Clinical Edge Journal Scan

Key clinical point: Baricitinib demonstrated long-term (52 weeks) efficacy in reducing disease severity in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: At week 52, >45% of patients achieved ≥75% improvement in the Eczema Area and Severity Index (EASI), with a mean improvement of 56.8 points in the total EASI score.

Study details: Findings are from the phase 3, BREEZE-AD5 study including 146 patients with moderate-to-severe AD who were assigned to receive 2 mg baricitinib, of which 98 patients participated in the open-label extension, BREEZE-AD6 study.

Disclosures: This study was funded by Eli Lilly and Company, under license from Incyte Corporation. Five authors declared being employees and shareholders of Eli Lilly, and the other authors reported ties with several sources, including Eli Lily.

Source: Simpson E et al. Baricitinib 2 mg for the treatment of atopic dermatitis in North America: Long-term efficacy and patient-reported outcomes. Dermatol Ther. 2022 (Oct 21). Doi: 10.1111/dth.15954

Key clinical point: Baricitinib demonstrated long-term (52 weeks) efficacy in reducing disease severity in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: At week 52, >45% of patients achieved ≥75% improvement in the Eczema Area and Severity Index (EASI), with a mean improvement of 56.8 points in the total EASI score.

Study details: Findings are from the phase 3, BREEZE-AD5 study including 146 patients with moderate-to-severe AD who were assigned to receive 2 mg baricitinib, of which 98 patients participated in the open-label extension, BREEZE-AD6 study.

Disclosures: This study was funded by Eli Lilly and Company, under license from Incyte Corporation. Five authors declared being employees and shareholders of Eli Lilly, and the other authors reported ties with several sources, including Eli Lily.

Source: Simpson E et al. Baricitinib 2 mg for the treatment of atopic dermatitis in North America: Long-term efficacy and patient-reported outcomes. Dermatol Ther. 2022 (Oct 21). Doi: 10.1111/dth.15954

Key clinical point: Baricitinib demonstrated long-term (52 weeks) efficacy in reducing disease severity in patients with moderate-to-severe atopic dermatitis (AD).

Major finding: At week 52, >45% of patients achieved ≥75% improvement in the Eczema Area and Severity Index (EASI), with a mean improvement of 56.8 points in the total EASI score.

Study details: Findings are from the phase 3, BREEZE-AD5 study including 146 patients with moderate-to-severe AD who were assigned to receive 2 mg baricitinib, of which 98 patients participated in the open-label extension, BREEZE-AD6 study.

Disclosures: This study was funded by Eli Lilly and Company, under license from Incyte Corporation. Five authors declared being employees and shareholders of Eli Lilly, and the other authors reported ties with several sources, including Eli Lily.

Source: Simpson E et al. Baricitinib 2 mg for the treatment of atopic dermatitis in North America: Long-term efficacy and patient-reported outcomes. Dermatol Ther. 2022 (Oct 21). Doi: 10.1111/dth.15954

Key clinical point: In patients with moderate-to-severe atopic dermatitis (AD), continuous long-term dupilumab treatment was not associated with an increased risk for overall systemic/cutaneous infections.

Major finding: At 4 years, the overall infection rate was 71.27 number of patients with ≥1 event per 100 patient-years (nP/100 PY), with most infections being mild to moderate in severity, and only a very small number of infections resulted in treatment discontinuation (0.34 nP/100 PY). The rate of total skin infections decreased from 28.10 to 11.48 nP/100 PY from week 16 to year 4.

Study details: Findings are from the analysis of the LIBERTY AD OLE study including 2677 patients with moderate-to-severe AD who received dupilumab, of which 13.1% completed treatment up to week 204.

Disclosures: This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Four authors declared being employees and shareholders of Regeneron Pharmaceuticals. Three authors declared being employees or holding stock options in Sanofi. The other authors reported ties with several sources, including Regeneron and Sanofi.

Source: Blauvelt A et al. No increased risk of overall infection in adults with moderate-to-severe atopic dermatitis treated for up to 4 years with dupilumab. Adv Ther. 2022 (Nov 1). Doi: 10.1007/s12325-022-02322-y

Key clinical point: In patients with moderate-to-severe atopic dermatitis (AD), continuous long-term dupilumab treatment was not associated with an increased risk for overall systemic/cutaneous infections.

Major finding: At 4 years, the overall infection rate was 71.27 number of patients with ≥1 event per 100 patient-years (nP/100 PY), with most infections being mild to moderate in severity, and only a very small number of infections resulted in treatment discontinuation (0.34 nP/100 PY). The rate of total skin infections decreased from 28.10 to 11.48 nP/100 PY from week 16 to year 4.

