William M. Steinberg

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. METHODS In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. RESULTS A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. CONCLUSIONS In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).

Infectious Causes of Acute Pancreatitis

A wide variety of infectious agents has been associated with acute pancreatitis. Strict diagnostic criteria were developed to assess with relationship between individual microorganisms and acute pancreatitis. Pathologic or radiologic evidence of pancreatitis associated with well-documented infection was noted with viruses (mumps, coxsackie, hepatitis B, cytomegalovirus, varicella-zoster virus, herpes simplex virus), bacteria (Mycoplasma, Legionella, Leptospira, Salmonella), fungi (Aspergillus), and parasites (Toxoplasma, Cryptosporidium, Ascaris). Clues to the infectious nature of pancreatitis lay in the characteristic signs and symptoms associated with the particular infectious agent. How often these agents are responsible for idiopathic pancreatitis is unclear.

Design of the liraglutide effect and action in diabetes: Evaluation of cardiovascular outcome results (LEADER) trial

BACKGROUND Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. CONCLUSIONS LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m2. There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM.

Elevated serum levels of tumor marker CA19-9 in acute cholangitis

The purpose of the present study was to examine the relationship between the “tumor marker,” CA19-9, and benign biliary tract disease. We measured serum and bile CA19-9 in 40 patients with (1) symptomatic cholelithiasis (N=14), (2) common bile duct obstruction without cholangitis (N=8), (3) acute cholangitis secondary to gallstone disease (N=7), and (4) acute cholecystitis (N=11). All seven patients with acute cholangitis had marked elevations of serum CA19-9 (range 190-32,000 units/ml; 75 units/ml cutoff), whereas none of the patients in the other groups had elevated levels despite similar degrees of cholestasis and similarly high levels of CA19-9 in gallbladder and common duct bile (range 7.3×104−2.3×109 units/ml). Of the three patients with cholangitis in whom CA19-9 levels were followed serially, all had rapid return of levels to normal after successful treatment. We conclude that the “tumor marker” CA19-9 is markedly elevated in the serum of patients with acute cholangitis but not in patients with other forms of benign biliary tract disease.

Urinary trypsinogen activation peptide (TAP) predicts severity in patients with acute pancreatitis.

SummaryConclusionsUrinary TAP obtained within the first 48 h of the onset of symptoms can distinguish patients with severe acute pancreatitis.BackgroundUrinary trypsinogen activation peptide (TAP) has recently been described as an early marker of severity in acute pancreatitis.MethodsIn a multicenter study, urine samples were collected for TAP concentration at 6–12, 24, and 48 h after admission from 139 patients with acute pancreatitis (99 with mild disease, 40 with severe disease) and from 50 control patients. Severity of acute pancreatitis was defined by the presence of organ failure and/or pancreatic necrosis on dynamic contrast-enhanced computed tomography.ResultsMedian urinary TAP in the 139 patients with acute pancreatitis compared to the 50 control patients was significantly higher at admission, 4.6 vs 0.8 ng/mL (p<0.001), and 6–12 h, 1.9 vs 0.55 ng/mL (p=0.04). Among patients who presented within 48h of the onset of symptoms, the median urinary TAP for severe pancreatitis (9 patients) compared to mild pancreatitis (40 patients) was significantly higher at admission, 29.6 vs. 3.6 ng/mL (p=0.001). Also, when obtained within 48h of the onset of symptoms, all patients with severe pancreatitis had an admission urinary TAP level>10 ng/mL. The sensitivity and specificity of an admission urinary TAP≥10 for severe pancreatitis was 100 and 85%, respectively. Given a cutoff of 10 ng/mL for an admission urinary TAP obtained within 48h of the onset of symptoms, the negative predictive value was 100% for mild pancreatitis.

Treatment of acute pancreatitis

In this review, we compared the outcome of 25 studies of experimentally induced pancreatitis in animals with 13 studies of human acute pancreatitis in which the same therapeutic agents were used (aprotinin, glucagon, 5-fluorouracil, somatostatin, peritoneal lavage). Whereas 81% of the animal studies had a positive outcome (improvement in survival), only 7.7% of the human studies showed a positive outcome on survival. Most animal studies suffered from a protocol in which treatment was not significantly delayed after induction of acute pancreatitis. Of the 12 human studies that showed no effect of treatment on survival, none had sufficient statistical power (1 - beta error) for the investigators to have confidence in the negative outcomes. This was due to the fact that the studies had too few patients or that the event rates in the untreated populations were too low. Only five of the human studies reported the complication rates of acute pancreatitis in patients who did not die of their disease. Treatment (by any agent) did not improve the complication rate in these studies, but only one of the five reports had sufficient statistical power for the investigators to have confidence in these negative results. Large multicenter studies with sufficient numbers of patients with severe pancreatitis (high mortality and complication rates) are needed to evaluate new therapies in this disease.

