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The mesalamine wars heat up–enter balsalazide
574
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 124, No. 2
help to prevent the vascular complications and reduce the incidence of ulcer complications to 1.6% over 1 year. Another option to prevent relapse of ulcer complications is to change to an antiplatelet agent, like clopidogrel, which lacks effect on gastric mucosa. Multiple studies have shown that these agents are better than aspirin in preventing vascular events but with much less gastrointestinal side effects (Eur Heart J 2000;21:2033–2041). A study comparing these newer antiplatelet agents with PPI in the prevention of ulcer relapse in both H. pylori–positive and H. pylori–negative patients with aspirin-related ulcer complications is now underway at our center. K. C. LAI, M.R.C.P. W. M. HUI, M.D. S. K. LAM, M.D.
THE MESALAMINE WARS HEAT UP–ENTER BALSALAZIDE Levine DS, Riff DS, Pruitt R, Weuble L, Koval G, Sales D, Bell JK, Johnson LK (Division of Gastroenterology, Seattle, Washington, and Salix Pharmaceuticals, Palo Alto, California). A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002;97:1398 –1407. First line therapy for patients with ulcerative colitis (UC) consists almost exclusively of sulfasalazine and its mesalamine (5-ASA) derivatives. The newest such agent introduced into the U.S. market, balsalazide disodium (Colazal; Salix Pharmaceuticals, Raleigh, NC), has undergone multiple studies of its use in ulcerative colitis, with direct comparison to other mesalamine products. Recently, Levine et al. (Am J Gastroenterol 2002;97:1398 – 1497) conducted an 8-week multicenter randomized, double blind, double-dummy dose response study with either of 2 doses of balsalazide (2.25 or 6.75g/day) or with mesalamine (2.4 g; Asacol European tablet formulation; Smith Kline and French Laboratories, Welwyn Garden City, UK) in 154 adult patients with recently relapsed mild to moderate UC. Primary endpoints included stool frequency, rectal bleeding, abdominal pain, and functional status. Flexible sigmoidoscopies with biopsies were performed at screening and at defined time points. Patient symptoms and sigmoidoscopic scores comprised the “Physician’s Global Assessment (PGA),” and patient diaries tracked functional status. Plasma samples were taken to measure 5-ASA and N-acetyl-5-ASA levels. The primary measure of efficacy was defined as a difference in rectal bleeding and at least one other symptom or sign. Remission (defined as a normal stool frequency and no blood in the stool for 48 hours before visit, a PGA score of “quiescent,” and a sigmoidoscopic score of “mild” or “normal”), rectal biopsy scores, and health-related quality of life (IBDQ) were secondary efficacy measures. Patients were discontinued from the study if they worsened or suffered from prohibitive adverse events.
Data was analyzed using both intent-to-treat (ITT) and eligible-for-efficacy (EFE) analyses, with statistical testing via the Cochran-Mantel-Haenszel, Wilcoxon-Mann-Whitney, 2, and ANOVA tests. There were 7 fewer patients in the EFE than the ITT group because of protocol violations. The results showed that the efficacy of balsalazide was found to be dose-dependent. The higher dose was superior in achieving the primary endpoint, as reflected in rectal bleeding, stool frequency, and sigmoidoscopic scores by ITT analysis, as well as PGA by EFE analysis. The disease activity score distribution for the secondary endpoints was also significantly better with the higher dose, as was histologic healing. Mean 5-ASA and N-acetyl-5-ASA levels were similar, suggesting minimal systemic absorption of the agent. The equimolar balsalazide 6.75 g and mesalamine 2.4 g were comparable in the achievement of the primary endpoint. The balsalazide group had higher sigmoidoscopic improvement rates at 2 (55% vs. 29%) and 8 weeks (74% vs. 45%, ITT analysis only), and significantly more favorable disease activity score distributions for the secondary endpoints of rectal bleeding, sigmoidoscopic score, and PGA. Remission rates, histologic healing, adverse event, and withdrawal rates were similar between the 2 agents. Mean 5-ASA plasma levels were over 4 times higher and N-acetyl-5-ASA levels twice as high in the mesalamine group. Remission rates, adverse event, and withdrawal rates (31% overall) were similar between the 3 groups. Health-related quality of life IBDQ scores are not reported for any of the groups. The authors’ conclusion was that the efficacy of balsalazide is dose-dependent and more rapid in onset than mesalamine. Comment. The “Mesalamine Wars” recently heated up with the introduction of balsalazide to the market in the United States. Comparisons between the mesalamine agents are rarely performed; most studies targeted the older, sulfa-plagued agent sulfasalazine. Despite a more favorable side-effect profile, it has been hard for any of