Louis Kuritzky

The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension

Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson’s disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards ‘best practices’ when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members’ discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension.

Recent developments in the management of overactive bladder: focus on the efficacy and tolerability of once daily solifenacin succinate 5 mg

ABSTRACT Background: Overactive bladder (OAB) is a highly prevalent symptom complex that may be extremely distressing to the patient, and can be associated with co-morbidities and reduced quality of life (QoL). One of the major pathophysiological causes of OAB is overactivity of the detrusor muscle, mediated via muscarinic receptors in the bladder. Urgency is the defining symptom of OAB, yet a significant proportion of patients also suffer from incontinence, which is the most distressing symptom to the patient. As such, restoration of continence should be a primary treatment goal. However, effective treatments should also impact on the other key symptoms of OAB, such as micturition frequency and urgency. Non-pharmacologic interventions to treat OAB can be effective but require patients to be highly motivated. In terms of pharmacologic therapy, treatment with an antimuscarinic agent is the mainstay of current therapy. Solifenacin succinate is a once-daily oral antimuscarinic for the treatment of OAB. The recommended dose is 5 mg once daily and can be increased to 10 mg once daily if 5 mg is well tolerated. Objectives: This paper reviews clinical experience with solifenacin 5 mg in patients with OAB as this is the recommended dose according to FDA product labeling. Findings: In Phase 3 studies, based on data captured in 3-day micturition diaries, greater than half of patients who were incontinent at baseline no longer reported experiencing incontinence episodes after 12 weeks of double-blind treatment with solifenacin 5 mg. Furthermore, compared with placebo, solifenacin treatment resulted in statistically significant reductions in incontinence episodes, micturition frequency and urgency episodes, with significant increases in volume voided (based on an analysis of key symptom outcomes in two pooled Phase 3 studies presented here). The most common treatment-related adverse events were expected anticholinergic side effects (dry mouth, constipation, and blurred vision), and these were generally mild to moderate. Discontinuation rates due to adverse events in the treatment and placebo groups were comparable. Conclusion: Solifenacin 5 mg was found to be efficacious and had an acceptable tolerability profile in patients with OAB in these trials and this treatment may provide QoL benefits to patients.

Advances in Rheumatology: Coxibs and Beyond

Arthritis is a growing health concern in the US with approximately 70 million Americans currently affected. This figure will inevitably rise as the population ages. The pain and decreased mobility associated with arthritis have a significant impact on quality of life and because patients with arthritis are less active than the general population, they are at risk of additional conditions such as obesity, heart disease, diabetes, and hypertension. There are currently no disease modifying osteoarthritis (OA) drugs available; therefore anti-inflammatory, and/or analgesic medications such as acetaminophen and NSAIDs and simple analgesics form the mainstay of treatment. Coxibs may be preferred to traditional NSAIDs because of their improved gastrointestinal (GI ) safety and tolerability profile. The use of topical agents may also be beneficial in some patients. In rheumatoid arthritis (RA) where disease modifying drugs (DMARDs) are available, anti-inflammatory agents such as NSAIDs and coxibs are used as adjuncts to disease modifying therapy. However, patients with RA are at increased risk of NSAID-related GI injury, particularly if they are also on corticosteroid medication. Pharmacological treatment of both RA and OA should be combined with appropriate nonpharmacological modalities such as patient education, exercise programs, and joint motion and strengthening exercises. Such activities may delay joint degradation and help maintain physical function.

Safety and Efficacy of Dulaglutide, a Once Weekly GLP-1 Receptor Agonist, for the Management of Type 2 Diabetes

Abstract Background: Type 2 diabetes (T2D) is an increasingly common endocrine disorder that is characterized by chronic hyperglycemia and tissue compartment abnormalities, including macrovascular and microvascular complications. More than 90% of patients with T2D will be diagnosed and treated in the primary care setting. One of the relatively recent additions to the increasing array of approved antidiabetic medications is the glucagon-like peptide-1 receptor agonist class. Mechanisms of action for glucagon-like peptide-1 receptor agonists include: 1) stimulation of insulin secretion through β-cells, though only when glucose levels are elevated (hence, minimizing risk for hypoglycemia); 2) blunting of glucagon secretion; 3) increased satiety; and 4) decreased rate of release of gastric contents into the small intestine, thereby reducing glycemic load. Recent T2D treatment guidelines encourage individualization of therapy. Many patients still do not achieve optimal glycemic control. Therefore, other treatment options are important. Methods: A literature search was performed using PubMed and MEDSCAPE to retrieve abstracts and articles pertinent to topics discussed in this review. Original research articles, reviews, and clinical trial manuscripts were identified based on relevance. Only English language articles were considered. Results: In 3 phase 3 registration trials in patients with T2D, once-weekly dulaglutide demonstrated superior efficacy at the primary endpoint to metformin as monotherapy, to sitagliptin as add-on to metformin, and to exenatide twice daily as add-on to metformin and pioglitazone. The safety profile of dulaglutide in these trials is similar to currently available glucagon-like peptide-1 receptor agonists, characterized predominantly by gastrointestinal symptoms (ie, nausea, vomiting, and diarrhea). Based on these results, once-weekly dulaglutide should be a relevant additional treatment option for the management of T2D.