Sphincter of Oddi dysfunction: A clinical controversy

This report analyzes the literature on sphincter of Oddi dysfunction as it applies to biliary-type pain. The sensitivities and specificities of the tests used to diagnose this condition (e.g., size of bile duct, drainage time of bile duct, provocative tests with morphine, sphincter of Oddi manometry) are poorly defined. Recent studies suggest that noninvasive tests such as quantitative nuclear scintigraphy and fatty meal sonography may aid in diagnosing functional common bile duct obstruction. Continuous manometry of the biliary tree with microtransducer technologies may allow a greater understanding of the causes of pain in this group of patients. Only 1 case report of pharmacologic management for this disorder exists in the literature. Endoscopic sphincterotomy may be helpful in relieving the pain that occurs in this condition but is associated with increased risks. There is no consensus in the literature as to the best test that will predict response to sphincterotomy. Controlled trials of medical therapies are needed.

Infected pancreatic necrosis and peripancreatic fluid collections: Serendipitous response to antibiotics and medical therapy in three patients

Three patients with clinical and radiologic evidence of pancreatic necrosis or peripancreatic fluid collections/inflammatory masses who were advised to have surgery on the basis of bacterial infection on skinnyneedle aspiration of the pancreas but were deemed medically unstable or refused operative intervention were treated with intensive antibiotic therapy. All three patients survived the attack of acute pancreatitis with infection on medical therapy alone. This suggests that occasional patients with infected necrosis and/or peripancreatic collections/inflammatory masses may respond to antibiotics, especially those antibiotics that have recently been shown to have a high penetration into pancreatic tissue.

Chronic pancreatitis: A complication of systemic lupus erythematosus

Systemic lupus erythematosus (SLE), an autoimmune disease with multisystem involvement, has been reported to be associated with a number of gastrointestinal complications. Acute pancreatitis is an unusual manifestation of this disorder. This report presents two cases of patients with SLE who developed chronic pancreatitis with no other identifiable etiology.

Controversies in clinical pancreatology

Dr. William M. Steinberg’s Introduction: Prior to the November 1998 meeting of the American Pancreatic Association (APA) in Chicago, the members of the APA were sent the following case report and asked to indicate how they would have managed this case; the results of this survey follow. In addition, Dr. Peter Layer, Professor of Medicine at Israelitic Hospital in Hamburg, Germany, and member of the Committee on Controversies in Pancreatology, arranged to have two experts in this area, Drs. John Neoptolemos, Professor and Head of the Department of Surgery at the University of Liverpool, United Kingdom, and Ulrich R. Fölsch, Professor of Medicine and Head of the Department of Internal Medicine at the Christian-Albrechts-University of Kiel, Germany, debate this case at the November 1998 meetings. The manuscript was received in 1999, and subsequently underwent revision prior to this publication. Background by Dr. Peter Layer: It is now commonly accepted that (transient) obstruction of the ampulla of Vater caused by a migrating common-bile-duct concrement and/or by local edema plays a crucial role in the pathogenesis of acute biliary pancreatitis. On the other hand, it is also undisputed that urgent endoscopic retrograde cholangiopancreatography (ERCP) with the aim of stone extraction is the optimal treatment for several specific complications of choledocholithiasis, such as clinical biliary obstruction, stone impaction, or cholangitis, with rapid clinical improvement after successful intervention. By contrast, mild acute biliary pancreatitis is not improved in its further course by urgent sphincterotomy and stone removal in the absence of these complications, as has been demonstrated by several randomized controlled trials (1–3). In cases of severe biliary pancreatitis, however, the issue has remained unsettled because results of these studies have led to contradicting conclusions. In particular, it has been debated controversially, on the basis of these studies, whether urgent endoscopic therapy decreases mortality, rates of some complications, and/or duration of disease. Drs. John Neoptolemos and Ulrich R. Fölsch, who have organized two of the large prospective studies, have debated this important issue, as exemplified by the case of a young woman with an initially mild, subsequently severe gallstone pancreatitis.