the agents to show a benefit over the venerable old dog of therapy (Aliment Pharmacol Ther 2002;16:69 –77). This is surprising, given the use of mesalamine doses up to 3 times higher than “high-dose sulfasalazine” (4 g sulfasalazine contains only 1.6 g mesalamine). When analyzing these agents, it is useful to understand their mechanisms of release, which may explain their varying degrees of coverage, absorption, and side-effect profile. Sulfasalazine is sulfapyridine linked by an azo-bond to mesalamine. This bond is broken by the bacterial azo-reductase in the colon (Ann Intern Med 1984;101: 377–386). As a result, sulfasalazine and the other agents that contain this azo-bond are colonic-released only. This would include olsalazine (Dipentum [Pharmacia, Upjohn, Peapack, NJ], two mesalamine molecules linked by such a bond) and balsalazide (Colazal, mesalaminelinked by the azo-bond to an inert carrier 4-aminobenzoyl-betaalanine). Asacol is coated mesalamine tablet or capsule (US) released at a pH of 7, typically in the distal ileum and throughout the colon, although some variability in colonic pH levels (Dig Dis Sci 1993;38: 1989 –1993), in release of the product in the fed and fasting state (Pract Gastroenterol 1999;Nov(suppl):1– 8), and in patients with and without diarrhea have been shown (Scand J Gastroenterol 1992;27: 863– 868). Pentasa’s (Roberts Pharmaceuticals Corp, Eatontown, NJ) mesalamine is released by moisture throughout the small and the
February 2003
SELECTED SUMMARIES
large colon. Mesalamine is also available in an enema (Rowasa; Solvay Pharmaceuticals, Inc, Marietta, GA), and as a suppository (Canasa; Axcan Scandipharm Inc, Birmingham, AL). Mesalamine is intended to coat the lining of the inflamed bowel, and not to be absorbed into the blood stream. Putative benefits due to specific release mechanisms have been difficult to validate in the absence of head-to-head comparisons between agents. However, this study as well as other recent comparisons between balsalazide and the Asacol formulation of mesalamine has raised a few eyebrows. This study’s findings suggested that equimolar doses of the 2 agents are equivalent by the primary endpoint, but that subanalysis and secondary endpoints suggest a benefit of balsalazide in multiple areas. These results echo previous studies comparing the same 2 agents. Green et al. (Gastroenterology 1998;114:15–22) initially showed superior remission rates, quicker time to first asymptomatic day, and fewer adverse events in the balsalazide-treated group. Comparing the same agents at the same dose, an abstract by Pruitt et al. (Gastroenterology 2000;118:A120 –A121) found faster time to symptom relief with balsalazide, but only in newly diagnosed left-sided colitis patients. It is hypothesized that more of the mesalamine in the colonic-released agents is available to the colonic mucosa (due to less small bowel absorption of the drug) than in the case of other formulations. This is supported by the finding of higher plasma 5-ASA and N-acetyl-5-ASA levels in the mesalamine-treated patients in the current study. Comparable efficacy of the 2 agents in maintenance of remission of ulcerative colitis has also been found (Gut 2001;49:783– 789). Critics have pointed out that the Asacol formulation used in these studies is different from the formulation available in the United States, and that higher doses of Asacol are used in some patients, although typically only if they fail the standard 2.4 g dose. It is unknown how the 2 agents would fare in comparisons at higher doses. The number of pills, 9 for balsalazide vs. 6 for mesalamine, and the capsule size (considerably larger for balsalazide) are also factors that need to be considered. However, the balsalazide capsules can be opened up and the compound mixed in foods such as applesauce for patients who cannot or will not swallow pills. When it comes down to it, my recommendations are as follows: if a patient is doing well on a mesalamine agent, then do not change it based on hypothetical benefits of another agent. However, do be aware that some patients are intolerant to one of the mesalamine-based agents, but may tolerate the others quite well. “More works better” when using oral mesalamine, and the side effects are typically not dose-related. The dose to induce remission is often the most effective dose to maintain remission. Finally, do not forget about topical therapy. Many patients with left-sided disease do extremely well very quickly with mesalamine enemas or suppositories, both for induction and maintenance of a remission (Am J Gastroenterol 2000;95:1263– 1276). The overall goal is to keep people well and to keep them off of corticosteroids, and if it takes manipulation of the mesalamine agents, their dose, or even a combination of oral and topical therapies, it is far preferable to suffering the many complications associated with corticosteroids. RUSSELL D. COHEN, M.D.
