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Doug Brunk is a San Diego-based award-winning reporter who began covering health care in 1991. Before joining the company, he wrote for the health sciences division of Columbia University and was an associate editor at Contemporary Long Term Care magazine when it won a Jesse H. Neal Award. His work has been syndicated by the Los Angeles Times and he is the author of two books related to the University of Kentucky Wildcats men's basketball program. Doug has a master’s degree in magazine journalism from the S.I. Newhouse School of Public Communications at Syracuse University. Follow him on Twitter @dougbrunk.
VIDEO: Efficacy of DMTs decreases with age
San Diego – , and high-efficacy drugs do a better job of inhibiting MS disability compared with low-efficacy drugs only in patients younger than 40.5 years.
Those are the key conclusions from a meta-analysis of the age-dependent efficacy of MS treatments that was published in the November 2017 issue of Frontiers in Neurology. In a video interview, Ann Marie Weideman, lead study author, discussed highlights from the meta-analysis at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The meta-analysis drew from more than 28,000 individuals with MS participating in 38 trials of 13 categories of immunomodulatory drugs.
Ms. Weideman is an IRTA Fellow at the National Institute of Neurological Disorders and Stroke, Bethesda, Md. She reported that study coauthor Bibiana Bielekova, MD, is coinventor of several patents related to daclizumab.
San Diego – , and high-efficacy drugs do a better job of inhibiting MS disability compared with low-efficacy drugs only in patients younger than 40.5 years.
Those are the key conclusions from a meta-analysis of the age-dependent efficacy of MS treatments that was published in the November 2017 issue of Frontiers in Neurology. In a video interview, Ann Marie Weideman, lead study author, discussed highlights from the meta-analysis at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The meta-analysis drew from more than 28,000 individuals with MS participating in 38 trials of 13 categories of immunomodulatory drugs.
Ms. Weideman is an IRTA Fellow at the National Institute of Neurological Disorders and Stroke, Bethesda, Md. She reported that study coauthor Bibiana Bielekova, MD, is coinventor of several patents related to daclizumab.
San Diego – , and high-efficacy drugs do a better job of inhibiting MS disability compared with low-efficacy drugs only in patients younger than 40.5 years.
Those are the key conclusions from a meta-analysis of the age-dependent efficacy of MS treatments that was published in the November 2017 issue of Frontiers in Neurology. In a video interview, Ann Marie Weideman, lead study author, discussed highlights from the meta-analysis at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The meta-analysis drew from more than 28,000 individuals with MS participating in 38 trials of 13 categories of immunomodulatory drugs.
Ms. Weideman is an IRTA Fellow at the National Institute of Neurological Disorders and Stroke, Bethesda, Md. She reported that study coauthor Bibiana Bielekova, MD, is coinventor of several patents related to daclizumab.
REPORTING FROM ACTRIMS FORUM 2018
Many drugs in the pipeline for IBD treatment
LAS VEGAS – .
“The challenge for all of us is to integrate the right drugs for the right patients,” William J. Sandborn, MD, AGAF, said at the inaugural Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Dr. Sandborn, professor and chief of the division of gastroenterology at the University of California, San Diego, began his presentation by highlighting anti-integrin therapies for inflammatory bowel disease (IBD) treatment. These leukocyte membrane glycoproteins target beta1 and beta7 subunits. They interact with endothelial ligands VCAM-1, fibronectin, and MadCAM-1, and mediate leukocyte adhesion and trafficking. Approved anti-integrin therapies to date include natalizumab and vedolizumab, while investigational therapies include etrolizumab, PF-00547,659, abrilumab, and AJM 300.
In a phase 2 study of etrolizumab as induction therapy for moderate to severe UC, Séverine Vermeire, MD, Dr. Sandborn, and associates randomized 124 patients to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2 or a 420-mg loading dose at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo (The Lancet 2014 348;309-18). They found that etrolizumab was more likely to lead to clinical remission at week 10 than was placebo, especially at the 100-mg dose. Meanwhile, a more recent study of the anti-MAdCAM antibody PF-00547659 in patients with moderate to severe ulcerative colitis found that it was better than placebo for induction of remission (The Lancet 2017;390:135-144). Investigators for the trial, known as TURANDOT, found that the greatest clinical effects were observed with the 22.5-mg and 75-mg doses. “This is now being taken forward in phase 3 trials by Shire,” Dr. Sandborn said.
The anti-interleukin 12/23 antibody (p40) ustekinumab is being investigated for efficacy in UC, while anti-interleukin 23 (p19) antibodies being studied include brazikumab (MEDI2070), risankizumab (BI 6555066), geslekumab, mirikizumab (LY3074828), and tildrakizumab (MK 3222). In 2015, Janssen launched NCT02407236, with the aim of evaluating the effectiveness and safety of continuing ustekinumab as a subcutaneous (injection) maintenance therapy in patients with moderately to severely active UC who have demonstrated a clinical response to an induction treatment with intravenous ustekinumab. The estimated primary completion date is April 12, 2018. Meanwhile, a phase 2a trial of 119 patients with moderate to severe Crohn’s disease who had failed treatment with tumor necrosis factor (TNF) antagonists showed that treatment with MEDI2070 was associated with clinical improvement after 8 and 24 weeks of therapy (Gastroenterol 2017;153:77-86). The investigators also found that patients with baseline serum IL-22 concentrations above the median threshold concentration of 15.6 pg/mL treated with MEDI2070 had higher rates of clinical response and remission, compared with those with baseline concentrations below this threshold. According to Dr. Sandborn, who was not involved in the study, these results provide support for further research on the value of IL-22 serum concentrations to predict response to MEDI2070. “It’s a small study and is hypothesis generating,” he said. “This will need to be confirmed in subsequent trials.”
In a short-term study of 121 patients with active Crohn’s disease, Brian G. Feagan, MD, Dr. Sandborn, and associates found that risankizumab was more effective than placebo for inducing clinical remission, particularly at the 600-mg dose, compared with the 200-mg dose (Lancet 2017;389:1699-709). The researchers also observed significant differences in endoscopic remission among patients on the study drug, compared with those on placebo (17% vs. 3%; P = .0015) as well as endoscopic response (32% vs. 13%; P = .0104). The trial provides further evidence that selective blockade of interleukin 23 via inhibition of p19 might be a viable therapeutic approach in Crohn’s disease.
Janus kinase (JAK) inhibitors under investigation for Crohn’s disease include tofacitinib, filgotinib, upadacitinib, baricitinib, and TD-1473. In the OCTAVE Induction 1 trial led by Dr. Sandborn, 18.5% of the patients in the tofacitinib group achieved remission at 8 weeks, compared with 8.2% in the placebo group (P = .007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% vs. 3.6% (P less than .001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group vs. 11.1% in the placebo group (P less than 0.001 for both comparisons with placebo; N Engl J Med. 2017;376:1723-36). “In subgroup analyses, it looks like the 10-mg dose is more effective for maintenance in patients who previously received anti-TNF therapy,” said Dr. Sandborn, who also directs the UCSD IBD Center. “All secondary outcomes were positive. You don’t see that very often. It tells you that this is a really effective therapy. It’s currently being reviewed by the FDA.”
Meanwhile, a phase 2 trial found that a higher percentage of patients with mild to moderate Crohn’s disease who received a 200-mg dose of filgotinib over 10 weeks achieved clinical remission, compared with those who received placebo (47% vs. 23%, respectively; P = .0077; The Lancet 2017;389:266-75). Serious treatment-emergent adverse effects occurred in 9% of the 152 patients treated with filgotinib and 3 of the 67 patients treated with placebo. According to Dr. Sandborn, filgotinib is currently in phase 3 development trials for both Crohn’s Disease and UC. At the same time, results from an unpublished study presented at the annual Digestive Disease Week in 2017 found that 16 weeks of treatment with the investigational agent upadacitinib led to modified clinical remission in 37% of patients on the 24-mg bid dose, compared with 30% of patients in the 6-mg bid dose. There was also a dose response for endoscopic response. “Based on these data, this drug is now in a phase 3 trial, so lots of JAK inhibitors are coming along,” he said.
Sphingosine-1–phosphate receptor 1 (S1P1) modulators currently under investigation include fingolimod (not studied in IBD), ozanimod, and etrasimod. “These modulators cause the S1P1 receptors that are expressed on the surface of positive lymphocytes to be eluded back into the cell, which leads to a reversible reduction in circulating lymphocytes in the blood,” Dr. Sandborn explained. In a phase 2 trial, he and his associates found that UC patients who received ozanimod at a daily dose of 1 mg had a slightly higher rate of clinical remission, compared with those who received placebo, but the study was not sufficiently powered to establish clinical efficacy or assess safety (N Engl J. Med 2016;374:1754-62).
Dr. Sandborn reported having consulting relationships with Takeda, Genentech, Pfizer, Shire, Amgen, and many other pharmaceutical companies.
LAS VEGAS – .
“The challenge for all of us is to integrate the right drugs for the right patients,” William J. Sandborn, MD, AGAF, said at the inaugural Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Dr. Sandborn, professor and chief of the division of gastroenterology at the University of California, San Diego, began his presentation by highlighting anti-integrin therapies for inflammatory bowel disease (IBD) treatment. These leukocyte membrane glycoproteins target beta1 and beta7 subunits. They interact with endothelial ligands VCAM-1, fibronectin, and MadCAM-1, and mediate leukocyte adhesion and trafficking. Approved anti-integrin therapies to date include natalizumab and vedolizumab, while investigational therapies include etrolizumab, PF-00547,659, abrilumab, and AJM 300.
In a phase 2 study of etrolizumab as induction therapy for moderate to severe UC, Séverine Vermeire, MD, Dr. Sandborn, and associates randomized 124 patients to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2 or a 420-mg loading dose at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo (The Lancet 2014 348;309-18). They found that etrolizumab was more likely to lead to clinical remission at week 10 than was placebo, especially at the 100-mg dose. Meanwhile, a more recent study of the anti-MAdCAM antibody PF-00547659 in patients with moderate to severe ulcerative colitis found that it was better than placebo for induction of remission (The Lancet 2017;390:135-144). Investigators for the trial, known as TURANDOT, found that the greatest clinical effects were observed with the 22.5-mg and 75-mg doses. “This is now being taken forward in phase 3 trials by Shire,” Dr. Sandborn said.
The anti-interleukin 12/23 antibody (p40) ustekinumab is being investigated for efficacy in UC, while anti-interleukin 23 (p19) antibodies being studied include brazikumab (MEDI2070), risankizumab (BI 6555066), geslekumab, mirikizumab (LY3074828), and tildrakizumab (MK 3222). In 2015, Janssen launched NCT02407236, with the aim of evaluating the effectiveness and safety of continuing ustekinumab as a subcutaneous (injection) maintenance therapy in patients with moderately to severely active UC who have demonstrated a clinical response to an induction treatment with intravenous ustekinumab. The estimated primary completion date is April 12, 2018. Meanwhile, a phase 2a trial of 119 patients with moderate to severe Crohn’s disease who had failed treatment with tumor necrosis factor (TNF) antagonists showed that treatment with MEDI2070 was associated with clinical improvement after 8 and 24 weeks of therapy (Gastroenterol 2017;153:77-86). The investigators also found that patients with baseline serum IL-22 concentrations above the median threshold concentration of 15.6 pg/mL treated with MEDI2070 had higher rates of clinical response and remission, compared with those with baseline concentrations below this threshold. According to Dr. Sandborn, who was not involved in the study, these results provide support for further research on the value of IL-22 serum concentrations to predict response to MEDI2070. “It’s a small study and is hypothesis generating,” he said. “This will need to be confirmed in subsequent trials.”
In a short-term study of 121 patients with active Crohn’s disease, Brian G. Feagan, MD, Dr. Sandborn, and associates found that risankizumab was more effective than placebo for inducing clinical remission, particularly at the 600-mg dose, compared with the 200-mg dose (Lancet 2017;389:1699-709). The researchers also observed significant differences in endoscopic remission among patients on the study drug, compared with those on placebo (17% vs. 3%; P = .0015) as well as endoscopic response (32% vs. 13%; P = .0104). The trial provides further evidence that selective blockade of interleukin 23 via inhibition of p19 might be a viable therapeutic approach in Crohn’s disease.