The efficacy of tadalafil in improving sexual satisfaction and overall satisfaction in men with mild, moderate, and severe erectile dysfunction: a retrospective pooled analysis of data from randomized, placebo-controlled clinical trials

ABSTRACT Background: Satisfaction with the sexual experience is considered important when evaluating the impact of treatments for erectile dysfunction (ED), yet satisfaction has been infrequently assessed in clinical trials. Objective: To evaluate satisfaction with, and enjoyment of, the sexual experience in men with ED enrolled in 11 placebo-controlled clinical trials of tadalafil. Study design and methods: Retrospective pooled analysis of data from 11 randomized, double blind, placebo-controlled clinical trials of tadalafil. Men with mild (N = 838), moderate (N = 558), or severe (N = 703) ED who were randomized to tadalafil 10 mg or 20 mg or placebo taken as needed for 12 weeks were included in this analysis. Efficacy measures included the International Index of Erectile Function (IIEF). Reported herein are the scores on the IIEF overall satisfaction domain and individual IIEF questions (IIEF‐Q7, satisfaction with intercourse; and IIEF‐Q8, enjoyment of intercourse). Results: At least moderate satisfaction (IIEF overall satisfaction domain) was reported by 55% and 72% of patients with mild ED taking tadalafil 10 mg and 20 mg, respectively, compared with 33% taking placebo ( p < 0.002); 60% and 65% vs. 19% of patients with moderate ED ( p < 0.001); and 32% and 49% vs. 9% with severe ED ( p < 0.001). Satisfactory intercourse during most attempts or almost always/always (IIEF‐Q7) was reported by 59% and 79% of patients with mild ED taking tadalafil 10 mg and 20 mg vs. 32% taking placebo ( p < 0.001); 52% and 65% vs. 18% with moderate ED ( p < 0.001); and 28% and 49% vs. 5% with severe ED ( p < 0.001). Highly or very highly enjoyable intercourse (IIEF‐Q8) was reported by 45% and 63% of patients with mild ED taking tadalafil 10 mg and 20 mg vs. 21% taking placebo ( p < 0.001); 43% and 56% vs. 16% with moderate ED ( p < 0.001); and 19% and 44% vs. 5% with severe ED ( p < 0.001). Conclusions: Compared with placebo, tadalafil 10 mg and 20 mg improved overall satisfaction with the sexual experience, intercourse satisfaction, and intercourse enjoyment in men with mild, moderate, and severe ED.

Identification and Management of Albuminuria in the Primary Care Setting

Albuminuria is an important risk marker for adverse cardiovascular (CV) and renal outcomes and mortality. The relationship between albuminuria and risk is continuous and linear, like that of blood pressure and cardiovascular risk. Evidence now supports increased risk even at levels traditionally considered within normal limits. In high‐risk patients, routine annual screening can detect changes in urine albumin excretion and improve the timely identification of albuminuria, and therefore should be considered in patients with diabetes, hypertension, and chronic kidney disease. Preferred simple screening methods appropriate for use in the primary care setting include microalbumin‐specific dipsticks and urinary albumin:creatinine ratio determination (from a spot urine sample). Cornerstones of albuminuria treatment include risk factor management, ongoing monitoring, and, in patients with hypertension, chronic kidney disease, or diabetes, the use of renin‐angiotensin‐aldosterone system (RAAS)–blocking agents. Both angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have demonstrated utility in this regard; data from studies of direct renin inhibition are promising. The combined use of an ACE inhibitor and ARB was once considered a viable option for the treatment of albuminuria; however, results of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) raised important questions regarding the benefits and limitations of dual RAAS blockade. Ongoing studies should provide important insight into the effects of this approach on renal outcomes. J Clin Hypertens (Greenwich). 2011;13:438–449. ©2011 Wiley Periodicals, Inc.