THE STOMACH AND WEIGHT REDUCTION: THE ROLE OF GHRELIN Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (Departments of Medicine and Surgery,
575
University of Washington, the Veterans Affairs Puget Sound Health Care System, Harborview Medical Center, and University Hospital, Seattle, Washington; and Department of Medicine, Oregon Health and Science University, Portland, Oregon). Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623–1630. Obese individuals who experience initial success with controlled dieting often regain much of the lost weight. In contrast, some surgical treatments of obesity produce prolonged weight reduction. Recently, a hormone produced by the stomach, ghrelin, was shown to evoke weight gain by actions in the hypothalamus. In the present study, Cummings and colleagues compared plasma ghrelin levels after supervised dieting versus gastric bypass surgery to ascertain why operative treatments may succeed when medical programs fail. Normal weight subjects at their lifetime maximal weight served as controls for 3 groups of obese volunteers. The dietaryweight-loss group was comprised of 13 obese subjects fed a 1000 kcal per day, low-fat, high-protein diet for 3 months followed by transition to a solid diet containing 30% fat, 15% protein, and 55% carbohydrate for 3 more months, which maintained a stable weight reduction of 17.4%. The postsurgical group consisted of 5 patients who had undergone proximal Roux-en-Y gastric bypass 9 –31 months, previously producing a 36% loss of body mass. Results from this group were compared with 5 obese controls from the dietary-weight-loss group who were matched to the gastric-bypass subjects according to final body mass indices, age, and sex. Subjects were admitted after overnight fasting for serial testing. Blood was withdrawn at 30 – 60-minute intervals for measurement of ghrelin, leptin, and insulin. Meals were ingested at standard times. Insulin sensitivity was assessed by tolbutamide-modified intravenous glucose tolerance testing. At the start and end of the study, body fat was quantified by underwater weight measurement and computed tomography. Adipocyte volumes were determined from the diameters of 400 adipocytes aspirated from the iliac crest region. The diet-treated group exhibited absolute reductions in body fat (35.3%), body fat as a percent of total weight (22%), intraabdominal fat (46.6%), and subcutaneous fat (35.8%). Fat cell volumes diminished by 28.8%, fasting leptin and insulin levels decreased, and insulin sensitivity improved. Ghrelin levels increased before meals and decreased to a trough 1–2 hours after eating. Diurnal cycling was noted with peaks between 12 and 2 AM and nadirs at 9 –10 AM. After dietinduced weight loss, plasma ghrelin was increased at every time point compared with before diet measurements. Positive correlations between weight loss and cumulative ghrelin release were observed. Gastric bypass subjects exhibited markedly different ghrelin profiles. The cumulative ghrelin release over 24 hours was 77% lower after gastric bypass than in the normal weight controls and 72% less than the diet-treated matched obese controls. Ghrelin levels did not fluctuate with meals and showed no diurnal variability. Conversely, bypass
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 124, No. 2
help to prevent the vascular complications and reduce the incidence of ulcer complications to 1.6% over 1 year. Another option to prevent relapse of ulcer complications is to change to an antiplatelet agent, like clopidogrel, which lacks effect on gastric mucosa. Multiple studies have shown that these agents are better than aspirin in preventing vascular events but with much less gastrointestinal side effects (Eur Heart J 2000;21:2033–2041). A study comparing these newer antiplatelet agents with PPI in the prevention of ulcer relapse in both H. pylori–positive and H. pylori–negative patients with aspirin-related ulcer complications is now underway at our center. K. C. LAI, M.R.C.P. W. M. HUI, M.D. S. K. LAM, M.D.