Janus kinase (JAK) inhibitors under investigation for Crohn’s disease include tofacitinib, filgotinib, upadacitinib, baricitinib, and TD-1473. In the OCTAVE Induction 1 trial led by Dr. Sandborn, 18.5% of the patients in the tofacitinib group achieved remission at 8 weeks, compared with 8.2% in the placebo group (P = .007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% vs. 3.6% (P less than .001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group vs. 11.1% in the placebo group (P less than 0.001 for both comparisons with placebo; N Engl J Med. 2017;376:1723-36). “In subgroup analyses, it looks like the 10-mg dose is more effective for maintenance in patients who previously received anti-TNF therapy,” said Dr. Sandborn, who also directs the UCSD IBD Center. “All secondary outcomes were positive. You don’t see that very often. It tells you that this is a really effective therapy. It’s currently being reviewed by the FDA.”
Meanwhile, a phase 2 trial found that a higher percentage of patients with mild to moderate Crohn’s disease who received a 200-mg dose of filgotinib over 10 weeks achieved clinical remission, compared with those who received placebo (47% vs. 23%, respectively; P = .0077; The Lancet 2017;389:266-75). Serious treatment-emergent adverse effects occurred in 9% of the 152 patients treated with filgotinib and 3 of the 67 patients treated with placebo. According to Dr. Sandborn, filgotinib is currently in phase 3 development trials for both Crohn’s Disease and UC. At the same time, results from an unpublished study presented at the annual Digestive Disease Week in 2017 found that 16 weeks of treatment with the investigational agent upadacitinib led to modified clinical remission in 37% of patients on the 24-mg bid dose, compared with 30% of patients in the 6-mg bid dose. There was also a dose response for endoscopic response. “Based on these data, this drug is now in a phase 3 trial, so lots of JAK inhibitors are coming along,” he said.
Sphingosine-1–phosphate receptor 1 (S1P1) modulators currently under investigation include fingolimod (not studied in IBD), ozanimod, and etrasimod. “These modulators cause the S1P1 receptors that are expressed on the surface of positive lymphocytes to be eluded back into the cell, which leads to a reversible reduction in circulating lymphocytes in the blood,” Dr. Sandborn explained. In a phase 2 trial, he and his associates found that UC patients who received ozanimod at a daily dose of 1 mg had a slightly higher rate of clinical remission, compared with those who received placebo, but the study was not sufficiently powered to establish clinical efficacy or assess safety (N Engl J. Med 2016;374:1754-62).
Dr. Sandborn reported having consulting relationships with Takeda, Genentech, Pfizer, Shire, Amgen, and many other pharmaceutical companies.
LAS VEGAS – .
“The challenge for all of us is to integrate the right drugs for the right patients,” William J. Sandborn, MD, AGAF, said at the inaugural Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.
Dr. Sandborn, professor and chief of the division of gastroenterology at the University of California, San Diego, began his presentation by highlighting anti-integrin therapies for inflammatory bowel disease (IBD) treatment. These leukocyte membrane glycoproteins target beta1 and beta7 subunits. They interact with endothelial ligands VCAM-1, fibronectin, and MadCAM-1, and mediate leukocyte adhesion and trafficking. Approved anti-integrin therapies to date include natalizumab and vedolizumab, while investigational therapies include etrolizumab, PF-00547,659, abrilumab, and AJM 300.
In a phase 2 study of etrolizumab as induction therapy for moderate to severe UC, Séverine Vermeire, MD, Dr. Sandborn, and associates randomized 124 patients to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2 or a 420-mg loading dose at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo (The Lancet 2014 348;309-18). They found that etrolizumab was more likely to lead to clinical remission at week 10 than was placebo, especially at the 100-mg dose. Meanwhile, a more recent study of the anti-MAdCAM antibody PF-00547659 in patients with moderate to severe ulcerative colitis found that it was better than placebo for induction of remission (The Lancet 2017;390:135-144). Investigators for the trial, known as TURANDOT, found that the greatest clinical effects were observed with the 22.5-mg and 75-mg doses. “This is now being taken forward in phase 3 trials by Shire,” Dr. Sandborn said.
The anti-interleukin 12/23 antibody (p40) ustekinumab is being investigated for efficacy in UC, while anti-interleukin 23 (p19) antibodies being studied include brazikumab (MEDI2070), risankizumab (BI 6555066), geslekumab, mirikizumab (LY3074828), and tildrakizumab (MK 3222). In 2015, Janssen launched NCT02407236, with the aim of evaluating the effectiveness and safety of continuing ustekinumab as a subcutaneous (injection) maintenance therapy in patients with moderately to severely active UC who have demonstrated a clinical response to an induction treatment with intravenous ustekinumab. The estimated primary completion date is April 12, 2018. Meanwhile, a phase 2a trial of 119 patients with moderate to severe Crohn’s disease who had failed treatment with tumor necrosis factor (TNF) antagonists showed that treatment with MEDI2070 was associated with clinical improvement after 8 and 24 weeks of therapy (Gastroenterol 2017;153:77-86). The investigators also found that patients with baseline serum IL-22 concentrations above the median threshold concentration of 15.6 pg/mL treated with MEDI2070 had higher rates of clinical response and remission, compared with those with baseline concentrations below this threshold. According to Dr. Sandborn, who was not involved in the study, these results provide support for further research on the value of IL-22 serum concentrations to predict response to MEDI2070. “It’s a small study and is hypothesis generating,” he said. “This will need to be confirmed in subsequent trials.”
In a short-term study of 121 patients with active Crohn’s disease, Brian G. Feagan, MD, Dr. Sandborn, and associates found that risankizumab was more effective than placebo for inducing clinical remission, particularly at the 600-mg dose, compared with the 200-mg dose (Lancet 2017;389:1699-709). The researchers also observed significant differences in endoscopic remission among patients on the study drug, compared with those on placebo (17% vs. 3%; P = .0015) as well as endoscopic response (32% vs. 13%; P = .0104). The trial provides further evidence that selective blockade of interleukin 23 via inhibition of p19 might be a viable therapeutic approach in Crohn’s disease.
Janus kinase (JAK) inhibitors under investigation for Crohn’s disease include tofacitinib, filgotinib, upadacitinib, baricitinib, and TD-1473. In the OCTAVE Induction 1 trial led by Dr. Sandborn, 18.5% of the patients in the tofacitinib group achieved remission at 8 weeks, compared with 8.2% in the placebo group (P = .007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% vs. 3.6% (P less than .001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group vs. 11.1% in the placebo group (P less than 0.001 for both comparisons with placebo; N Engl J Med. 2017;376:1723-36). “In subgroup analyses, it looks like the 10-mg dose is more effective for maintenance in patients who previously received anti-TNF therapy,” said Dr. Sandborn, who also directs the UCSD IBD Center. “All secondary outcomes were positive. You don’t see that very often. It tells you that this is a really effective therapy. It’s currently being reviewed by the FDA.”
Meanwhile, a phase 2 trial found that a higher percentage of patients with mild to moderate Crohn’s disease who received a 200-mg dose of filgotinib over 10 weeks achieved clinical remission, compared with those who received placebo (47% vs. 23%, respectively; P = .0077; The Lancet 2017;389:266-75). Serious treatment-emergent adverse effects occurred in 9% of the 152 patients treated with filgotinib and 3 of the 67 patients treated with placebo. According to Dr. Sandborn, filgotinib is currently in phase 3 development trials for both Crohn’s Disease and UC. At the same time, results from an unpublished study presented at the annual Digestive Disease Week in 2017 found that 16 weeks of treatment with the investigational agent upadacitinib led to modified clinical remission in 37% of patients on the 24-mg bid dose, compared with 30% of patients in the 6-mg bid dose. There was also a dose response for endoscopic response. “Based on these data, this drug is now in a phase 3 trial, so lots of JAK inhibitors are coming along,” he said.
Sphingosine-1–phosphate receptor 1 (S1P1) modulators currently under investigation include fingolimod (not studied in IBD), ozanimod, and etrasimod. “These modulators cause the S1P1 receptors that are expressed on the surface of positive lymphocytes to be eluded back into the cell, which leads to a reversible reduction in circulating lymphocytes in the blood,” Dr. Sandborn explained. In a phase 2 trial, he and his associates found that UC patients who received ozanimod at a daily dose of 1 mg had a slightly higher rate of clinical remission, compared with those who received placebo, but the study was not sufficiently powered to establish clinical efficacy or assess safety (N Engl J. Med 2016;374:1754-62).
Dr. Sandborn reported having consulting relationships with Takeda, Genentech, Pfizer, Shire, Amgen, and many other pharmaceutical companies.
EXPERT ANALYSIS FROM THE CROHN’S & COLITIS CONGRESS
Ibudilast shows promise in progressive MS
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
San Diego – In a phase 2 trial, .
“That was a striking result,” one of the study authors, Robert T. Naismith, MD, said in an interview prior to presenting the study at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We’ll need to see how that translates into a possible clinical benefit.”
In a trial known as SPRINT-MS/NN 102, researchers led by principal investigator Robert Fox, MD, a neurologist at the Cleveland Clinic in Ohio, along with colleagues in the NeuroNEXT Network, randomized 255 subjects with primary or secondary progressive MS to receive either ibudilast up to 100 mg/day (50 mg twice daily) or matching placebo and followed them for 96 weeks. They assessed clinical and imaging outcomes every 24 weeks, and the primary outcome was change in brain atrophy as measured by brain parenchymal fraction (BPF) over 96 weeks. Secondary outcomes included magnetization transfer ratio (MTR), diffusion tensor imaging, and optical coherence tomography. Analysis was based on a modified intention-to-treat approach, and linear mixed effects modeling was used to estimate the rate of change within imaging measures for each treatment group.
The 255 subjects were enrolled at 28 U.S. sites and their last follow-up visit was completed on May 11, 2017. The retention rate through week 96 was 86%, or 219 patients. The researchers found that treatment with ibudilast was associated with a 48% slowing in the rate of decline in brain atrophy as measured by BPF. A per-protocol analysis yielded similar results (P = .045). In addition, no increased rate of serious adverse events and no opportunistic infections or cancer signals were observed. As for tolerability, 25% of subjects on placebo and 30% of those on ibudilast discontinued treatment (P = .30). The main treatment-related adverse events were gastrointestinal in nature (20% in the placebo group vs. 67% in the ibudilast group; P = .002), primarily nausea.
In the analysis of key secondary outcomes, the researchers found that the change in MTR in normal-appearing brain tissue was reduced –0.00558 for ibudilast and –0.03064 for placebo, which was a relative reduction of 82% in MTR decline. At the same time, the change in MTR in normal-appearing gray matter was reduced –0.00753 for ibudilast and –0.03210 for placebo, which was a relative reduction of 77% in MTR decline. No significant difference in white matter changes were observed in transverse diffusivity (P = .15) or longitudinal diffusivity (P = .73), compared with placebo.
For the secondary endpoint of disability, a blinded evaluator assessed Expanded Disability Status Scale (EDSS) score at baseline and every 24 weeks. The researchers used a time-to-event Kaplan-Meier analysis and a Cox proportional hazards model to determine time to confirmed EDSS progression not due to relapse. They found that the hazard ratio for progression in the ibudilast group, compared with the placebo group, was 0.74, with a 90% confidence interval of 0.47-1.17 (P = .29).
“Ibudilast is a novel therapy for progressive MS, with a positive phase 2 study,” Dr. Naismith concluded. “Safety and tolerability were favorable. Clinical endpoints from this trial will be forthcoming.”
The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
SOURCE: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
REPORTING FROM ACTRIMS FORUM 2018
Key clinical point: Ibudilast’s positive phase 2 trial results in progressive multiple sclerosis patients bode well for future development.
Major finding: Ibudilast treatment was associated with a 48% slowing in the rate of decline in brain atrophy as measured by brain parenchymal fraction.
Study details: A randomized trial of 255 subjects with progressive MS enrolled at 28 U.S. sites.
Disclosures: The NeuroNEXT Network is supported by the National Institute of Neurological Disorders and Stroke. Dr. Naismith reported having no financial disclosures.
Source: Naismith R et al. ACTRIMS Forum 2018 Abstract P029.