Study details: Findings are from the analysis of the LIBERTY AD OLE study including 2677 patients with moderate-to-severe AD who received dupilumab, of which 13.1% completed treatment up to week 204.

Disclosures: This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Four authors declared being employees and shareholders of Regeneron Pharmaceuticals. Three authors declared being employees or holding stock options in Sanofi. The other authors reported ties with several sources, including Regeneron and Sanofi.

Source: Blauvelt A et al. No increased risk of overall infection in adults with moderate-to-severe atopic dermatitis treated for up to 4 years with dupilumab. Adv Ther. 2022 (Nov 1). Doi: 10.1007/s12325-022-02322-y

Key clinical point: In patients with moderate-to-severe atopic dermatitis (AD), continuous long-term dupilumab treatment was not associated with an increased risk for overall systemic/cutaneous infections.

Major finding: At 4 years, the overall infection rate was 71.27 number of patients with ≥1 event per 100 patient-years (nP/100 PY), with most infections being mild to moderate in severity, and only a very small number of infections resulted in treatment discontinuation (0.34 nP/100 PY). The rate of total skin infections decreased from 28.10 to 11.48 nP/100 PY from week 16 to year 4.

Study details: Findings are from the analysis of the LIBERTY AD OLE study including 2677 patients with moderate-to-severe AD who received dupilumab, of which 13.1% completed treatment up to week 204.

Disclosures: This research was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Four authors declared being employees and shareholders of Regeneron Pharmaceuticals. Three authors declared being employees or holding stock options in Sanofi. The other authors reported ties with several sources, including Regeneron and Sanofi.

Source: Blauvelt A et al. No increased risk of overall infection in adults with moderate-to-severe atopic dermatitis treated for up to 4 years with dupilumab. Adv Ther. 2022 (Nov 1). Doi: 10.1007/s12325-022-02322-y

Key clinical point: Air pollution due to a wildfire increased the rate of clinic visits for atopic dermatitis (AD), especially at a 0-week lag, in adults aged ≥65 years.

Major finding: In adults aged ≥65 years, the adjusted rate of clinic visits for AD during a week with a wildfire was 1.4 (95% CI 1.1-1.9) times the rate during weeks without wildfire and every 1-unit increase in the mean weekly smoke plume density score increased the rate of clinic visits for AD by 1.3 (95% CI 1.1-1.6) times.

Study details: This study analyzed the data of outpatient dermatology visits for AD (5529 visits) and itch (1319 visits).

Disclosures: This study did not report the source of funding. Dr. Grimes declared receiving grants from the University of California, San Francisco.

Source: Fadadu RP et al. Association of exposure to wildfire air pollution with exacerbations of atopic dermatitis and itch among older adults. JAMA Netw Open. 2022;5(10):e2238594 (Oct 26). Doi: 10.1001/jamanetworkopen.2022.38594

Key clinical point: Air pollution due to a wildfire increased the rate of clinic visits for atopic dermatitis (AD), especially at a 0-week lag, in adults aged ≥65 years.

Major finding: In adults aged ≥65 years, the adjusted rate of clinic visits for AD during a week with a wildfire was 1.4 (95% CI 1.1-1.9) times the rate during weeks without wildfire and every 1-unit increase in the mean weekly smoke plume density score increased the rate of clinic visits for AD by 1.3 (95% CI 1.1-1.6) times.

Study details: This study analyzed the data of outpatient dermatology visits for AD (5529 visits) and itch (1319 visits).

Disclosures: This study did not report the source of funding. Dr. Grimes declared receiving grants from the University of California, San Francisco.

Source: Fadadu RP et al. Association of exposure to wildfire air pollution with exacerbations of atopic dermatitis and itch among older adults. JAMA Netw Open. 2022;5(10):e2238594 (Oct 26). Doi: 10.1001/jamanetworkopen.2022.38594

Key clinical point: Air pollution due to a wildfire increased the rate of clinic visits for atopic dermatitis (AD), especially at a 0-week lag, in adults aged ≥65 years.

Major finding: In adults aged ≥65 years, the adjusted rate of clinic visits for AD during a week with a wildfire was 1.4 (95% CI 1.1-1.9) times the rate during weeks without wildfire and every 1-unit increase in the mean weekly smoke plume density score increased the rate of clinic visits for AD by 1.3 (95% CI 1.1-1.6) times.