THE MESALAMINE WARS HEAT UP–ENTER BALSALAZIDE Levine DS, Riff DS, Pruitt R, Weuble L, Koval G, Sales D, Bell JK, Johnson LK (Division of Gastroenterology, Seattle, Washington, and Salix Pharmaceuticals, Palo Alto, California). A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis. Am J Gastroenterol 2002;97:1398 –1407. First line therapy for patients with ulcerative colitis (UC) consists almost exclusively of sulfasalazine and its mesalamine (5-ASA) derivatives. The newest such agent introduced into the U.S. market, balsalazide disodium (Colazal; Salix Pharmaceuticals, Raleigh, NC), has undergone multiple studies of its use in ulcerative colitis, with direct comparison to other mesalamine products. Recently, Levine et al. (Am J Gastroenterol 2002;97:1398 – 1497) conducted an 8-week multicenter randomized, double blind, double-dummy dose response study with either of 2 doses of balsalazide (2.25 or 6.75g/day) or with mesalamine (2.4 g; Asacol European tablet formulation; Smith Kline and French Laboratories, Welwyn Garden City, UK) in 154 adult patients with recently relapsed mild to moderate UC. Primary endpoints included stool frequency, rectal bleeding, abdominal pain, and functional status. Flexible sigmoidoscopies with biopsies were performed at screening and at defined time points. Patient symptoms and sigmoidoscopic scores comprised the “Physician’s Global Assessment (PGA),” and patient diaries tracked functional status. Plasma samples were taken to measure 5-ASA and N-acetyl-5-ASA levels. The primary measure of efficacy was defined as a difference in rectal bleeding and at least one other symptom or sign. Remission (defined as a normal stool frequency and no blood in the stool for 48 hours before visit, a PGA score of “quiescent,” and a sigmoidoscopic score of “mild” or “normal”), rectal biopsy scores, and health-related quality of life (IBDQ) were secondary efficacy measures. Patients were discontinued from the study if they worsened or suffered from prohibitive adverse events.
Data was analyzed using both intent-to-treat (ITT) and eligible-for-efficacy (EFE) analyses, with statistical testing via the Cochran-Mantel-Haenszel, Wilcoxon-Mann-Whitney, 2, and ANOVA tests. There were 7 fewer patients in the EFE than the ITT group because of protocol violations. The results showed that the efficacy of balsalazide was found to be dose-dependent. The higher dose was superior in achieving the primary endpoint, as reflected in rectal bleeding, stool frequency, and sigmoidoscopic scores by ITT analysis, as well as PGA by EFE analysis. The disease activity score distribution for the secondary endpoints was also significantly better with the higher dose, as was histologic healing. Mean 5-ASA and N-acetyl-5-ASA levels were similar, suggesting minimal systemic absorption of the agent. The equimolar balsalazide 6.75 g and mesalamine 2.4 g were comparable in the achievement of the primary endpoint. The balsalazide group had higher sigmoidoscopic improvement rates at 2 (55% vs. 29%) and 8 weeks (74% vs. 45%, ITT analysis only), and significantly more favorable disease activity score distributions for the secondary endpoints of rectal bleeding, sigmoidoscopic score, and PGA. Remission rates, histologic healing, adverse event, and withdrawal rates were similar between the 2 agents. Mean 5-ASA plasma levels were over 4 times higher and N-acetyl-5-ASA levels twice as high in the mesalamine group. Remission rates, adverse event, and withdrawal rates (31% overall) were similar between the 3 groups. Health-related quality of life IBDQ scores are not reported for any of the groups. The authors’ conclusion was that the efficacy of balsalazide is dose-dependent and more rapid in onset than mesalamine. Comment. The “Mesalamine Wars” recently heated up with the introduction of balsalazide to the market in the United States. Comparisons between the mesalamine agents are rarely performed; most studies targeted the older, sulfa-plagued agent sulfasalazine. Despite a more favorable side-effect profile, it has been hard for any of the agents to show a benefit over the venerable old dog of therapy (Aliment Pharmacol Ther 2002;16:69 –77). This is surprising, given the use of mesalamine doses up to 3 times higher than “high-dose sulfasalazine” (4 g sulfasalazine contains only 1.6 g mesalamine). When analyzing these agents, it is useful to understand their mechanisms of release, which may explain their varying degrees of coverage, absorption, and side-effect