Study finds rising use of newer DMTs in pediatric-onset MS
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Newer disease-modifying therapies are often used in patients with pediatric-onset MS, and they appear to have short-term side effect profiles similar to those observed in adults, a study of data from multiple clinics demonstrated.
“There are limited studies of MS treatments in pediatric-onset MS (onset before 18 years) as the main trials used to approve disease-modifying therapies [DMTs] are performed in adults,” lead study author Kristen Krysko, MD, said in an interview prior to a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis in San Diego. “This makes it difficult to treat children with MS as there is limited high-quality evidence for safety and effectiveness of treatments.”
DMTs considered to be “newer” include dimethyl fumarate (Tecfidera), fingolimod (Gilenya), teriflunomide (Aubagio), natalizumab (Tysabri), rituximab (Rituxan), ocrelizumab (Ocrevus), alemtuzumab (Lemtrada), and daclizumab (Zinbryta). DMTs were classified as injectable (glatiramer acetate, beta-interferons), oral (dimethyl fumarate, fingolimod, teriflunomide) or intravenous (natalizumab, rituximab, alemtuzumab, ocrelizumab).
Dr. Krysko, a multiple sclerosis clinical research fellow at the University of California, San Francisco, and her associates reported findings from 749 pediatric patients with MS and 274 with clinically-isolated syndrome whose data had been entered into the network as of August 2017 and who were followed for a mean of 3.3 years. The majority of patients were female (65%) with a mean age at disease onset of 12.9 years. Over time, the researchers observed increasing overall and first-line use of newer oral and intravenous DMTs in those younger than and older than 12 years of age at the start of a DMT (P less than .001).
Of the 618 patients who received a DMT before 18 years of age, 259 (42%) received a newer DMT and 104 (17%) received a newer DMT as first-line therapy. Dimethyl fumarate was the newer DMT used most often (ever in 100, as a first-line therapy in 36), followed by natalizumab (ever in 101, as a first-line therapy in 30), rituximab (ever in 57, as a first-line therapy in 22), fingolimod (ever in 37, as a first-line therapy in 14), daclizumab (ever in 5, as a first-line therapy in none), and teriflunomide (ever in 3, as a first-line therapy in 2).
The overall side effect profiles of newer DMTs were not different from those reported with the same agents in adults. Specifically, the number of side effects was greatest for dimethyl fumarate (37.7 per 100 person-years), followed by rituximab (20.1 per 100 person-years), natalizumab (15.7 per 100 person-years), and daclizumab (9.6 per 100 person-years).
“We found that newer medications are being prescribed more often in children with MS over time,” Dr. Krysko said. “Even children who were quite young (younger than 12 years old) received newer MS treatments in some cases, although older children (12 years and older) were more likely to receive newer treatments than were the very young children. We did not find new safety concerns with these medications compared to adults.”
She acknowledged certain limitations of the study, including the “likely underestimate” of side effects and the lack of access to laboratory results of children while on these medications. “Thus, further investigation of the safety of these newer medications in children is needed,” she said.
The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
FROM ACTRIMS FORUM 2018
Key clinical point: Newer DMTs are often used in individuals with pediatric MS.
Major finding: Among pediatric MS patients, the first agent used was a newer DMT in 17% of cases.
Study details: A retrospective review of prospectively collected data on 1,023 pediatric patients with MS.
Disclosures: The National MS Society funded the study. Dr. Krysko disclosed that she is funded by the society as a Sylvia Lawry Physician Fellow.
Source: Krysko K et al. ACTRIMS Forum 2018 Poster 68.
‘Smoker’s paradox’ found in study of IBD patients
Las Vegas – Smoking is more prevalent in Crohn’s disease (CD) patients than in patients with ulcerative colitis (UC), results from a retrospective analysis of national data showed. In addition, , a so-called “smoker’s paradox.”
“This paradox seems to be real, because we know that it has been shown in some heart diseases, that the patients who were smokers had better outcomes,” Zubair Khan, MD, said in an interview at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. In fact, a recent analysis of a nationwide cohort of patients who underwent primary percutaneous coronary intervention for ST-segment elevation myocardial infarction found that smokers had significantly lower risk‐adjusted in‐hospital mortality, compared with nonsmokers (J Am Heart Assoc. 2016 Apr 22;5:e003370. doi: 10.1161/JAHA.116.003370).
Between 2002 and 2014, a higher proportion of CD patients than UC patients were smokers (25.1% vs. 17.2%; P less than .001), while CD patients who smoked were more likely to be younger than age 50 years, compared with UC patients who smoked (53.9% vs. 36.9%; P less than .001). The researchers also found that African Americans with CD were more likely than were those with UC to smoke (10% vs. 7.8%, respectively; P less than .001). On the other hand, both Hispanics and Asians with UC were more likely to be smokers than were their counterparts with CD (5% vs. 2.9% and 3.4% vs. 2.5%, respectively). From a geographical standpoint, UC patients in the Northeast and Western United States were more likely to be smokers, compared with CD patients in those regions (20.7% vs. 18.3% and 21.4% vs. 15%, respectively). Meanwhile, CD patients in the Midwest and South were more likely to be smokers, compared with UC patients in those regions (29.3% vs 26% and 37.2% vs. 31.9%, respectively).
Dr. Khan and his associates also found that a higher proportion of female CD patients were smokers, compared with female UC patients (57% vs. 47.3%; P less than .001), and that mortality among UC and CD patients with no smoking history was higher than that of their counterparts who had a smoking history (2.5% vs. 1.2% and 1.2% vs. 0.7%, respectively; P less than .001 for both associations).
“I would certainly not encourage IBD patients to smoke, but maybe we need to so some more prospective studies to better understand this smoker’s paradox,” Dr. Khan said. He reported having no financial disclosures.
*This story was updated on 3/26.
SOURCE: Khan et al. Crohn’s & Colitis Congress, Poster 213.
Las Vegas – Smoking is more prevalent in Crohn’s disease (CD) patients than in patients with ulcerative colitis (UC), results from a retrospective analysis of national data showed. In addition, , a so-called “smoker’s paradox.”
“This paradox seems to be real, because we know that it has been shown in some heart diseases, that the patients who were smokers had better outcomes,” Zubair Khan, MD, said in an interview at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. In fact, a recent analysis of a nationwide cohort of patients who underwent primary percutaneous coronary intervention for ST-segment elevation myocardial infarction found that smokers had significantly lower risk‐adjusted in‐hospital mortality, compared with nonsmokers (J Am Heart Assoc. 2016 Apr 22;5:e003370. doi: 10.1161/JAHA.116.003370).
Between 2002 and 2014, a higher proportion of CD patients than UC patients were smokers (25.1% vs. 17.2%; P less than .001), while CD patients who smoked were more likely to be younger than age 50 years, compared with UC patients who smoked (53.9% vs. 36.9%; P less than .001). The researchers also found that African Americans with CD were more likely than were those with UC to smoke (10% vs. 7.8%, respectively; P less than .001). On the other hand, both Hispanics and Asians with UC were more likely to be smokers than were their counterparts with CD (5% vs. 2.9% and 3.4% vs. 2.5%, respectively). From a geographical standpoint, UC patients in the Northeast and Western United States were more likely to be smokers, compared with CD patients in those regions (20.7% vs. 18.3% and 21.4% vs. 15%, respectively). Meanwhile, CD patients in the Midwest and South were more likely to be smokers, compared with UC patients in those regions (29.3% vs 26% and 37.2% vs. 31.9%, respectively).
Dr. Khan and his associates also found that a higher proportion of female CD patients were smokers, compared with female UC patients (57% vs. 47.3%; P less than .001), and that mortality among UC and CD patients with no smoking history was higher than that of their counterparts who had a smoking history (2.5% vs. 1.2% and 1.2% vs. 0.7%, respectively; P less than .001 for both associations).
“I would certainly not encourage IBD patients to smoke, but maybe we need to so some more prospective studies to better understand this smoker’s paradox,” Dr. Khan said. He reported having no financial disclosures.
*This story was updated on 3/26.
SOURCE: Khan et al. Crohn’s & Colitis Congress, Poster 213.
Las Vegas – Smoking is more prevalent in Crohn’s disease (CD) patients than in patients with ulcerative colitis (UC), results from a retrospective analysis of national data showed. In addition, , a so-called “smoker’s paradox.”
“This paradox seems to be real, because we know that it has been shown in some heart diseases, that the patients who were smokers had better outcomes,” Zubair Khan, MD, said in an interview at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. In fact, a recent analysis of a nationwide cohort of patients who underwent primary percutaneous coronary intervention for ST-segment elevation myocardial infarction found that smokers had significantly lower risk‐adjusted in‐hospital mortality, compared with nonsmokers (J Am Heart Assoc. 2016 Apr 22;5:e003370. doi: 10.1161/JAHA.116.003370).
Between 2002 and 2014, a higher proportion of CD patients than UC patients were smokers (25.1% vs. 17.2%; P less than .001), while CD patients who smoked were more likely to be younger than age 50 years, compared with UC patients who smoked (53.9% vs. 36.9%; P less than .001). The researchers also found that African Americans with CD were more likely than were those with UC to smoke (10% vs. 7.8%, respectively; P less than .001). On the other hand, both Hispanics and Asians with UC were more likely to be smokers than were their counterparts with CD (5% vs. 2.9% and 3.4% vs. 2.5%, respectively). From a geographical standpoint, UC patients in the Northeast and Western United States were more likely to be smokers, compared with CD patients in those regions (20.7% vs. 18.3% and 21.4% vs. 15%, respectively). Meanwhile, CD patients in the Midwest and South were more likely to be smokers, compared with UC patients in those regions (29.3% vs 26% and 37.2% vs. 31.9%, respectively).
Dr. Khan and his associates also found that a higher proportion of female CD patients were smokers, compared with female UC patients (57% vs. 47.3%; P less than .001), and that mortality among UC and CD patients with no smoking history was higher than that of their counterparts who had a smoking history (2.5% vs. 1.2% and 1.2% vs. 0.7%, respectively; P less than .001 for both associations).
“I would certainly not encourage IBD patients to smoke, but maybe we need to so some more prospective studies to better understand this smoker’s paradox,” Dr. Khan said. He reported having no financial disclosures.
*This story was updated on 3/26.
SOURCE: Khan et al. Crohn’s & Colitis Congress, Poster 213.
REPORTING FROM THE CROHN’S & COLITIS CONGRESS
Key clinical point: In IBD patients, smoker status was paradoxically associated with mortality and other outcomes.
Major finding: Mortality among UC and CD patients with no smoking history was higher than that of their counterparts who had a smoking history (2.5% vs. 1.2% and 1.2% vs. 0.7%, respectively; P less than .001 for both associations).
Study details: An analysis of 22,620 patients with a primary or secondary discharge diagnosis of IBD during 2002-2014.
Disclosures: Dr. Khan reported having no financial disclosures.
Source: Khan et al. Crohn’s & Colitis Congress, Poster 213.
Higher BMI linked to problems for IBD patients
LAS VEGAS – Higher body mass index among inflammatory bowel disease patients is independently associated with an increased risk of treatment failure and IBD-related surgery or hospitalization, a single-center, retrospective cohort study demonstrated.
“The problem of IBD and obesity is on the rise,” Soumya Kurnool said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “Today, 15%-40% of IBD patients are obese. This is significant because there is a decreased prevalence of remission and an increased risk of relapse in obese IBD patients. These patients also have a higher annual burden of hospitalization.”
She and her associates set out to evaluate the effect of obesity on response to biologic therapy in patients with ulcerative colitis (UC). They conducted a single-center, retrospective cohort study of biologic-treated adults with UC who started therapy during 2011-2016. The researchers excluded patients who had undergone a prior colectomy, as well as those who were underweight at the time of starting a biologic agent and those who had fewer than 6 months of follow-up data.
The primary outcome was time to treatment failure, defined as a composite of IBD-related surgery, hospitalization, and/or treatment modification. Secondary outcomes were time to IBD-related surgery and/or hospitalization and whether the patient achieved endoscopic remission within 1 year of starting biologic therapy. They conducted multivariate Cox proportional hazard analyses after adjusting for key confounders.