Study details: This study analyzed the data of outpatient dermatology visits for AD (5529 visits) and itch (1319 visits).

Disclosures: This study did not report the source of funding. Dr. Grimes declared receiving grants from the University of California, San Francisco.

Source: Fadadu RP et al. Association of exposure to wildfire air pollution with exacerbations of atopic dermatitis and itch among older adults. JAMA Netw Open. 2022;5(10):e2238594 (Oct 26). Doi: 10.1001/jamanetworkopen.2022.38594

Key clinical point: In patients with atopic dermatitis (AD), serum dupilumab levels at week 16 were not associated with treatment response or adverse effects due to dupilumab during the first year of treatment.

Major finding: Serum dupilumab levels at 16 weeks were not associated with the prediction of treatment response at 52 weeks (≥90% improvement in the Eczema Area and Severity Index; odds ratio [OR] 0.96; P = .34) or adverse events during the first year of treatment (OR 1.01; P = .83).

Study details: Findings are from a prospective clinical cohort study including 295 patients with AD who started dupilumab and had treatment week 16 serum samples available.

Disclosures: This study was funded by AbbVie, Eli Lilly, and other sources. The authors declared receiving consulting fees, speaking fees, investigator fees, or research funding from several sources.

Source: Spekhorst LS et al. Association of serum dupilumab levels at 16 weeks with treatment response and adverse effects in patients with atopic dermatitis: A prospective clinical cohort study from the BioDay registry. JAMA Dermatol. 2022 (Nov 2). Doi: 10.1001/jamadermatol.2022.4639

Key clinical point: In patients with atopic dermatitis (AD), serum dupilumab levels at week 16 were not associated with treatment response or adverse effects due to dupilumab during the first year of treatment.

Major finding: Serum dupilumab levels at 16 weeks were not associated with the prediction of treatment response at 52 weeks (≥90% improvement in the Eczema Area and Severity Index; odds ratio [OR] 0.96; P = .34) or adverse events during the first year of treatment (OR 1.01; P = .83).

Study details: Findings are from a prospective clinical cohort study including 295 patients with AD who started dupilumab and had treatment week 16 serum samples available.

Disclosures: This study was funded by AbbVie, Eli Lilly, and other sources. The authors declared receiving consulting fees, speaking fees, investigator fees, or research funding from several sources.

Source: Spekhorst LS et al. Association of serum dupilumab levels at 16 weeks with treatment response and adverse effects in patients with atopic dermatitis: A prospective clinical cohort study from the BioDay registry. JAMA Dermatol. 2022 (Nov 2). Doi: 10.1001/jamadermatol.2022.4639

Key clinical point: In patients with atopic dermatitis (AD), serum dupilumab levels at week 16 were not associated with treatment response or adverse effects due to dupilumab during the first year of treatment.

Major finding: Serum dupilumab levels at 16 weeks were not associated with the prediction of treatment response at 52 weeks (≥90% improvement in the Eczema Area and Severity Index; odds ratio [OR] 0.96; P = .34) or adverse events during the first year of treatment (OR 1.01; P = .83).

Study details: Findings are from a prospective clinical cohort study including 295 patients with AD who started dupilumab and had treatment week 16 serum samples available.

Disclosures: This study was funded by AbbVie, Eli Lilly, and other sources. The authors declared receiving consulting fees, speaking fees, investigator fees, or research funding from several sources.

Source: Spekhorst LS et al. Association of serum dupilumab levels at 16 weeks with treatment response and adverse effects in patients with atopic dermatitis: A prospective clinical cohort study from the BioDay registry. JAMA Dermatol. 2022 (Nov 2). Doi: 10.1001/jamadermatol.2022.4639

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Calcitonin gene-related peptide (CGRP) antagonist medications are becoming more and more of a mainstay of both migraine prevention and acute treatment. Four CGRP monoclonal antibody medications and three oral CGRP antagonists are now available for prevention and acute treatment of migraine. When this class of medications was developed, many patients and providers were initially concerned regarding any potentially unanticipated long-term adverse events. The first CGRP antagonist medication, erenumab, was associated with constipation, and, although this has not been formally reported with other CGRP medications, there is some anecdotal evidence of gastrointestinal (GI) discomfort with both oral and other monoclonal antibody medications in this class. In 2021, erenumab was also reported to be associated with hypertension and a formal warning was issued for this.