profile. Sulfasalazine is sulfapyridine linked by an azo-bond to mesalamine. This bond is broken by the bacterial azo-reductase in the colon (Ann Intern Med 1984;101: 377–386). As a result, sulfasalazine and the other agents that contain this azo-bond are colonic-released only. This would include olsalazine (Dipentum [Pharmacia, Upjohn, Peapack, NJ], two mesalamine molecules linked by such a bond) and balsalazide (Colazal, mesalaminelinked by the azo-bond to an inert carrier 4-aminobenzoyl-betaalanine). Asacol is coated mesalamine tablet or capsule (US) released at a pH of 7, typically in the distal ileum and throughout the colon, although some variability in colonic pH levels (Dig Dis Sci 1993;38: 1989 –1993), in release of the product in the fed and fasting state (Pract Gastroenterol 1999;Nov(suppl):1– 8), and in patients with and without diarrhea have been shown (Scand J Gastroenterol 1992;27: 863– 868). Pentasa’s (Roberts Pharmaceuticals Corp, Eatontown, NJ) mesalamine is released by moisture throughout the small and the
February 2003
SELECTED SUMMARIES
large colon. Mesalamine is also available in an enema (Rowasa; Solvay Pharmaceuticals, Inc, Marietta, GA), and as a suppository (Canasa; Axcan Scandipharm Inc, Birmingham, AL). Mesalamine is intended to coat the lining of the inflamed bowel, and not to be absorbed into the blood stream. Putative benefits due to specific release mechanisms have been difficult to validate in the absence of head-to-head comparisons between agents. However, this study as well as other recent comparisons between balsalazide and the Asacol formulation of mesalamine has raised a few eyebrows. This study’s findings suggested that equimolar doses of the 2 agents are equivalent by the primary endpoint, but that subanalysis and secondary endpoints suggest a benefit of balsalazide in multiple areas. These results echo previous studies comparing the same 2 agents. Green et al. (Gastroenterology 1998;114:15–22) initially showed superior remission rates, quicker time to first asymptomatic day, and fewer adverse events in the balsalazide-treated group. Comparing the same agents at the same dose, an abstract by Pruitt et al. (Gastroenterology 2000;118:A120 –A121) found faster time to symptom relief with balsalazide, but only in newly diagnosed left-sided colitis patients. It is hypothesized that more of the mesalamine in the colonic-released agents is available to the colonic mucosa (due to less small bowel absorption of the drug) than in the case of other formulations. This is supported by the finding of higher plasma 5-ASA and N-acetyl-5-ASA levels in the mesalamine-treated patients in the current study. Comparable efficacy of the 2 agents in maintenance of remission of ulcerative colitis has also been found (Gut 2001;49:783– 789). Critics have pointed out that the Asacol formulation used in these studies is different from the formulation available in the United States, and that higher doses of Asacol are used in some patients, although typically only if they fail the standard 2.4 g dose. It is unknown how the 2 agents would fare in comparisons at higher doses. The number of pills, 9 for balsalazide vs. 6 for mesalamine, and the capsule size (considerably larger for balsalazide) are also factors that need to be considered. However, the balsalazide capsules can be opened up and the compound mixed in foods such as applesauce for patients who cannot or will not swallow pills. When it comes down to it, my recommendations are as follows: if a patient is doing well on a mesalamine agent, then do not change it based on hypothetical benefits of another agent. However, do be aware that some patients are intolerant to one of the mesalamine-based agents, but may tolerate the others quite well. “More works better” when using oral mesalamine, and the side effects are typically not dose-related. The dose to induce remission is often the most effective dose to maintain remission. Finally, do not forget about topical therapy. Many patients with left-sided disease do extremely well very quickly with mesalamine enemas or suppositories, both for induction and maintenance of a remission (Am J Gastroenterol 2000;95:1263– 1276). The overall goal is to keep people well and to keep them off of corticosteroids, and if it takes manipulation of the mesalamine agents, their dose, or even a combination of oral and topical therapies, it is far preferable to suffering the many complications associated with corticosteroids. RUSSELL D. COHEN, M.D.
