless, previous research suggests that there remain racial/ethnic disparities in the access to and quality of care for hyperlipidemia. OBJECTIVE: The aim of this study was to examine the extent of racial/ethnic disparities in the provision of pharmacotherapy, cholesterol screening and diet/nutrition or exercise counseling during US office-based physician-patient encounters (visits) by patients with hyperlipidemia. METHODS: We examined data from the 2005 US National Ambulatory Medical Care Survey for office-based visits for hyperlipidemia for patients aged > or =20 years in terms of prescribing for hyperlipidemia, and the ordering/provision of cholesterol testing, diet/nutrition counseling, and exercise counseling. RESULTS: Use of pharmacotherapy for hyperlipidemia varied by ethnicity/race (chi2, p < 0.05). Physician-ordered/provided cholesterol screening occurred in 44.2% of all office-based visits; 46.5% for Whites, 35.4% for Blacks, and 30.3% for Hispanics (chi2, p < 0.05). Diet/nutrition counseling was ordered/provided in 39.7% of office-based visits; 40.4% for Whites, 32.6% for Blacks, and 39.0% for Hispanics (chi2, p < 0.05). Exercise counseling was ordered/provided in 32.1% of office-based visits; 32.7% for Whites, 27.2% for Blacks, and 30.6% for Hispanics (chi2, p < 0.05). CONCLUSIONS: These findings reveal a disparity in use of pharmacotherapy for hyperlipidemia, physician-ordered/provided cholesterol screening, diet/nutrition counseling, and exercise counseling by ethnicity/race. Further research is required to discern, in greater detail, reasons for the observed differences reported, and to ensure equitable access to established standards of care.

Pharmacology, efficacy and safety of liraglutide in the management of type 2 diabetes.

Liraglutide is a glucagon-like peptide-1 analog with pharmacokinetic properties suitable for once-daily administration approved by the Food and Drug Administration for the treatment of patients with type 2 diabetes. Clinical trial data from large, controlled studies demonstrate the safety and efficacy of liraglutide in terms of hemoglobin A(1c) (HbA(1c)) reduction, reductions in body weight, and the drug's low risk for hypoglycemic events when used as monotherapy. Liraglutide has been studied as monotherapy and in combination with metformin, glimepiride, and rosiglitazone for the treatment of type 2 diabetes. Additionally, comparative data with insulin glargine and exenatide therapy are available from Phase III trials. Once-daily administration may provide a therapeutic advantage for liraglutide over twice-daily exenatide, with similar improvements in HbA(1c) and body weight observed when liraglutide was compared with exenatide. The glucose-dependent mechanism of insulin release with incretin analog therapy holds potential clinical significance in the management of postprandial hyperglycemic excursions, with minimal risk of hypoglycemia when used with non-secretagogue medications. Data to date on patient-reported outcomes with liraglutide treatment are encouraging. The most common adverse events associated with liraglutide therapy are dose-dependent nausea, vomiting, and diarrhea. Diligent postmarketing surveillance to elucidate the risk of pancreatitis and medullary thyroid carcinoma in a heterogeneous population are likely warranted.

Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors.

OBJECTIVE: To review the pharmacology (absorption, metabolism, distribution, elimination, and contraindications) of incretin-based agents currently available and in regulatory review for the treatment of patients with type 2 diabetes. DATA SOURCES: Medline search of all relevant clinical and review articles. STUDY SELECTION: English-language articles pertinent to the pharmacology, pharmacodynamics, pharmacokinetics, efficacy, and safety of glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors were reviewed for relevance. DATA EXTRACTION: Data pertinent to the pharmacology, pharmacodynamics, pharmacokinetics, efficacy, and safety of GLP-1 agonists and DPP-4 inhibitors were extracted and used. DATA SYNTHESIS: Incretin hormones are secreted from the gastrointestinal tract following meal ingestion, the two most important of which are glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. Patients with type 2 diabetes have an impaired response to GIP, while intravenous GLP-1 has been shown to increase insulin secretion in response to elevated glucose levels. Incretin-based agents include GLP-1 receptor agonists, which mimic endogenous GLP-1, and DPP-4 inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, alogliptin), which inhibit the breakdown of endogenous incretin hormones. GLP-1 receptor agonists stimulate insulin secretion in a glucose-dependent manner and suppress glucagon secretion with a low risk of hypoglycemia. The GLP-1 receptor agonists are further differentiated as either human analogues (e.g., liraglutide) or synthetic exendin-based mimetics (e.g., exenatide). These agents delay gastric emptying and may beneficially affect satiety and are thus associated with weight reduction. CONCLUSION: GLP-1 receptor agonists and DPP-4 inhibitors facilitate therapy intensification and achievement of established glycemic goals. They enhance postprandial and fasting glycemic control, and use may improve beta-cell function and possibly preserve beta-cell mass. GLP-1 receptor agonists may also have favorable effects on blood pressure. They may be introduced as adjuncts to ongoing therapy with conventional agents with a potential benefit of slowing the progression of type 2 diabetes.