Before CGRP was used for migraine prevention, it had been known to be a potent vasodilator. Although the randomized controlled trials (RCT) for all CGRP medications included a longitudinal review of blood pressure (BP) measures, none of those initial trials revealed an increased risk for hypertension or other cardiovascular events or concerns. Some of the initial trials even included patients at higher cardiovascular risk. Migraine itself is associated with an increased vascular risk; it is therefore extremely important to determine whether a potential treatment may be increasing this risk further.

In the study by de Vries and colleagues, all patients were started on either erenumab or fremanezumab and were included if they had a follow-up blood pressure measurement within 6 months. All patients had at least8 migraine days per month and had used four or more preventive medications. Patients taking erenumab were first started at 70 mg monthly and were optionally increased to 140 mg after 3 months. Fremanezumab was always given at a dose of 225 mg monthly (as opposed to 675 mg every 3 months). BP data were collected at baseline and followed up at every visit, with a maximum of 12 months of review. Patients were excluded if their baseline BP was measured while they were undergoing tapering an antihypertensive medication at the same time that they were starting the CGRP antagonist. Patients already treated for hypertension were included only if there were no changes to their hypertensive regimen.

Patients were also compared with a control group with a similar distribution in sex, age, and diagnosis, and who were not taking any migraine preventive medication that would affect their BP. Control group BP was also measured at least two different time points 1-3 months from baseline.

A total of 211 patients were enrolled: 109 in the erenumab group and 87 in the fremanezumab group. The erenumab group was also associated with an increase in both systolic BP (SBP) and diastolic BP (DBP) (SBP ≤ 9 mm Hg; DBP ≤ 6.3 mm Hg). The fremanezumab group had a lower increase in SBP (1 mm Hg) and no increase in DBP. Nine patients were started on antihypertensive medications, five of them after the baseline BP recording only. There was no change over time in the control group.

As noted, CGRP has a potent vasodilatory effect. Although not proven, a theory has been posited that CGRP receptor antagonist medications are somewhat more likely to lead to systemic adverse effects than are ligand-blocking medications. This may, at least in part, explain why erenumab appears to have more associated GI discomfort and constipation as well as a vascular effect with hypertension. In light of these findings, it is absolutely necessary for the additional CGRP medications to also be studied for these potential risk factors.

With the advent of novel acute treatments for migraine, many providers ask themselves what the potential risks and benefits are for each new class of drugs developed and approved over the past few years. Johnston and colleagues reviewed five recently published RCT to compare risk-benefit profiles for lasmiditan, rimegepant, and ubrogepant. Lasmiditan is the only medication in the ditan class, a serotonin (5HT-1F) receptor agonist medication approved for the acute treatment of migraine. Rimegepant and ubrogepant are oral CGRP antagonists.

Lasmiditan does have a potential risk for impairment while driving due to excessive sedation and dizziness; it is also more likely than the CGRP medications to lead to the development of medication overuse headache. The CGRP medications, however, are associated with a smaller responder rate for headache freedom at 2 hours. The investigators reviewed the data published in five RCT to develop a statistically based decision-making process that correlates with the number needed to treat vs the number needed to harm for all three of these medications. The number needed to treat is a statistically defined parameter that characterizes the number of patients that need to be treated with an intervention to achieve a positive event. The number needed to harm refers to an additional negative event relative to the reference treatment (placebo in the case of an RCT).

The reviewed studies compared multiple dosages of these medications. Efficacy outcomes were pain relief and pain freedom at 2 hours, sustained pain relief from 2 to 24 hours, and freedom from the most bothersome symptom at 2 hours. Safety outcomes were dizziness and nausea.

The number needed to treat was the lowest for 200 mg lasmiditan (twice the highest recommended acute dose), followed by 75 mg rimegepant. The number needed to harm was highest for 25 mg ubrogepant (half of the lowest recommended acute dose). Nausea was lowest for 75 mg rimegepant.

An individualized approach is always recommended when considering both preventive and acute treatments for migraine. It is definitely worth keeping these results in mind when discussing potential acute treatment options with patients. This is especially true when considering patients who may be more likely to experience either dizziness or nausea with other acute treatments. It is also worth individualizing a potential acute treatment when a patient experiences rapid-onset migraine symptoms. Further investigations into both acute and preventive treatments would enlighten and further individualize our clinical approaches.

Erenumab currently carries a prescriber warning for constipation. Although there has been some anecdotal evidence for constipation with other CGRP antagonists, this has never fully been investigated. Currently, the other CGRP medication options have fewer side effects and not all  are associated with constipation. Kudrow and colleagues sought to review the incidence of constipation, and GI motility in general, with both erenumab and galcanezumab. Their hypothesis was that a single dose of erenumab would be associated with delayed GI motility and a single dose of galcanezumab would not be.