Nonsteroidal anti-inflammatory drugs in the treatment of low back pain

Low back pain (LBP) is amongst the top ten most common conditions presenting to primary care clinicians in the ambulatory setting. Further, it accounts for a significant amount of health care expenditure; indeed, over one third of all disability dollars spent in the United States is attributable to low back pain. In most cases, acute low back pain is a self-limiting disease. There are many evidence-based guidelines for the management of LBP. The most common risk factor for development of LBP is previous LBP, heavy physical work, and psychosocial risk factors. Management of LBP includes identification of red flags, exclusion of specific secondary causes, and comprehensive musculoskeletal/neurological examination of the lower extremities. In uncomplicated LBP, imaging is unnecessary unless symptoms become protracted. Reassurance that LBP will likely resolve and advice to maintain an active lifestyle despite LBP are the cornerstones of management. Medications are provided not because they change the natural history of the disorder, but rather because they enhance the ability of the patient to become more active, and in some cases, to sleep better. The most commonly prescribed medications include nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants. Although NSAIDs are a chemically diverse class, their similarities, efficacy, tolerability, and adverse effect profile have more similarities than differences. The most common side effects of NSAIDs are gastrointestinal. Agents with cyclo-oxygenase 2 selectivity are associated with reduced gastrointestinal bleeding, but problematic increases in adverse cardiovascular outcomes continue to spark concern. Fortunately, short-term use of NSAIDs for LBP is generally both safe and effective. This review will focus on the role of NSAIDs in the management of LBP.

A practical approach for implementation of a basal-prandial insulin therapy regimen in patients with type 2 diabetes

Basal-prandial insulin therapy is a physiologic approach to insulin delivery that utilizes multiple daily injections to cover both basal (ie, overnight fasting and between-meal) and prandial (ie, glucose excursions above basal at mealtime) insulin needs. While basal-prandial therapy with multiple daily injections is an important therapeutic option for patients with type 2 diabetes, there is a common perception that this therapy is difficult to initiate in the primary care setting. To address this issue, a panel of clinical experts convened to develop practical recommendations on how to initiate basal-prandial therapy in patients with type 2 diabetes, focusing on patient selection, simple dosing and titration, and monitoring. Patients with type 2 diabetes who are appropriate candidates for basal-prandial insulin therapy include those who: 1) are unable to achieve glycemic control on oral antidiabetic drugs, 2) are unable to achieve glycemic control on split-mixed/premixed insulin regimens, 3) are newly diagnosed but unlikely to respond to oral antidiabetic drugs alone (ie, the patient has severe hyperglycemia or a markedly elevated glycosylated hemoglobin A1C level for which oral antidiabetic drug therapy alone is unlikely to achieve goals), and 4) prefer this therapy due to socioeconomic or other individual considerations. Basal-prandial insulin can be initiated in a simple stepwise manner, starting first with the addition of basal insulin to the existing oral antidiabetic drug regimen, followed by the introduction of 1 prandial insulin injection to the basal insulin plus oral antidiabetic drug regimen (after basal insulin has been optimized). Subsequently, other injections of prandial insulin may be added when needed. Based on home glucose monitoring data, patients may be converted from split-mixed or premixed insulin regimens to basal-prandial regimens with similar ease. Basal-prandial therapy using newer insulin formulations, such as long- and rapid-acting insulin analogs, can be relatively simple to use in patients with type 2 diabetes and is an appropriate methodology for application by primary care clinicians.

Answers to the most common questions about the hepatic safety profile of duloxetine.

Since its first FDA approval in 2004, duloxetine has been taken by more than 5 million patients. A small fraction of patients treated with duloxetine develop elevations in liver enzymes, which generally resolve spontaneously without any change in treatment. Very rare cases (estimated 1-2 per 100,000 exposures) of idiosyncratic hepatic toxicity have been reported in patients taking duloxetine, particularly in those with substantial alcohol use and/or preexisting liver disease. In the context of more than 23,000 patients exposed during clinical trials, and more than 1.5 million patient years of exposure subsequent to product launch, the hepatic risk after exposure to duloxetine appears to be within the range identified for other therapeutic agents. Therefore, it does not warrant hepatic enzyme monitoring. As with any medication, physicians should follow prescribing guidelines and educate patients on the risks and benefits of duloxetine.

Enhanced glycemic control with combination therapy for type 2 diabetes in primary care.

Type 2 diabetes mellitus is an increasingly common medical problem for primary care clinicians to address. Treatment of diabetes has evolved from simple replacement of insulin (directly or through insulin secretagogs) through capture of mechanisms such as insulin sensitizers, alpha-glucosidase inhibitors, and incretins. Only very recently has recognition of the critical role of the gastrointestinal system as a major culprit in glucose dysregulation been established. Since glycated hemoglobin A1c reductions provide meaningful risk reduction as well as improved quality of life, it is worthwhile to explore evolving paths for more efficient use of the currently available pharmacotherapies. Because diabetes is a progressive disease, even transiently successful treatment will likely require augmentation as the disorder progresses. Pharmacotherapies with complementary mechanisms of action will be necessary to achieve glycemic goals. Hence, clinicians need to be well informed about the various noninsulin alternatives that have been shown to be successful in glycemic goal attainment. This article reviews the benefits of glucose control, the current status of diabetes control, pertinent pathophysiology, available pharmacological classes for combination, limitations of current therapies, and suggestions for appropriate combination therapies, including specific suggestions for thresholds at which different strategies might be most effectively utilized by primary care clinicians.