Pharmacologic management of the older patient with type 2 diabetes mellitus.

BACKGROUND: Pharmacologic options for the treatment of elderly patients with type 2 diabetes mellitus (T2DM) are the same as in younger adults; however, treatment considerations differ in the elderly due to changes in renal and hepatic function, life expectancy, and various other clinical and practical considerations. OBJECTIVE: This article discusses geriatric considerations in the pharmacologic management of T2DM and reviews the potential clinical advantages and disadvantages of pharmacologic agents currently available for the treatment of T2DM, including oral and injectable medications. METHODS: A search of MEDLINE was conducted for articles published in English between January 1966 and September 2009 using the terms type 2 diabetes mellitus, elderly, geriatric, treatment, insulin, metformin, sulfonylurea, thiazolidinedione, alpha-glucosidase inhibitor, meglitinide, DPP-4 inhibitor, colesevelam, exenatide, and pramlintide. Meta-analyses, randomized controlled trials of pharmacologic treatment, and evidence-based reviews and/or expert opinions regarding the treatment of T2DM in the elderly were selected for review. RESULTS: In overweight patients, metformin has been associated with reductions in risk for all-cause mortality and stroke compared with insulin and sulfonylureas. Older patients who are frail, anorexic, or underweight and those with congestive heart failure (CHF), renal or hepatic insufficiency, or dehydration may not be appropriate candidates for metformin therapy. The substantial risk of hypoglycemia with insulin secretagogues is increased by 36% in the elderly compared with younger adults; however, this risk is counterbalanced by the extensive clinical experience with these agents in the geriatric population. Thiazolidinediones should generally be avoided in patients with CHF and are absolutely contraindicated in patients with class II-IV heart failure. They have been associated with peripheral edema, as well as with decreases in bone mineral density in women. There is limited information on the use of dipeptidyl peptidase-4 inhibitors in the elderly, although dose adjustment is required in patients with renal compromise. In practice, substantial gastrointestinal adverse effects limit the use of alpha-glucosidase inhibitors in older patients. Colesevelam is associated with numerous drug interactions and can cause new or worsening constipation. There are limited data on the use of exenatide in the elderly. It may be beneficial in older patients with limited mobility who could benefit from weight loss, whereas it may not be a good option for frail, underweight adults. Use of exenatide is not recommended in patients with a creatinine clearance <30 mL/min. Given the increased monitoring required to avoid hypoglycemic events with pramlintide, this agent should be used with caution in older adults, particularly the frail elderly. Most patients with T2DM eventually require insulin; however, due to the risk of hypoglycemia and related morbidity, careful use of insulin is warranted in the geriatric population. CONCLUSIONS: Overall, there is a scarcity of data regarding the use of pharmacologic agents in older adults with T2DM, and clinical guidance is largely based on data obtained from younger populations. The selection of appropriate drug regimens for these patients remains challenging.

Looking to the future: focus on DPP-4 inhibitors for the treatment of type 2 diabetes and emerging therapies.

Strong evidence exists demonstrating the benefits of tight glycemic control in type 1 and type 2 diabetes mellitus patients, but glycemic goals are not adequately achieved for many patients. Advancement in the knowledge surrounding the physiology of endogenous glucoregulatory peptide hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, has led to new therapeutic targets for the treatment of type 2 diabetes mellitus. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide practitioners with a novel mechanism of action to use for combination therapies for the treatment of type 2 diabetes mellitus. This article, part 3 of a 3-part series, reviews the new class of medications known as DPP-4 inhibitors as well as discusses a future buccal insulin formulation, Oral-Lyn, on the horizon for the treatment of diabetes mellitus.

Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus.

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1alpha, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12-24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.