This study was conducted as a multicenter trial with single-blinding. A total of 65 patients were enrolled and given either 140 mg erenumab or 240 mg galcanezumab (the loading dose). GI motility was measured via a wireless motility capsule at baseline before treatment and repeated at 2 weeks. This test is approved by the US Food and Drug Administration for evaluation of gastric transit time in patients with suspected gastroparesis and for evaluation of colonic transit time in patients with chronic idiopathic constipation. Patients with prior GI symptoms were excluded, as were patients taking a tricyclic antidepressant or a calcium-channel blocker, owing to known constipation with these agents.

The primary endpoint in this study was change from a baseline colonic transit time 2 weeks after injection with the CGRP monoclonal antibody. Secondary endpoints included change from baseline in whole-gut transit time, gastric emptying time, small-bowel transfer time, and combined small- and large-bowel transfer time. The Gastrointestinal Symptom Rating Scale (GSRS) was also used, evaluating abdominal pain, reflux, indigestion, constipation, and diarrhea based on a 7-point response, ranging from no discomfort to very severe discomfort.

The primary endpoint of baseline change in colonic transit time was not statistically significant between the groups: A mean change of 5.8 hours was noted for erenumab and 5.4 hours for galcanezumab. Most secondary endpoints were also not statistically significantly different between the two groups. Small-bowel transit time was  decreased in the galcanezumab group. When the patient-reported scales were reviewed, spontaneous bowel movements decreased significantly in the erenumab group, a finding that was not seen in the galcanezumab group and was statistically significant. The GSRS also showed a small but statistically significant change in the erenumab group.

This study does appear to show a significant difference in the two CGRP antagonist medications. The full side-effect profiles of the four CGRP monoclonal antibodies and three oral CGRP blocking medications available remain unknown. Further head-to-head comparisons will allow better differentiation of these options and better individualization of patient care.

Acupuncture is a very popular treatment strategy in some areas of the world and is extensively applied in Chinese practice. Though this is a regularly applied treatment, a direct comparison with first-line antispasmodics has not been previously completed. The study by Shi and colleagues sought to compare the treatment of IBS using an adjusted indirect treatment comparison meta-analysis. This study proves that cimetropium was the most effective for relieving abdominal pain, whereas drotaverine, acupuncture, and pinaverium remained superior to the placebo. That being said, acupuncture was shown to be superior in relieving global IBS symptoms and caused fewer side effects than did antispasmodics. This shows that acupuncture may have a role in the treatment algorithm for IBS even outside of China, where it is used broadly.

The study by Formica and colleagues provides new insights on the etiology and pathogenesis of IBS. These insights include the positive correlation between disgust sensitivity and IBS quality of life (QOL) scores. The relationship between IBS and the emotional intensity of the experience of disgust is discussed throughout this study and more severe IBS-QOL scores were linked to those with high levels of disgust sensitivity. This study had gender limitations because of the low number of male participants, so these correlations were patterned mostly in female participants. 

Acupuncture is a very popular treatment strategy in some areas of the world and is extensively applied in Chinese practice. Though this is a regularly applied treatment, a direct comparison with first-line antispasmodics has not been previously completed. The study by Shi and colleagues sought to compare the treatment of IBS using an adjusted indirect treatment comparison meta-analysis. This study proves that cimetropium was the most effective for relieving abdominal pain, whereas drotaverine, acupuncture, and pinaverium remained superior to the placebo. That being said, acupuncture was shown to be superior in relieving global IBS symptoms and caused fewer side effects than did antispasmodics. This shows that acupuncture may have a role in the treatment algorithm for IBS even outside of China, where it is used broadly.

The study by Formica and colleagues provides new insights on the etiology and pathogenesis of IBS. These insights include the positive correlation between disgust sensitivity and IBS quality of life (QOL) scores. The relationship between IBS and the emotional intensity of the experience of disgust is discussed throughout this study and more severe IBS-QOL scores were linked to those with high levels of disgust sensitivity. This study had gender limitations because of the low number of male participants, so these correlations were patterned mostly in female participants. 