Ms. Kurnool reported results from 160 patients with a median age of 36 years. Half were male, and the mean follow-up was 24 months. The median BMI of the cohort was 24.3 kg/m2; 26% were overweight and 18% were obese. More than half of patients (55%) were on infliximab with weight-based dosing and 45% were on other fixed-dosing regimens, including 19% on vedolizumab. In terms of outcomes, 68% of patients experienced treatment failure. All who failed treatment underwent treatment modifications; 15% had IBD-related surgery, and 19% had IBD-related hospitalization.
After adjusting for age, sex, disease duration, prior hospitalization, prior anti-TNF therapy, steroid use, and albumin level, Ms. Kurnool and her associates found that every 1-kg/m2 increase in BMI was associated with a 4% higher risk of treatment failure (adjusted hazard ratio, 1.04), an 8% higher risk of surgery or hospitalization (adjusted HR, 1.08), and a 6% lower risk of achieving endoscopic remission (adjusted HR, 0.94).
“This increase in the risk of treatment failure and IBD-related surgery or hospitalization was consistent across strata of patients treated with infliximab and fixed-dosing regimens,” she said. “Based on these findings, physicians should consider proactive monitoring in obese patients treated with biologic agents.”
Ms. Kurnool reported having received a National Institutes of Health Short Term Training Grant from the University of California, San Diego.
*This story was updated on 3/26.
SOURCE: Kurnool S et al. Crohn’s & Colitis Congress, Clinical Abstract 24.
LAS VEGAS – Higher body mass index among inflammatory bowel disease patients is independently associated with an increased risk of treatment failure and IBD-related surgery or hospitalization, a single-center, retrospective cohort study demonstrated.
“The problem of IBD and obesity is on the rise,” Soumya Kurnool said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “Today, 15%-40% of IBD patients are obese. This is significant because there is a decreased prevalence of remission and an increased risk of relapse in obese IBD patients. These patients also have a higher annual burden of hospitalization.”
She and her associates set out to evaluate the effect of obesity on response to biologic therapy in patients with ulcerative colitis (UC). They conducted a single-center, retrospective cohort study of biologic-treated adults with UC who started therapy during 2011-2016. The researchers excluded patients who had undergone a prior colectomy, as well as those who were underweight at the time of starting a biologic agent and those who had fewer than 6 months of follow-up data.
The primary outcome was time to treatment failure, defined as a composite of IBD-related surgery, hospitalization, and/or treatment modification. Secondary outcomes were time to IBD-related surgery and/or hospitalization and whether the patient achieved endoscopic remission within 1 year of starting biologic therapy. They conducted multivariate Cox proportional hazard analyses after adjusting for key confounders.
Ms. Kurnool reported results from 160 patients with a median age of 36 years. Half were male, and the mean follow-up was 24 months. The median BMI of the cohort was 24.3 kg/m2; 26% were overweight and 18% were obese. More than half of patients (55%) were on infliximab with weight-based dosing and 45% were on other fixed-dosing regimens, including 19% on vedolizumab. In terms of outcomes, 68% of patients experienced treatment failure. All who failed treatment underwent treatment modifications; 15% had IBD-related surgery, and 19% had IBD-related hospitalization.
After adjusting for age, sex, disease duration, prior hospitalization, prior anti-TNF therapy, steroid use, and albumin level, Ms. Kurnool and her associates found that every 1-kg/m2 increase in BMI was associated with a 4% higher risk of treatment failure (adjusted hazard ratio, 1.04), an 8% higher risk of surgery or hospitalization (adjusted HR, 1.08), and a 6% lower risk of achieving endoscopic remission (adjusted HR, 0.94).
“This increase in the risk of treatment failure and IBD-related surgery or hospitalization was consistent across strata of patients treated with infliximab and fixed-dosing regimens,” she said. “Based on these findings, physicians should consider proactive monitoring in obese patients treated with biologic agents.”
Ms. Kurnool reported having received a National Institutes of Health Short Term Training Grant from the University of California, San Diego.
*This story was updated on 3/26.
SOURCE: Kurnool S et al. Crohn’s & Colitis Congress, Clinical Abstract 24.
LAS VEGAS – Higher body mass index among inflammatory bowel disease patients is independently associated with an increased risk of treatment failure and IBD-related surgery or hospitalization, a single-center, retrospective cohort study demonstrated.
“The problem of IBD and obesity is on the rise,” Soumya Kurnool said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “Today, 15%-40% of IBD patients are obese. This is significant because there is a decreased prevalence of remission and an increased risk of relapse in obese IBD patients. These patients also have a higher annual burden of hospitalization.”
She and her associates set out to evaluate the effect of obesity on response to biologic therapy in patients with ulcerative colitis (UC). They conducted a single-center, retrospective cohort study of biologic-treated adults with UC who started therapy during 2011-2016. The researchers excluded patients who had undergone a prior colectomy, as well as those who were underweight at the time of starting a biologic agent and those who had fewer than 6 months of follow-up data.
The primary outcome was time to treatment failure, defined as a composite of IBD-related surgery, hospitalization, and/or treatment modification. Secondary outcomes were time to IBD-related surgery and/or hospitalization and whether the patient achieved endoscopic remission within 1 year of starting biologic therapy. They conducted multivariate Cox proportional hazard analyses after adjusting for key confounders.
Ms. Kurnool reported results from 160 patients with a median age of 36 years. Half were male, and the mean follow-up was 24 months. The median BMI of the cohort was 24.3 kg/m2; 26% were overweight and 18% were obese. More than half of patients (55%) were on infliximab with weight-based dosing and 45% were on other fixed-dosing regimens, including 19% on vedolizumab. In terms of outcomes, 68% of patients experienced treatment failure. All who failed treatment underwent treatment modifications; 15% had IBD-related surgery, and 19% had IBD-related hospitalization.
After adjusting for age, sex, disease duration, prior hospitalization, prior anti-TNF therapy, steroid use, and albumin level, Ms. Kurnool and her associates found that every 1-kg/m2 increase in BMI was associated with a 4% higher risk of treatment failure (adjusted hazard ratio, 1.04), an 8% higher risk of surgery or hospitalization (adjusted HR, 1.08), and a 6% lower risk of achieving endoscopic remission (adjusted HR, 0.94).
“This increase in the risk of treatment failure and IBD-related surgery or hospitalization was consistent across strata of patients treated with infliximab and fixed-dosing regimens,” she said. “Based on these findings, physicians should consider proactive monitoring in obese patients treated with biologic agents.”
Ms. Kurnool reported having received a National Institutes of Health Short Term Training Grant from the University of California, San Diego.
*This story was updated on 3/26.
SOURCE: Kurnool S et al. Crohn’s & Colitis Congress, Clinical Abstract 24.
REPORTING FROM THE CROHN’S & COLITIS CONGRESS
Key clinical point: Consider proactive monitoring in obese patients treated with biologic agents.
Major finding: Every 1-kg/m2 increase in BMI was associated with a 4% higher risk of treatment failure (adjusted HR, 1.04).
Study details: A single-center retrospective analysis of 160 IBD patients.
Disclosures: Ms. Kurnool reported having received a National Institutes of Health Short-Term Training Grant from the University of California, San Diego.
Source: Kurnool S et al. Crohn’s & Colitis Congress, Clinical Abstract 24.
Learn ‘four Ds’ approach to heart failure in diabetes
LOS ANGELES – , such as lung cancer, because diabetes makes the pathophysiology of heart failure worse, according to Mark Kearney, MD.
“Diabetes amplifies the neurohormonal response to heart failure, so it drives progressive heart failure and increases the risk for sudden death,” Dr. Kearney said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As left ventricular function goes down, patients with diabetes have heightened activation of the renin angiotensin system. They have increased left ventricular hypertrophy, and they have increased sympathetic nervous system activation.”
Dr. Kearney, a cardiologist who directs the Leeds Institute of Cardiovascular & Metabolic Medicine at Leeds (England) University, offered a “four Ds” framework that clinicians can use to improve prognosis in these patients.
1. Use a loop diuretic to control symptoms. “If the patient has fluid retention, it’s important to get them out of congestive cardiac syndrome as quickly as possible,” he said.
2. Disease modification with beta-blockers and ACE inhibitors, to the maximal dose tolerated. “These are still the mainstays of treatment for patients with heart failure, and they’re even more important in patients with diabetes and heart failure,” he said.
3. Consider device therapy, including defibrillators and resynchronization therapy.4. Optimize diabetes management.
“If you keep these things in your mind as you see a patient with heart failure and diabetes, it will give you a guide to approaching these patients,” said Dr. Kearney, who is also research lead for heart failure services at the University of Leeds. “When I see patients, I’ll check for edema right away. If they have it, I’ll increase the diuretic, and I’ll think about the different steps in the treatment pathway.”
He described heart failure due to systolic dysfunction as a reduction in cardiac output that doesn’t meet the demands of the body, the endpoint of a whole range of insults to the left ventricle.
“The most common cause today is ischemic heart disease; it used to be hypertension,” he said. “People over 40 have a one in five chance of developing heart failure, so it’s really important for all of us to improve outcomes in this terrible syndrome.”
According to a study of nearly 2,000 unselected patients conducted by Dr. Kearney and his associates, those with diabetes and heart failure are more likely to have ischemia, compared with those who have heart failure and no diabetes (75% vs. 58%, respectively), lower hemoglobin (13 g/dL vs. 13.7 g/dL), and worse renal function (eGFR of 51 mL/min per 1.732 m2 vs 57 mL/min per 1.732 m2) (Diab Vasc Dis Res. 2013 Jul;10[4]:330-6).
He added that type 2 diabetes is a sudden death risk equivalent to patients with ischemic heart disease and left ventricular systolic dysfunction (Heart 2016 May 15;102[10]:735-40).
“So, if you have diabetes and the U.K. National Institute for Health and Care Excellence guidelines indication for a defibrillator, your risk of sudden death in 5 years is probably 50%,” Dr. Kearney said. “The best treatment in this case is a prophylactic defibrillator.”
ACE inhibitors are used to protect these patients against cardiac myocyte cell death and vasoconstriction, while beta-blockers are used to protect against the activation of the sympathetic nervous system.
“Often, patients don’t like taking beta-blockers because they say they make them feel tired – when in fact they don’t realize it’s their heart failure that’s making them feel tired,” Dr. Kearney said.
He and his associates examined the effect of different drugs doses on all-cause mortality at 5 years. They found that, among patients with heart failure, reduced ejection fraction, and no diabetes, ramipril conferred a 3% improvement in mortality per milligram. At the same time, the mortality among patients with diabetes and heart failure who did not receive a beta-blocker was about 7%.
However, the absolute gain from beta-blocker use in patients with diabetes and heart failure was three times that of patients without diabetes.
“So, every milligram you increase the dose by, there’s an associated improvement in risk,” Dr. Kearney said. “Over 5 years, comparing the lowest beta-blocker dose to the highest beta-blocker dose, it was 1 year of life gained. So, when I see my patients and they ask about side effects of beta-blockers, I now say to them, ‘The side effects actually make you live longer.’”
He concluded his remarks by noting that while he is not a diabetes expert, it’s clear that diabetes is intimately linked to the pathophysiology of heart failure.
“If you’re insulin resistant, you have hypertension, hyperglycemia, you have inflammation and bone marrow dysfunction – all of which can exacerbate left ventricle dysfunction,” he said. “You have a syndrome in which you have cardiac dysfunction and metabolic dysfunction that conspire to lead to worsening of left ventricular dysfunction.”
Dr. Kearney disclosed that he has been a speaker for Merck.
LOS ANGELES – , such as lung cancer, because diabetes makes the pathophysiology of heart failure worse, according to Mark Kearney, MD.
“Diabetes amplifies the neurohormonal response to heart failure, so it drives progressive heart failure and increases the risk for sudden death,” Dr. Kearney said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As left ventricular function goes down, patients with diabetes have heightened activation of the renin angiotensin system. They have increased left ventricular hypertrophy, and they have increased sympathetic nervous system activation.”
Dr. Kearney, a cardiologist who directs the Leeds Institute of Cardiovascular & Metabolic Medicine at Leeds (England) University, offered a “four Ds” framework that clinicians can use to improve prognosis in these patients.
1. Use a loop diuretic to control symptoms. “If the patient has fluid retention, it’s important to get them out of congestive cardiac syndrome as quickly as possible,” he said.