THE STOMACH AND WEIGHT REDUCTION: THE ROLE OF GHRELIN Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (Departments of Medicine and Surgery,
575
University of Washington, the Veterans Affairs Puget Sound Health Care System, Harborview Medical Center, and University Hospital, Seattle, Washington; and Department of Medicine, Oregon Health and Science University, Portland, Oregon). Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623–1630. Obese individuals who experience initial success with controlled dieting often regain much of the lost weight. In contrast, some surgical treatments of obesity produce prolonged weight reduction. Recently, a hormone produced by the stomach, ghrelin, was shown to evoke weight gain by actions in the hypothalamus. In the present study, Cummings and colleagues compared plasma ghrelin levels after supervised dieting versus gastric bypass surgery to ascertain why operative treatments may succeed when medical programs fail. Normal weight subjects at their lifetime maximal weight served as controls for 3 groups of obese volunteers. The dietaryweight-loss group was comprised of 13 obese subjects fed a 1000 kcal per day, low-fat, high-protein diet for 3 months followed by transition to a solid diet containing 30% fat, 15% protein, and 55% carbohydrate for 3 more months, which maintained a stable weight reduction of 17.4%. The postsurgical group consisted of 5 patients who had undergone proximal Roux-en-Y gastric bypass 9 –31 months, previously producing a 36% loss of body mass. Results from this group were compared with 5 obese controls from the dietary-weight-loss group who were matched to the gastric-bypass subjects according to final body mass indices, age, and sex. Subjects were admitted after overnight fasting for serial testing. Blood was withdrawn at 30 – 60-minute intervals for measurement of ghrelin, leptin, and insulin. Meals were ingested at standard times. Insulin sensitivity was assessed by tolbutamide-modified intravenous glucose tolerance testing. At the start and end of the study, body fat was quantified by underwater weight measurement and computed tomography. Adipocyte volumes were determined from the diameters of 400 adipocytes aspirated from the iliac crest region. The diet-treated group exhibited absolute reductions in body fat (35.3%), body fat as a percent of total weight (22%), intraabdominal fat (46.6%), and subcutaneous fat (35.8%). Fat cell volumes diminished by 28.8%, fasting leptin and insulin levels decreased, and insulin sensitivity improved. Ghrelin levels increased before meals and decreased to a trough 1–2 hours after eating. Diurnal cycling was noted with peaks between 12 and 2 AM and nadirs at 9 –10 AM. After dietinduced weight loss, plasma ghrelin was increased at every time point compared with before diet measurements. Positive correlations between weight loss and cumulative ghrelin release were observed. Gastric bypass subjects exhibited markedly different ghrelin profiles. The cumulative ghrelin release over 24 hours was 77% lower after gastric bypass than in the normal weight controls and 72% less than the diet-treated matched obese controls. Ghrelin levels did not fluctuate with meals and showed no diurnal variability. Conversely, bypass