Acupuncture is a very popular treatment strategy in some areas of the world and is extensively applied in Chinese practice. Though this is a regularly applied treatment, a direct comparison with first-line antispasmodics has not been previously completed. The study by Shi and colleagues sought to compare the treatment of IBS using an adjusted indirect treatment comparison meta-analysis. This study proves that cimetropium was the most effective for relieving abdominal pain, whereas drotaverine, acupuncture, and pinaverium remained superior to the placebo. That being said, acupuncture was shown to be superior in relieving global IBS symptoms and caused fewer side effects than did antispasmodics. This shows that acupuncture may have a role in the treatment algorithm for IBS even outside of China, where it is used broadly.

The study by Formica and colleagues provides new insights on the etiology and pathogenesis of IBS. These insights include the positive correlation between disgust sensitivity and IBS quality of life (QOL) scores. The relationship between IBS and the emotional intensity of the experience of disgust is discussed throughout this study and more severe IBS-QOL scores were linked to those with high levels of disgust sensitivity. This study had gender limitations because of the low number of male participants, so these correlations were patterned mostly in female participants. 

Orimo and colleagues addressed the use of liver resection in patients with more than one HCC in the liver. Patients with no or Child-Pugh A/B cirrhosis were included in this single-center retrospective study of 1088 patients who underwent hepatectomy for Barcelona Clinic Liver Cancer (BCLC) stage 0 (n = 88), A (n = 750), or B (n = 250) HCC, with stages A and B subcategorized into A1 (single nodule 2-5 cm or ≤ 3 nodules ≤ 3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥ 10 cm), B1 (2-3 nodules > 3 cm), and B2 (≥ 4 nodules). The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (P < .0001). Significant differences in overall survival (OS) were found between stages A1 and A2 (P = .0118), A2 and A3 (P = .0013), and B1 and B2 (P = .0050), but not between stages A3 and B1 (P = .4742). In stage B1 patients, Child-Pugh B cirrhosis was the only independent prognostic factor for OS. The authors concluded that hepatectomy is beneficial in patients with three or fewer hepatocellular carcinomas and either no or Child-Pugh class A cirrhosis, with the long-term results being comparable to those in patients who underwent a resection of a single HCC. Therefore, resection of up to three HCC is safe and should be considered in clinically appropriate patients.

Many patients with multifocal HCC are not eligible for liver-directed therapies. The standard of care for first-line systemic therapy is the combination of atezolizumab and bevacizumab, as reported in the IMbrave150 clinical trial. Fulgenzi and colleagues published the results of a multicenter prospective observational study, AB-Real, that included 433 patients who received atezolizumab and bevacizumab in routine clinical practice. The investigators confirmed the efficacy of the combination and found that portal vein tumor thrombosis and worse albumin-bilirubin grade were independent prognostic factors for poor OS and were associated with an increased risk for hemorrhagic events. In addition, the authors reported that the overall response rate (ORR) predicted better outcomes, including longer OS. Therefore, atezolizumab and bevacizumab remains a safe and effective first-line treatment for many patients with unresectable HCC.

Finally, Finn and colleagues reported the results of an open-label, noncomparative cohort of the REACH-2 study of ramucirumab in 47 patients with advanced HCC and an alpha-fetoprotein (AFP) level ≥ 400 ng/mL. These patients had previously received one to two lines of systemic therapy, excluding sorafenib or chemotherapy. Lenvatinib was the most common prior systemic therapy (n = 20; 43%). Others included immune checkpoint inhibitor (CPI) monotherapies (n = 11), CPI/antiangiogenic therapy (n = 14), or dual CPI therapy (n = 5). The ORR was 10.6% (95% CI 1.8-19.5) and disease control rate was 46.8% (95% CI 32.5-61.1), with a median duration of response of 8.3 months [95% CI 2.4 to not reached). The grade 3 or more adverse event rate was 57%, with hypertension (11%) being the most common, allowing the authors to conclude that ramucirumab offers clinically significant efficacy with no new safety signals in this setting. Therefore, ramucirumab remains as a safe and effective later-line treatment option for patients with unresectable HCC and an AFP ≥ 400 ng/mL.

Orimo and colleagues addressed the use of liver resection in patients with more than one HCC in the liver. Patients with no or Child-Pugh A/B cirrhosis were included in this single-center retrospective study of 1088 patients who underwent hepatectomy for Barcelona Clinic Liver Cancer (BCLC) stage 0 (n = 88), A (n = 750), or B (n = 250) HCC, with stages A and B subcategorized into A1 (single nodule 2-5 cm or ≤ 3 nodules ≤ 3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥ 10 cm), B1 (2-3 nodules > 3 cm), and B2 (≥ 4 nodules). The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (P < .0001). Significant differences in overall survival (OS) were found between stages A1 and A2 (P = .0118), A2 and A3 (P = .0013), and B1 and B2 (P = .0050), but not between stages A3 and B1 (P = .4742). In stage B1 patients, Child-Pugh B cirrhosis was the only independent prognostic factor for OS. The authors concluded that hepatectomy is beneficial in patients with three or fewer hepatocellular carcinomas and either no or Child-Pugh class A cirrhosis, with the long-term results being comparable to those in patients who underwent a resection of a single HCC. Therefore, resection of up to three HCC is safe and should be considered in clinically appropriate patients.