2. Disease modification with beta-blockers and ACE inhibitors, to the maximal dose tolerated. “These are still the mainstays of treatment for patients with heart failure, and they’re even more important in patients with diabetes and heart failure,” he said.
3. Consider device therapy, including defibrillators and resynchronization therapy.4. Optimize diabetes management.
“If you keep these things in your mind as you see a patient with heart failure and diabetes, it will give you a guide to approaching these patients,” said Dr. Kearney, who is also research lead for heart failure services at the University of Leeds. “When I see patients, I’ll check for edema right away. If they have it, I’ll increase the diuretic, and I’ll think about the different steps in the treatment pathway.”
He described heart failure due to systolic dysfunction as a reduction in cardiac output that doesn’t meet the demands of the body, the endpoint of a whole range of insults to the left ventricle.
“The most common cause today is ischemic heart disease; it used to be hypertension,” he said. “People over 40 have a one in five chance of developing heart failure, so it’s really important for all of us to improve outcomes in this terrible syndrome.”
According to a study of nearly 2,000 unselected patients conducted by Dr. Kearney and his associates, those with diabetes and heart failure are more likely to have ischemia, compared with those who have heart failure and no diabetes (75% vs. 58%, respectively), lower hemoglobin (13 g/dL vs. 13.7 g/dL), and worse renal function (eGFR of 51 mL/min per 1.732 m2 vs 57 mL/min per 1.732 m2) (Diab Vasc Dis Res. 2013 Jul;10[4]:330-6).
He added that type 2 diabetes is a sudden death risk equivalent to patients with ischemic heart disease and left ventricular systolic dysfunction (Heart 2016 May 15;102[10]:735-40).
“So, if you have diabetes and the U.K. National Institute for Health and Care Excellence guidelines indication for a defibrillator, your risk of sudden death in 5 years is probably 50%,” Dr. Kearney said. “The best treatment in this case is a prophylactic defibrillator.”
ACE inhibitors are used to protect these patients against cardiac myocyte cell death and vasoconstriction, while beta-blockers are used to protect against the activation of the sympathetic nervous system.
“Often, patients don’t like taking beta-blockers because they say they make them feel tired – when in fact they don’t realize it’s their heart failure that’s making them feel tired,” Dr. Kearney said.
He and his associates examined the effect of different drugs doses on all-cause mortality at 5 years. They found that, among patients with heart failure, reduced ejection fraction, and no diabetes, ramipril conferred a 3% improvement in mortality per milligram. At the same time, the mortality among patients with diabetes and heart failure who did not receive a beta-blocker was about 7%.
However, the absolute gain from beta-blocker use in patients with diabetes and heart failure was three times that of patients without diabetes.
“So, every milligram you increase the dose by, there’s an associated improvement in risk,” Dr. Kearney said. “Over 5 years, comparing the lowest beta-blocker dose to the highest beta-blocker dose, it was 1 year of life gained. So, when I see my patients and they ask about side effects of beta-blockers, I now say to them, ‘The side effects actually make you live longer.’”
He concluded his remarks by noting that while he is not a diabetes expert, it’s clear that diabetes is intimately linked to the pathophysiology of heart failure.
“If you’re insulin resistant, you have hypertension, hyperglycemia, you have inflammation and bone marrow dysfunction – all of which can exacerbate left ventricle dysfunction,” he said. “You have a syndrome in which you have cardiac dysfunction and metabolic dysfunction that conspire to lead to worsening of left ventricular dysfunction.”
Dr. Kearney disclosed that he has been a speaker for Merck.
LOS ANGELES – , such as lung cancer, because diabetes makes the pathophysiology of heart failure worse, according to Mark Kearney, MD.
“Diabetes amplifies the neurohormonal response to heart failure, so it drives progressive heart failure and increases the risk for sudden death,” Dr. Kearney said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As left ventricular function goes down, patients with diabetes have heightened activation of the renin angiotensin system. They have increased left ventricular hypertrophy, and they have increased sympathetic nervous system activation.”
Dr. Kearney, a cardiologist who directs the Leeds Institute of Cardiovascular & Metabolic Medicine at Leeds (England) University, offered a “four Ds” framework that clinicians can use to improve prognosis in these patients.
1. Use a loop diuretic to control symptoms. “If the patient has fluid retention, it’s important to get them out of congestive cardiac syndrome as quickly as possible,” he said.
2. Disease modification with beta-blockers and ACE inhibitors, to the maximal dose tolerated. “These are still the mainstays of treatment for patients with heart failure, and they’re even more important in patients with diabetes and heart failure,” he said.
3. Consider device therapy, including defibrillators and resynchronization therapy.4. Optimize diabetes management.
“If you keep these things in your mind as you see a patient with heart failure and diabetes, it will give you a guide to approaching these patients,” said Dr. Kearney, who is also research lead for heart failure services at the University of Leeds. “When I see patients, I’ll check for edema right away. If they have it, I’ll increase the diuretic, and I’ll think about the different steps in the treatment pathway.”
He described heart failure due to systolic dysfunction as a reduction in cardiac output that doesn’t meet the demands of the body, the endpoint of a whole range of insults to the left ventricle.
“The most common cause today is ischemic heart disease; it used to be hypertension,” he said. “People over 40 have a one in five chance of developing heart failure, so it’s really important for all of us to improve outcomes in this terrible syndrome.”
According to a study of nearly 2,000 unselected patients conducted by Dr. Kearney and his associates, those with diabetes and heart failure are more likely to have ischemia, compared with those who have heart failure and no diabetes (75% vs. 58%, respectively), lower hemoglobin (13 g/dL vs. 13.7 g/dL), and worse renal function (eGFR of 51 mL/min per 1.732 m2 vs 57 mL/min per 1.732 m2) (Diab Vasc Dis Res. 2013 Jul;10[4]:330-6).
He added that type 2 diabetes is a sudden death risk equivalent to patients with ischemic heart disease and left ventricular systolic dysfunction (Heart 2016 May 15;102[10]:735-40).
“So, if you have diabetes and the U.K. National Institute for Health and Care Excellence guidelines indication for a defibrillator, your risk of sudden death in 5 years is probably 50%,” Dr. Kearney said. “The best treatment in this case is a prophylactic defibrillator.”
ACE inhibitors are used to protect these patients against cardiac myocyte cell death and vasoconstriction, while beta-blockers are used to protect against the activation of the sympathetic nervous system.
“Often, patients don’t like taking beta-blockers because they say they make them feel tired – when in fact they don’t realize it’s their heart failure that’s making them feel tired,” Dr. Kearney said.
He and his associates examined the effect of different drugs doses on all-cause mortality at 5 years. They found that, among patients with heart failure, reduced ejection fraction, and no diabetes, ramipril conferred a 3% improvement in mortality per milligram. At the same time, the mortality among patients with diabetes and heart failure who did not receive a beta-blocker was about 7%.
However, the absolute gain from beta-blocker use in patients with diabetes and heart failure was three times that of patients without diabetes.
“So, every milligram you increase the dose by, there’s an associated improvement in risk,” Dr. Kearney said. “Over 5 years, comparing the lowest beta-blocker dose to the highest beta-blocker dose, it was 1 year of life gained. So, when I see my patients and they ask about side effects of beta-blockers, I now say to them, ‘The side effects actually make you live longer.’”
He concluded his remarks by noting that while he is not a diabetes expert, it’s clear that diabetes is intimately linked to the pathophysiology of heart failure.
“If you’re insulin resistant, you have hypertension, hyperglycemia, you have inflammation and bone marrow dysfunction – all of which can exacerbate left ventricle dysfunction,” he said. “You have a syndrome in which you have cardiac dysfunction and metabolic dysfunction that conspire to lead to worsening of left ventricular dysfunction.”
Dr. Kearney disclosed that he has been a speaker for Merck.
EXPERT ANALYSIS FROM WCIRDC 2017
Whatever the substance, adolescents’ abuse shares common links
SAN DIEGO – Among adolescent daily cigarette smokers, the individual and concomitant use of alcohol, marijuana, and tobacco have unique and common associations with reinforcement sensitivity, with negative affect, and with electrophysiological signatures of reward function, results from a novel study demonstrated.
“The co-use of alcohol, marijuana, and tobacco in youth are associated bidirectionally with higher rates of substance use, higher levels of addiction severity, and with poorer treatment outcomes for youth who present for treatment,” lead study author Christopher J. Hammond, MD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
Currently, the effects of combined alcohol, marijuana, and tobacco use on brain function are poorly understood, noted Dr. Hammond of the division of child and adolescent psychiatry at Johns Hopkins Bayview Medical Center, Baltimore.
Published studies to date suggest that alcohol, marijuana, and tobacco use disorders are linked separately to dysfunction in the neural substrates of reward and punishment processing, but none has examined co-use or comorbid disorders in adolescents.
In a cross-sectional, single-visit study, Dr. Hammond and his associates examined a population of 36 adolescent non-deprived daily cigarette smokers and 29 healthy controls from the greater New Haven, Conn., area, matched for age, gender, and grade level. The subjects ranged in age from 14 to 20 years and were administered self-report measures characterizing tobacco, marijuana, and alcohol use. The researchers also collected urine and breathalyzer measures to characterize tobacco and cannabis use.
All subjects completed a number of self-report questionnaires characterizing their substance use patterns, their addiction severity, impulsivity, sensitivity to reward and punishment, and depression. They also underwent a 45-minute EEG, during which they completed a resting EEG test and completed a reward task.
The adolescent daily cigarette smoker group had blunted or decreased sensitivity to punishment and increased impulsivity, compared with the healthy controls, Dr. Hammond reported.
Co-occurring drug use was high in the adolescent daily smoker group, with 80% reporting heavy marijuana use (defined as using it over 100 times during adolescence), and 67% reporting heavy episodic binge drinking (defined as consuming greater than four alcoholic beverages for females during one sitting and greater than five for males at least two or more times a month).
One out of two of the daily cigarette smokers were also daily marijuana smokers, and about 75% of the adolescent smokers had a positive urine drug screen for marijuana. They smoked an average of eight cigarettes per day, used cannabis about 17 days out of the month, and they had about 1.5 binge drinking episodes per month.
Next, the researchers used linear regression analyses to examine which of the psychological variables were associated with alcohol, marijuana, and tobacco use severity within the smoker group, after co-varying for age, gender, race/ethnicity, and full-scale IQ.
“For alcohol use, we found that depression, sensitivity to reward, and impulsivity were significantly associated with alcohol problem severity scores, even after controlling for sociodemographics and other drug use (P less than .05),” Dr. Hammond said.
“For marijuana use, we found that sensitivity to reward and impulsivity were significantly associated with cannabis problem severity, even after controlling for demographics and alcohol and other drug use (P less than .01),” he continued. “For tobacco use, we found that anxiety sensitivity was significantly associated with nicotine dependence scores, even after controlling for demographics and alcohol and marijuana use (P less than .001).”
On EEG analyses, the researchers found no main effects for group or group by condition for the feedback-related negativity (FRN) signal or for the event-related Theta oscillation between the adolescent non-deprived smokers and the healthy controls.
However, examination of the smoker subgroups revealed a unique and shared association between alcohol, marijuana, and tobacco and the EEG signals.
“With regard to substance use associations with the FRN smokers, regression analyses showed that cannabis use problem severity was associated with an increased FRN amplitude during the reward condition only,” Dr. Hammond said. “This finding remained significant after co-varying for demographics, for other drug use, for nicotine dependence and alcohol severity as well.
“We also found an association between alcohol problem severity and mean FRN amplitude, but with no differences across conditions,” he added. There was an association also “ between nicotine dependence and decreased FRN latency, but only during the reward and draw conditions, suggesting a nicotine severity association with speed of processing salient reward and stimuli.”
While the findings need to be better studied and replicated, “these associations may be leveraged to better personalize our interventions for these different substances of abuse,” Dr. Hammond observed. “The study also provides preliminary evidence for a dual-process model of substance use, specifically for cannabis. Cannabis severity in adolescent smokers is associated with increased bottom-up reward signaling and impaired top-down cognitive control over a salient or rewarding stimulus.”
The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
SOURCE: Hammond et al. AAAP 2017. Paper session A3.
SAN DIEGO – Among adolescent daily cigarette smokers, the individual and concomitant use of alcohol, marijuana, and tobacco have unique and common associations with reinforcement sensitivity, with negative affect, and with electrophysiological signatures of reward function, results from a novel study demonstrated.
“The co-use of alcohol, marijuana, and tobacco in youth are associated bidirectionally with higher rates of substance use, higher levels of addiction severity, and with poorer treatment outcomes for youth who present for treatment,” lead study author Christopher J. Hammond, MD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
Currently, the effects of combined alcohol, marijuana, and tobacco use on brain function are poorly understood, noted Dr. Hammond of the division of child and adolescent psychiatry at Johns Hopkins Bayview Medical Center, Baltimore.
Published studies to date suggest that alcohol, marijuana, and tobacco use disorders are linked separately to dysfunction in the neural substrates of reward and punishment processing, but none has examined co-use or comorbid disorders in adolescents.
In a cross-sectional, single-visit study, Dr. Hammond and his associates examined a population of 36 adolescent non-deprived daily cigarette smokers and 29 healthy controls from the greater New Haven, Conn., area, matched for age, gender, and grade level. The subjects ranged in age from 14 to 20 years and were administered self-report measures characterizing tobacco, marijuana, and alcohol use. The researchers also collected urine and breathalyzer measures to characterize tobacco and cannabis use.
All subjects completed a number of self-report questionnaires characterizing their substance use patterns, their addiction severity, impulsivity, sensitivity to reward and punishment, and depression. They also underwent a 45-minute EEG, during which they completed a resting EEG test and completed a reward task.
The adolescent daily cigarette smoker group had blunted or decreased sensitivity to punishment and increased impulsivity, compared with the healthy controls, Dr. Hammond reported.
Co-occurring drug use was high in the adolescent daily smoker group, with 80% reporting heavy marijuana use (defined as using it over 100 times during adolescence), and 67% reporting heavy episodic binge drinking (defined as consuming greater than four alcoholic beverages for females during one sitting and greater than five for males at least two or more times a month).
One out of two of the daily cigarette smokers were also daily marijuana smokers, and about 75% of the adolescent smokers had a positive urine drug screen for marijuana. They smoked an average of eight cigarettes per day, used cannabis about 17 days out of the month, and they had about 1.5 binge drinking episodes per month.
Next, the researchers used linear regression analyses to examine which of the psychological variables were associated with alcohol, marijuana, and tobacco use severity within the smoker group, after co-varying for age, gender, race/ethnicity, and full-scale IQ.
“For alcohol use, we found that depression, sensitivity to reward, and impulsivity were significantly associated with alcohol problem severity scores, even after controlling for sociodemographics and other drug use (P less than .05),” Dr. Hammond said.
“For marijuana use, we found that sensitivity to reward and impulsivity were significantly associated with cannabis problem severity, even after controlling for demographics and alcohol and other drug use (P less than .01),” he continued. “For tobacco use, we found that anxiety sensitivity was significantly associated with nicotine dependence scores, even after controlling for demographics and alcohol and marijuana use (P less than .001).”
On EEG analyses, the researchers found no main effects for group or group by condition for the feedback-related negativity (FRN) signal or for the event-related Theta oscillation between the adolescent non-deprived smokers and the healthy controls.
However, examination of the smoker subgroups revealed a unique and shared association between alcohol, marijuana, and tobacco and the EEG signals.
“With regard to substance use associations with the FRN smokers, regression analyses showed that cannabis use problem severity was associated with an increased FRN amplitude during the reward condition only,” Dr. Hammond said. “This finding remained significant after co-varying for demographics, for other drug use, for nicotine dependence and alcohol severity as well.
“We also found an association between alcohol problem severity and mean FRN amplitude, but with no differences across conditions,” he added. There was an association also “ between nicotine dependence and decreased FRN latency, but only during the reward and draw conditions, suggesting a nicotine severity association with speed of processing salient reward and stimuli.”
While the findings need to be better studied and replicated, “these associations may be leveraged to better personalize our interventions for these different substances of abuse,” Dr. Hammond observed. “The study also provides preliminary evidence for a dual-process model of substance use, specifically for cannabis. Cannabis severity in adolescent smokers is associated with increased bottom-up reward signaling and impaired top-down cognitive control over a salient or rewarding stimulus.”
The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
SOURCE: Hammond et al. AAAP 2017. Paper session A3.
SAN DIEGO – Among adolescent daily cigarette smokers, the individual and concomitant use of alcohol, marijuana, and tobacco have unique and common associations with reinforcement sensitivity, with negative affect, and with electrophysiological signatures of reward function, results from a novel study demonstrated.
“The co-use of alcohol, marijuana, and tobacco in youth are associated bidirectionally with higher rates of substance use, higher levels of addiction severity, and with poorer treatment outcomes for youth who present for treatment,” lead study author Christopher J. Hammond, MD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
Currently, the effects of combined alcohol, marijuana, and tobacco use on brain function are poorly understood, noted Dr. Hammond of the division of child and adolescent psychiatry at Johns Hopkins Bayview Medical Center, Baltimore.
Published studies to date suggest that alcohol, marijuana, and tobacco use disorders are linked separately to dysfunction in the neural substrates of reward and punishment processing, but none has examined co-use or comorbid disorders in adolescents.
In a cross-sectional, single-visit study, Dr. Hammond and his associates examined a population of 36 adolescent non-deprived daily cigarette smokers and 29 healthy controls from the greater New Haven, Conn., area, matched for age, gender, and grade level. The subjects ranged in age from 14 to 20 years and were administered self-report measures characterizing tobacco, marijuana, and alcohol use. The researchers also collected urine and breathalyzer measures to characterize tobacco and cannabis use.
All subjects completed a number of self-report questionnaires characterizing their substance use patterns, their addiction severity, impulsivity, sensitivity to reward and punishment, and depression. They also underwent a 45-minute EEG, during which they completed a resting EEG test and completed a reward task.
The adolescent daily cigarette smoker group had blunted or decreased sensitivity to punishment and increased impulsivity, compared with the healthy controls, Dr. Hammond reported.
Co-occurring drug use was high in the adolescent daily smoker group, with 80% reporting heavy marijuana use (defined as using it over 100 times during adolescence), and 67% reporting heavy episodic binge drinking (defined as consuming greater than four alcoholic beverages for females during one sitting and greater than five for males at least two or more times a month).
One out of two of the daily cigarette smokers were also daily marijuana smokers, and about 75% of the adolescent smokers had a positive urine drug screen for marijuana. They smoked an average of eight cigarettes per day, used cannabis about 17 days out of the month, and they had about 1.5 binge drinking episodes per month.
Next, the researchers used linear regression analyses to examine which of the psychological variables were associated with alcohol, marijuana, and tobacco use severity within the smoker group, after co-varying for age, gender, race/ethnicity, and full-scale IQ.
“For alcohol use, we found that depression, sensitivity to reward, and impulsivity were significantly associated with alcohol problem severity scores, even after controlling for sociodemographics and other drug use (P less than .05),” Dr. Hammond said.
“For marijuana use, we found that sensitivity to reward and impulsivity were significantly associated with cannabis problem severity, even after controlling for demographics and alcohol and other drug use (P less than .01),” he continued. “For tobacco use, we found that anxiety sensitivity was significantly associated with nicotine dependence scores, even after controlling for demographics and alcohol and marijuana use (P less than .001).”
On EEG analyses, the researchers found no main effects for group or group by condition for the feedback-related negativity (FRN) signal or for the event-related Theta oscillation between the adolescent non-deprived smokers and the healthy controls.
However, examination of the smoker subgroups revealed a unique and shared association between alcohol, marijuana, and tobacco and the EEG signals.
“With regard to substance use associations with the FRN smokers, regression analyses showed that cannabis use problem severity was associated with an increased FRN amplitude during the reward condition only,” Dr. Hammond said. “This finding remained significant after co-varying for demographics, for other drug use, for nicotine dependence and alcohol severity as well.
“We also found an association between alcohol problem severity and mean FRN amplitude, but with no differences across conditions,” he added. There was an association also “ between nicotine dependence and decreased FRN latency, but only during the reward and draw conditions, suggesting a nicotine severity association with speed of processing salient reward and stimuli.”
While the findings need to be better studied and replicated, “these associations may be leveraged to better personalize our interventions for these different substances of abuse,” Dr. Hammond observed. “The study also provides preliminary evidence for a dual-process model of substance use, specifically for cannabis. Cannabis severity in adolescent smokers is associated with increased bottom-up reward signaling and impaired top-down cognitive control over a salient or rewarding stimulus.”
The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
SOURCE: Hammond et al. AAAP 2017. Paper session A3.
REPORTING FROM AAAP
Key clinical point:
Major finding: Among adolescents who smoked cigarettes daily, 80% reported co-occurring heavy marijuana use, and 67% reported heavy episodic binge drinking.
Study details: A cross-sectional, single visit study of 36 adolescent nondeprived daily cigarette smokers and 29 healthy, age-matched controls.
Disclosures: The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
Source: Hammond et al. AAAP 2017. Paper session A3.
How to prioritize CVD reduction in type 2 diabetes
LOS ANGELES – In the opinion of Mikhail N. Kosiborod, MD, the paradigm of treating patients with type 2 diabetes should shift from a narrow focus on hemoglobin A1c control to a broader strategy of reducing cardiovascular risk.
“We already know that the number one killer of patients with diabetes is cardiovascular disease, and we already know that lowering HbA1c as a general strategy does not substantially lower the risk of most important CVD events,” Dr. Kosiborod, a cardiologist at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
Physicians know that some medications lower the risk of cardiovascular events – including cardiovascular death – substantially, and other drugs don’t. “The bottom line is that we are not talking about ignoring HbA1c, but it’s how you get there that’s important – how you do it and in whom,” Dr. Kosiborod explained.
He pointed to a meta-analysis of four large diabetes trials involving 27,049 participants and 2,370 major vascular events (Diabetologia. 2009 Nov;52[11]:2288-98). It found that the general strategy of targeting more-intensive glucose lowering modestly reduced nonfatal myocardial infarction and increased major hypoglycemia over 4.4 years in people with type 2 diabetes – yet there was no difference in the effect of intensive glucose control on cardiovascular death or hospitalization for heart failure.
“Some point to the benefit of glucose control on the risk of nonfatal myocardial infarction, but that’s a modest benefit,” he said. “It’s observed beyond the randomization phase of clinical trials and takes many years to see it. It’s a large, very long-term investment for a modest reduction in MI risk, with no benefit in death or heart failure. So, when you test intensive glucose control as a general strategy, it has not been successful in reducing cardiovascular complications of type 2 diabetes.”
However, there is now evidence that specific classes of medications, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for glucose lowering in type 2 diabetes, can significantly reduce cardiovascular risk within a relatively short time frame.
In EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), the first trial to demonstrate such benefits, all patients had established CVD, compared with 67% of patients in CANVAS (Canagliflozin Cardiovascular Assessment Study), a second RCT program to report cardiovascular outcomes with SGLT2 inhibitors. In the meantime, about 15%-20% of patients in real-world clinical practice have established CVD.
This led Dr. Kosiborod and his associates to launch CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors), a real-world comparative effectiveness study that evaluated hospitalization for heart failure and total mortality among new users of SGLT2 inhibitors, compared with other glucose-lowering drugs.
In all, 154,528 patients in six countries were initiated on an SGLT2 inhibitor, and 154,528 were initiated on other glucose-lowering drugs (Circulation. 2017 May 18. doi: 10/1161/circulationaha.117.029190). The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%).
The pooled analysis showed that initiation of SGLT2 inhibitors was associated with a significantly lower risk of heart failure events, compared with other glucose-lowering drugs (risk ratio, 0.61; P less than .001). The researchers observed an overall 39% lower risk of heart failure hospitalization, 51% reduction in total death, and 46% reduction in the composite of heart failure hospitalization or death.
“There was no heterogeneity across countries, despite the fact that the health care systems were very different and the prescribing patterns were very different,” he said.
Dr. Kosiborod, who is also professor of medicine at the University of Missouri-Kansas City, noted that 13% of patients from CVD-REAL had established CVD, while 87% did not. When comparing the results within these two key subgroups, “what’s striking is the difference in event rates, stratified by treatment allocation,” he said of the unpublished data.