Many patients with multifocal HCC are not eligible for liver-directed therapies. The standard of care for first-line systemic therapy is the combination of atezolizumab and bevacizumab, as reported in the IMbrave150 clinical trial. Fulgenzi and colleagues published the results of a multicenter prospective observational study, AB-Real, that included 433 patients who received atezolizumab and bevacizumab in routine clinical practice. The investigators confirmed the efficacy of the combination and found that portal vein tumor thrombosis and worse albumin-bilirubin grade were independent prognostic factors for poor OS and were associated with an increased risk for hemorrhagic events. In addition, the authors reported that the overall response rate (ORR) predicted better outcomes, including longer OS. Therefore, atezolizumab and bevacizumab remains a safe and effective first-line treatment for many patients with unresectable HCC.

Finally, Finn and colleagues reported the results of an open-label, noncomparative cohort of the REACH-2 study of ramucirumab in 47 patients with advanced HCC and an alpha-fetoprotein (AFP) level ≥ 400 ng/mL. These patients had previously received one to two lines of systemic therapy, excluding sorafenib or chemotherapy. Lenvatinib was the most common prior systemic therapy (n = 20; 43%). Others included immune checkpoint inhibitor (CPI) monotherapies (n = 11), CPI/antiangiogenic therapy (n = 14), or dual CPI therapy (n = 5). The ORR was 10.6% (95% CI 1.8-19.5) and disease control rate was 46.8% (95% CI 32.5-61.1), with a median duration of response of 8.3 months [95% CI 2.4 to not reached). The grade 3 or more adverse event rate was 57%, with hypertension (11%) being the most common, allowing the authors to conclude that ramucirumab offers clinically significant efficacy with no new safety signals in this setting. Therefore, ramucirumab remains as a safe and effective later-line treatment option for patients with unresectable HCC and an AFP ≥ 400 ng/mL.

Orimo and colleagues addressed the use of liver resection in patients with more than one HCC in the liver. Patients with no or Child-Pugh A/B cirrhosis were included in this single-center retrospective study of 1088 patients who underwent hepatectomy for Barcelona Clinic Liver Cancer (BCLC) stage 0 (n = 88), A (n = 750), or B (n = 250) HCC, with stages A and B subcategorized into A1 (single nodule 2-5 cm or ≤ 3 nodules ≤ 3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥ 10 cm), B1 (2-3 nodules > 3 cm), and B2 (≥ 4 nodules). The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (P < .0001). Significant differences in overall survival (OS) were found between stages A1 and A2 (P = .0118), A2 and A3 (P = .0013), and B1 and B2 (P = .0050), but not between stages A3 and B1 (P = .4742). In stage B1 patients, Child-Pugh B cirrhosis was the only independent prognostic factor for OS. The authors concluded that hepatectomy is beneficial in patients with three or fewer hepatocellular carcinomas and either no or Child-Pugh class A cirrhosis, with the long-term results being comparable to those in patients who underwent a resection of a single HCC. Therefore, resection of up to three HCC is safe and should be considered in clinically appropriate patients.

Many patients with multifocal HCC are not eligible for liver-directed therapies. The standard of care for first-line systemic therapy is the combination of atezolizumab and bevacizumab, as reported in the IMbrave150 clinical trial. Fulgenzi and colleagues published the results of a multicenter prospective observational study, AB-Real, that included 433 patients who received atezolizumab and bevacizumab in routine clinical practice. The investigators confirmed the efficacy of the combination and found that portal vein tumor thrombosis and worse albumin-bilirubin grade were independent prognostic factors for poor OS and were associated with an increased risk for hemorrhagic events. In addition, the authors reported that the overall response rate (ORR) predicted better outcomes, including longer OS. Therefore, atezolizumab and bevacizumab remains a safe and effective first-line treatment for many patients with unresectable HCC.