“If you look at the composite outcome of heart failure or death, you see an almost seven-fold difference in annualized event rates – about 7% per year in patients with established CVD, compared with about 1% per year in the primary prevention cohort,” he explained. “But the relative risk reduction associated with SGLT2 inhibitors versus other glucose-lowering drugs is identical across both patient groups. That’s a good lesson in epidemiology: You can have patients with dramatically different absolute risks, dramatically different absolute risk reductions, and therefore dramatically different numbers needed to treat, but identical relative risk reductions.”
Dr. Kosiborod also pointed out that heart failure is emerging as one of the most important outcomes in trials patents with type 2 diabetes.
“That’s because people with diabetes who develop heart failure have very poor outcomes,” he said. “Among elderly patients with type 2 diabetes who develop new heart failure, there’s less than 25% survival at 5 years. That’s the reason, I think, that if you really want to impact survival and complication rates in people with diabetes, preventing and treating heart failure is one of the surest ways of doing so.
“You shouldn’t just think of the patient in front of you as someone who has an A1c of 7%, 8%, or 9%,” he cautioned. “You should also start thinking of where the patient is on the spectrum of cardiovascular disease, all the way from CVD risk factors only to symptomatic heart failure.”
Some evidence already exists to help clinicians make treatment decisions based on where the patients fall on that spectrum, he continued.
For example, clinical trials have demonstrated that in patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors can reduce the risk of cardiovascular events, including, in some cases, cardiovascular death.
“We don’t have a lot of data demonstrating benefit for patients with recent acute coronary syndrome,” he said. “Some compounds have proven to be neutral, but none has been proven to save lives in this patient group.
“Now, we also have data for people with prior stroke that pioglitazone may be beneficial in managing those patients to prevent recurrent stroke and MI, based on the recent IRIS Trial, provided they don’t have heart failure at baseline,” Dr. Kosiborod added. “We don’t have definitive data yet in people with established heart failure, but those studies are ongoing.”
Dr. Kosiborod disclosed that he is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Intarcia, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and ZS Pharma. He has also received research grants from AstraZeneca and Boehringer Ingelheim.
LOS ANGELES – In the opinion of Mikhail N. Kosiborod, MD, the paradigm of treating patients with type 2 diabetes should shift from a narrow focus on hemoglobin A1c control to a broader strategy of reducing cardiovascular risk.
“We already know that the number one killer of patients with diabetes is cardiovascular disease, and we already know that lowering HbA1c as a general strategy does not substantially lower the risk of most important CVD events,” Dr. Kosiborod, a cardiologist at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
Physicians know that some medications lower the risk of cardiovascular events – including cardiovascular death – substantially, and other drugs don’t. “The bottom line is that we are not talking about ignoring HbA1c, but it’s how you get there that’s important – how you do it and in whom,” Dr. Kosiborod explained.
He pointed to a meta-analysis of four large diabetes trials involving 27,049 participants and 2,370 major vascular events (Diabetologia. 2009 Nov;52[11]:2288-98). It found that the general strategy of targeting more-intensive glucose lowering modestly reduced nonfatal myocardial infarction and increased major hypoglycemia over 4.4 years in people with type 2 diabetes – yet there was no difference in the effect of intensive glucose control on cardiovascular death or hospitalization for heart failure.
“Some point to the benefit of glucose control on the risk of nonfatal myocardial infarction, but that’s a modest benefit,” he said. “It’s observed beyond the randomization phase of clinical trials and takes many years to see it. It’s a large, very long-term investment for a modest reduction in MI risk, with no benefit in death or heart failure. So, when you test intensive glucose control as a general strategy, it has not been successful in reducing cardiovascular complications of type 2 diabetes.”
However, there is now evidence that specific classes of medications, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for glucose lowering in type 2 diabetes, can significantly reduce cardiovascular risk within a relatively short time frame.
In EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), the first trial to demonstrate such benefits, all patients had established CVD, compared with 67% of patients in CANVAS (Canagliflozin Cardiovascular Assessment Study), a second RCT program to report cardiovascular outcomes with SGLT2 inhibitors. In the meantime, about 15%-20% of patients in real-world clinical practice have established CVD.
This led Dr. Kosiborod and his associates to launch CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors), a real-world comparative effectiveness study that evaluated hospitalization for heart failure and total mortality among new users of SGLT2 inhibitors, compared with other glucose-lowering drugs.
In all, 154,528 patients in six countries were initiated on an SGLT2 inhibitor, and 154,528 were initiated on other glucose-lowering drugs (Circulation. 2017 May 18. doi: 10/1161/circulationaha.117.029190). The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%).
The pooled analysis showed that initiation of SGLT2 inhibitors was associated with a significantly lower risk of heart failure events, compared with other glucose-lowering drugs (risk ratio, 0.61; P less than .001). The researchers observed an overall 39% lower risk of heart failure hospitalization, 51% reduction in total death, and 46% reduction in the composite of heart failure hospitalization or death.
“There was no heterogeneity across countries, despite the fact that the health care systems were very different and the prescribing patterns were very different,” he said.
Dr. Kosiborod, who is also professor of medicine at the University of Missouri-Kansas City, noted that 13% of patients from CVD-REAL had established CVD, while 87% did not. When comparing the results within these two key subgroups, “what’s striking is the difference in event rates, stratified by treatment allocation,” he said of the unpublished data.
“If you look at the composite outcome of heart failure or death, you see an almost seven-fold difference in annualized event rates – about 7% per year in patients with established CVD, compared with about 1% per year in the primary prevention cohort,” he explained. “But the relative risk reduction associated with SGLT2 inhibitors versus other glucose-lowering drugs is identical across both patient groups. That’s a good lesson in epidemiology: You can have patients with dramatically different absolute risks, dramatically different absolute risk reductions, and therefore dramatically different numbers needed to treat, but identical relative risk reductions.”
Dr. Kosiborod also pointed out that heart failure is emerging as one of the most important outcomes in trials patents with type 2 diabetes.
“That’s because people with diabetes who develop heart failure have very poor outcomes,” he said. “Among elderly patients with type 2 diabetes who develop new heart failure, there’s less than 25% survival at 5 years. That’s the reason, I think, that if you really want to impact survival and complication rates in people with diabetes, preventing and treating heart failure is one of the surest ways of doing so.
“You shouldn’t just think of the patient in front of you as someone who has an A1c of 7%, 8%, or 9%,” he cautioned. “You should also start thinking of where the patient is on the spectrum of cardiovascular disease, all the way from CVD risk factors only to symptomatic heart failure.”
Some evidence already exists to help clinicians make treatment decisions based on where the patients fall on that spectrum, he continued.
For example, clinical trials have demonstrated that in patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors can reduce the risk of cardiovascular events, including, in some cases, cardiovascular death.
“We don’t have a lot of data demonstrating benefit for patients with recent acute coronary syndrome,” he said. “Some compounds have proven to be neutral, but none has been proven to save lives in this patient group.
“Now, we also have data for people with prior stroke that pioglitazone may be beneficial in managing those patients to prevent recurrent stroke and MI, based on the recent IRIS Trial, provided they don’t have heart failure at baseline,” Dr. Kosiborod added. “We don’t have definitive data yet in people with established heart failure, but those studies are ongoing.”
Dr. Kosiborod disclosed that he is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Intarcia, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and ZS Pharma. He has also received research grants from AstraZeneca and Boehringer Ingelheim.
LOS ANGELES – In the opinion of Mikhail N. Kosiborod, MD, the paradigm of treating patients with type 2 diabetes should shift from a narrow focus on hemoglobin A1c control to a broader strategy of reducing cardiovascular risk.
“We already know that the number one killer of patients with diabetes is cardiovascular disease, and we already know that lowering HbA1c as a general strategy does not substantially lower the risk of most important CVD events,” Dr. Kosiborod, a cardiologist at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
Physicians know that some medications lower the risk of cardiovascular events – including cardiovascular death – substantially, and other drugs don’t. “The bottom line is that we are not talking about ignoring HbA1c, but it’s how you get there that’s important – how you do it and in whom,” Dr. Kosiborod explained.
He pointed to a meta-analysis of four large diabetes trials involving 27,049 participants and 2,370 major vascular events (Diabetologia. 2009 Nov;52[11]:2288-98). It found that the general strategy of targeting more-intensive glucose lowering modestly reduced nonfatal myocardial infarction and increased major hypoglycemia over 4.4 years in people with type 2 diabetes – yet there was no difference in the effect of intensive glucose control on cardiovascular death or hospitalization for heart failure.
“Some point to the benefit of glucose control on the risk of nonfatal myocardial infarction, but that’s a modest benefit,” he said. “It’s observed beyond the randomization phase of clinical trials and takes many years to see it. It’s a large, very long-term investment for a modest reduction in MI risk, with no benefit in death or heart failure. So, when you test intensive glucose control as a general strategy, it has not been successful in reducing cardiovascular complications of type 2 diabetes.”
However, there is now evidence that specific classes of medications, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for glucose lowering in type 2 diabetes, can significantly reduce cardiovascular risk within a relatively short time frame.
In EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), the first trial to demonstrate such benefits, all patients had established CVD, compared with 67% of patients in CANVAS (Canagliflozin Cardiovascular Assessment Study), a second RCT program to report cardiovascular outcomes with SGLT2 inhibitors. In the meantime, about 15%-20% of patients in real-world clinical practice have established CVD.
This led Dr. Kosiborod and his associates to launch CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors), a real-world comparative effectiveness study that evaluated hospitalization for heart failure and total mortality among new users of SGLT2 inhibitors, compared with other glucose-lowering drugs.
In all, 154,528 patients in six countries were initiated on an SGLT2 inhibitor, and 154,528 were initiated on other glucose-lowering drugs (Circulation. 2017 May 18. doi: 10/1161/circulationaha.117.029190). The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%).
The pooled analysis showed that initiation of SGLT2 inhibitors was associated with a significantly lower risk of heart failure events, compared with other glucose-lowering drugs (risk ratio, 0.61; P less than .001). The researchers observed an overall 39% lower risk of heart failure hospitalization, 51% reduction in total death, and 46% reduction in the composite of heart failure hospitalization or death.
“There was no heterogeneity across countries, despite the fact that the health care systems were very different and the prescribing patterns were very different,” he said.
Dr. Kosiborod, who is also professor of medicine at the University of Missouri-Kansas City, noted that 13% of patients from CVD-REAL had established CVD, while 87% did not. When comparing the results within these two key subgroups, “what’s striking is the difference in event rates, stratified by treatment allocation,” he said of the unpublished data.
“If you look at the composite outcome of heart failure or death, you see an almost seven-fold difference in annualized event rates – about 7% per year in patients with established CVD, compared with about 1% per year in the primary prevention cohort,” he explained. “But the relative risk reduction associated with SGLT2 inhibitors versus other glucose-lowering drugs is identical across both patient groups. That’s a good lesson in epidemiology: You can have patients with dramatically different absolute risks, dramatically different absolute risk reductions, and therefore dramatically different numbers needed to treat, but identical relative risk reductions.”
Dr. Kosiborod also pointed out that heart failure is emerging as one of the most important outcomes in trials patents with type 2 diabetes.
“That’s because people with diabetes who develop heart failure have very poor outcomes,” he said. “Among elderly patients with type 2 diabetes who develop new heart failure, there’s less than 25% survival at 5 years. That’s the reason, I think, that if you really want to impact survival and complication rates in people with diabetes, preventing and treating heart failure is one of the surest ways of doing so.
“You shouldn’t just think of the patient in front of you as someone who has an A1c of 7%, 8%, or 9%,” he cautioned. “You should also start thinking of where the patient is on the spectrum of cardiovascular disease, all the way from CVD risk factors only to symptomatic heart failure.”
Some evidence already exists to help clinicians make treatment decisions based on where the patients fall on that spectrum, he continued.
For example, clinical trials have demonstrated that in patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors can reduce the risk of cardiovascular events, including, in some cases, cardiovascular death.
“We don’t have a lot of data demonstrating benefit for patients with recent acute coronary syndrome,” he said. “Some compounds have proven to be neutral, but none has been proven to save lives in this patient group.
“Now, we also have data for people with prior stroke that pioglitazone may be beneficial in managing those patients to prevent recurrent stroke and MI, based on the recent IRIS Trial, provided they don’t have heart failure at baseline,” Dr. Kosiborod added. “We don’t have definitive data yet in people with established heart failure, but those studies are ongoing.”
Dr. Kosiborod disclosed that he is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Intarcia, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and ZS Pharma. He has also received research grants from AstraZeneca and Boehringer Ingelheim.
EXPERT ANALYSIS FROM WCIRDC 2017
Delayed ileal pouch anal anastomosis creation linked to lower 30-day adverse events
LAS VEGAS – compared with creating the pouch at the time of initial surgery, results from an analysis of national data demonstrated.
“More than 600,000 Americans have UC, and 20%-30% of them require surgical management,” Bharati Kochar, MD, said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “The surgical procedure of choice for many UC patients is total proctocolectomy with ileal pouch anal anastomosis creation.”
According to Dr. Kochar, an advanced fellow in inflammatory bowel diseases at the University of North Carolina at Chapel Hill, existing American medical literature regarding ileal pouch anal anastomosis (IPAA) comes mostly from quaternary care centers and compares one-stage procedures with multistage procedures.
“The risks between two- to three-stage procedures are not described, and there are no prospective national reports of postoperative adverse events after IPAA creation,” she said.
Using data from the National Surgical Quality Improvement Program, Dr. Kochar and her associates conducted an observational cohort analysis of 2,390 adult patients with a postoperative diagnosis of UC who underwent IPAA procedures between 2011 and 2015. Their aims were to evaluate adverse events within 30 days after an IPAA creation and to compare adverse events between pouch creation at the time of colectomy and delayed pouch creation.
They also performed a subanalysis of total abdominal colectomy with ileostomy (TAC), the first stage in the delayed pouch procedures, versus pouch creation at the time of colectomy. Multivariable modified Poisson regression models were used to estimate risk ratios adjusted for age, sex, race, body mass index, smoking status, diabetes, preoperative albumin, and American Society of Anesthesiologists class.
Of the 2,390 patients, 1,571 had pouches created at the time of colectomy (group A), and 819 had delayed pouch creation (group B).
Compared with patients in group B, those in group A were older (a median age of 40 years vs. 37 years, respectively; P less than .01), were more likely to be on an immunosuppressant (51% vs. 15%; P less than .01), have a lower median preoperative albumin level (3.9 vs. 4.2; P less than .01), and a longer median length of stay (6 days vs. 5 days; P less than .01).
On unadjusted analyses, the researchers also observed that, at 30 days, patients in group A had significantly more major complications, such as mortality and cardiac arrest (12.4% vs. 8.7%; P less than .01); minor complications, such as superficial surgical site infections and pneumonia (11.8% vs. 6.1%; P less than .01); unplanned readmissions (statistically similar at 23.3% vs. 21.3%), and unplanned reoperations (7.7% vs. 3.8%; P less than .01).
After controlling for confounders, patients in group B were significantly less likely to have major complications (relative risk, 0.72), minor complications (RR, 0.48), unplanned readmissions (RR, 0.95), and unplanned reoperations (RR, 0.42).
In the subgroup analysis, Dr. Kochar and her associates observed that patients who underwent TAC were significantly older, compared with patients in group A (a median of 46 years vs. 40 years, respectively; P less than .01), and a higher proportion were on immunosuppressants (69% vs. 51%; P less than .01). “Despite these factors, the risk of adverse events after TAC was lower,” Dr. Kochar said.
She acknowledged certain limitations of the study, including the inability to accurately determine the risk of linked surgeries together and the inability to assess institution and operator factors. Also, data were not collected for the purposes of studying inflammatory bowel disease.
“This is the first prospective assessment of morbidity following IPAA creation in UC patients from a national database,” Dr. Kochar concluded. “Delayed pouch procedures are associated with a lower risk of unplanned reoperations and major and minor complications. Immunosuppression at the time of pouch creation may result in an increased risk of adverse events postoperatively. The findings can be valuable for preoperative risk assessment and postoperative management.”
Dr. Kochar reported having no financial disclosures.
*This story was updated on 3/26.
SOURCE: Kochar et al. Crohn’s & Colitis Congress 2018 Clinical Abstract 11.
LAS VEGAS – compared with creating the pouch at the time of initial surgery, results from an analysis of national data demonstrated.
“More than 600,000 Americans have UC, and 20%-30% of them require surgical management,” Bharati Kochar, MD, said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “The surgical procedure of choice for many UC patients is total proctocolectomy with ileal pouch anal anastomosis creation.”
According to Dr. Kochar, an advanced fellow in inflammatory bowel diseases at the University of North Carolina at Chapel Hill, existing American medical literature regarding ileal pouch anal anastomosis (IPAA) comes mostly from quaternary care centers and compares one-stage procedures with multistage procedures.
“The risks between two- to three-stage procedures are not described, and there are no prospective national reports of postoperative adverse events after IPAA creation,” she said.
Using data from the National Surgical Quality Improvement Program, Dr. Kochar and her associates conducted an observational cohort analysis of 2,390 adult patients with a postoperative diagnosis of UC who underwent IPAA procedures between 2011 and 2015. Their aims were to evaluate adverse events within 30 days after an IPAA creation and to compare adverse events between pouch creation at the time of colectomy and delayed pouch creation.
They also performed a subanalysis of total abdominal colectomy with ileostomy (TAC), the first stage in the delayed pouch procedures, versus pouch creation at the time of colectomy. Multivariable modified Poisson regression models were used to estimate risk ratios adjusted for age, sex, race, body mass index, smoking status, diabetes, preoperative albumin, and American Society of Anesthesiologists class.
Of the 2,390 patients, 1,571 had pouches created at the time of colectomy (group A), and 819 had delayed pouch creation (group B).
Compared with patients in group B, those in group A were older (a median age of 40 years vs. 37 years, respectively; P less than .01), were more likely to be on an immunosuppressant (51% vs. 15%; P less than .01), have a lower median preoperative albumin level (3.9 vs. 4.2; P less than .01), and a longer median length of stay (6 days vs. 5 days; P less than .01).
On unadjusted analyses, the researchers also observed that, at 30 days, patients in group A had significantly more major complications, such as mortality and cardiac arrest (12.4% vs. 8.7%; P less than .01); minor complications, such as superficial surgical site infections and pneumonia (11.8% vs. 6.1%; P less than .01); unplanned readmissions (statistically similar at 23.3% vs. 21.3%), and unplanned reoperations (7.7% vs. 3.8%; P less than .01).
After controlling for confounders, patients in group B were significantly less likely to have major complications (relative risk, 0.72), minor complications (RR, 0.48), unplanned readmissions (RR, 0.95), and unplanned reoperations (RR, 0.42).
In the subgroup analysis, Dr. Kochar and her associates observed that patients who underwent TAC were significantly older, compared with patients in group A (a median of 46 years vs. 40 years, respectively; P less than .01), and a higher proportion were on immunosuppressants (69% vs. 51%; P less than .01). “Despite these factors, the risk of adverse events after TAC was lower,” Dr. Kochar said.
She acknowledged certain limitations of the study, including the inability to accurately determine the risk of linked surgeries together and the inability to assess institution and operator factors. Also, data were not collected for the purposes of studying inflammatory bowel disease.
“This is the first prospective assessment of morbidity following IPAA creation in UC patients from a national database,” Dr. Kochar concluded. “Delayed pouch procedures are associated with a lower risk of unplanned reoperations and major and minor complications. Immunosuppression at the time of pouch creation may result in an increased risk of adverse events postoperatively. The findings can be valuable for preoperative risk assessment and postoperative management.”
Dr. Kochar reported having no financial disclosures.
*This story was updated on 3/26.
SOURCE: Kochar et al. Crohn’s & Colitis Congress 2018 Clinical Abstract 11.
LAS VEGAS – compared with creating the pouch at the time of initial surgery, results from an analysis of national data demonstrated.
“More than 600,000 Americans have UC, and 20%-30% of them require surgical management,” Bharati Kochar, MD, said at the Crohn’s & Colitis Congress, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association. “The surgical procedure of choice for many UC patients is total proctocolectomy with ileal pouch anal anastomosis creation.”
According to Dr. Kochar, an advanced fellow in inflammatory bowel diseases at the University of North Carolina at Chapel Hill, existing American medical literature regarding ileal pouch anal anastomosis (IPAA) comes mostly from quaternary care centers and compares one-stage procedures with multistage procedures.
“The risks between two- to three-stage procedures are not described, and there are no prospective national reports of postoperative adverse events after IPAA creation,” she said.
Using data from the National Surgical Quality Improvement Program, Dr. Kochar and her associates conducted an observational cohort analysis of 2,390 adult patients with a postoperative diagnosis of UC who underwent IPAA procedures between 2011 and 2015. Their aims were to evaluate adverse events within 30 days after an IPAA creation and to compare adverse events between pouch creation at the time of colectomy and delayed pouch creation.
They also performed a subanalysis of total abdominal colectomy with ileostomy (TAC), the first stage in the delayed pouch procedures, versus pouch creation at the time of colectomy. Multivariable modified Poisson regression models were used to estimate risk ratios adjusted for age, sex, race, body mass index, smoking status, diabetes, preoperative albumin, and American Society of Anesthesiologists class.
Of the 2,390 patients, 1,571 had pouches created at the time of colectomy (group A), and 819 had delayed pouch creation (group B).
Compared with patients in group B, those in group A were older (a median age of 40 years vs. 37 years, respectively; P less than .01), were more likely to be on an immunosuppressant (51% vs. 15%; P less than .01), have a lower median preoperative albumin level (3.9 vs. 4.2; P less than .01), and a longer median length of stay (6 days vs. 5 days; P less than .01).
On unadjusted analyses, the researchers also observed that, at 30 days, patients in group A had significantly more major complications, such as mortality and cardiac arrest (12.4% vs. 8.7%; P less than .01); minor complications, such as superficial surgical site infections and pneumonia (11.8% vs. 6.1%; P less than .01); unplanned readmissions (statistically similar at 23.3% vs. 21.3%), and unplanned reoperations (7.7% vs. 3.8%; P less than .01).
After controlling for confounders, patients in group B were significantly less likely to have major complications (relative risk, 0.72), minor complications (RR, 0.48), unplanned readmissions (RR, 0.95), and unplanned reoperations (RR, 0.42).
In the subgroup analysis, Dr. Kochar and her associates observed that patients who underwent TAC were significantly older, compared with patients in group A (a median of 46 years vs. 40 years, respectively; P less than .01), and a higher proportion were on immunosuppressants (69% vs. 51%; P less than .01). “Despite these factors, the risk of adverse events after TAC was lower,” Dr. Kochar said.
She acknowledged certain limitations of the study, including the inability to accurately determine the risk of linked surgeries together and the inability to assess institution and operator factors. Also, data were not collected for the purposes of studying inflammatory bowel disease.
“This is the first prospective assessment of morbidity following IPAA creation in UC patients from a national database,” Dr. Kochar concluded. “Delayed pouch procedures are associated with a lower risk of unplanned reoperations and major and minor complications. Immunosuppression at the time of pouch creation may result in an increased risk of adverse events postoperatively. The findings can be valuable for preoperative risk assessment and postoperative management.”
Dr. Kochar reported having no financial disclosures.
*This story was updated on 3/26.
SOURCE: Kochar et al. Crohn’s & Colitis Congress 2018 Clinical Abstract 11.
REPORTING FROM THE CROHN’S & COLITIS CONGRESS
Key clinical point: Delayed ileal pouch anal anastomosis procedures are associated with a lower 30-day adverse-event rate.
Major finding: After controlling for confounders, patients who underwent delayed IPAA procedures were significantly less likely to have major complications (relative risk, 0.72), minor complications (RR, 0.48), unplanned readmissions (RR, 0.95), and unplanned reoperations (RR, 0.42) at 30 days, compared with those who underwent pouch creation at the time of initial surgery.
Study details: An observational cohort analysis of 2,390 adult patients with a postoperative diagnosis of UC.
Disclosures: Dr. Kochar reported having no financial disclosures.
Source: Kochar et al. Crohn’s & Colitis Congress 2018 Clinical Abstract 11. Gastroenterology. 2018;154(1)Suppl:S1-S114.