Finally, Finn and colleagues reported the results of an open-label, noncomparative cohort of the REACH-2 study of ramucirumab in 47 patients with advanced HCC and an alpha-fetoprotein (AFP) level ≥ 400 ng/mL. These patients had previously received one to two lines of systemic therapy, excluding sorafenib or chemotherapy. Lenvatinib was the most common prior systemic therapy (n = 20; 43%). Others included immune checkpoint inhibitor (CPI) monotherapies (n = 11), CPI/antiangiogenic therapy (n = 14), or dual CPI therapy (n = 5). The ORR was 10.6% (95% CI 1.8-19.5) and disease control rate was 46.8% (95% CI 32.5-61.1), with a median duration of response of 8.3 months [95% CI 2.4 to not reached). The grade 3 or more adverse event rate was 57%, with hypertension (11%) being the most common, allowing the authors to conclude that ramucirumab offers clinically significant efficacy with no new safety signals in this setting. Therefore, ramucirumab remains as a safe and effective later-line treatment option for patients with unresectable HCC and an AFP ≥ 400 ng/mL.

Orimo and colleagues addressed the use of liver resection in patients with more than one HCC in the liver. Patients with no or Child-Pugh A/B cirrhosis were included in this single-center retrospective study of 1088 patients who underwent hepatectomy for Barcelona Clinic Liver Cancer (BCLC) stage 0 (n = 88), A (n = 750), or B (n = 250) HCC, with stages A and B subcategorized into A1 (single nodule 2-5 cm or ≤ 3 nodules ≤ 3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥ 10 cm), B1 (2-3 nodules > 3 cm), and B2 (≥ 4 nodules). The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (P < .0001). Significant differences in overall survival (OS) were found between stages A1 and A2 (P = .0118), A2 and A3 (P = .0013), and B1 and B2 (P = .0050), but not between stages A3 and B1 (P = .4742). In stage B1 patients, Child-Pugh B cirrhosis was the only independent prognostic factor for OS. The authors concluded that hepatectomy is beneficial in patients with three or fewer hepatocellular carcinomas and either no or Child-Pugh class A cirrhosis, with the long-term results being comparable to those in patients who underwent a resection of a single HCC. Therefore, resection of up to three HCC is safe and should be considered in clinically appropriate patients.

Many patients with multifocal HCC are not eligible for liver-directed therapies. The standard of care for first-line systemic therapy is the combination of atezolizumab and bevacizumab, as reported in the IMbrave150 clinical trial. Fulgenzi and colleagues published the results of a multicenter prospective observational study, AB-Real, that included 433 patients who received atezolizumab and bevacizumab in routine clinical practice. The investigators confirmed the efficacy of the combination and found that portal vein tumor thrombosis and worse albumin-bilirubin grade were independent prognostic factors for poor OS and were associated with an increased risk for hemorrhagic events. In addition, the authors reported that the overall response rate (ORR) predicted better outcomes, including longer OS. Therefore, atezolizumab and bevacizumab remains a safe and effective first-line treatment for many patients with unresectable HCC.

Finally, Finn and colleagues reported the results of an open-label, noncomparative cohort of the REACH-2 study of ramucirumab in 47 patients with advanced HCC and an alpha-fetoprotein (AFP) level ≥ 400 ng/mL. These patients had previously received one to two lines of systemic therapy, excluding sorafenib or chemotherapy. Lenvatinib was the most common prior systemic therapy (n = 20; 43%). Others included immune checkpoint inhibitor (CPI) monotherapies (n = 11), CPI/antiangiogenic therapy (n = 14), or dual CPI therapy (n = 5). The ORR was 10.6% (95% CI 1.8-19.5) and disease control rate was 46.8% (95% CI 32.5-61.1), with a median duration of response of 8.3 months (95% CI 2.4 to not reached). The grade 3 or more adverse event rate was 57%, with hypertension (11%) being the most common, allowing the authors to conclude that ramucirumab offers clinically significant efficacy with no new safety signals in this setting. Therefore, ramucirumab remains as a safe and effective later-line treatment option for patients with unresectable HCC and an AFP ≥ 400 ng/mL.

Orimo and colleagues addressed the use of liver resection in patients with more than one HCC in the liver. Patients with no or Child-Pugh A/B cirrhosis were included in this single-center retrospective study of 1088 patients who underwent hepatectomy for Barcelona Clinic Liver Cancer (BCLC) stage 0 (n = 88), A (n = 750), or B (n = 250) HCC, with stages A and B subcategorized into A1 (single nodule 2-5 cm or ≤ 3 nodules ≤ 3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥ 10 cm), B1 (2-3 nodules > 3 cm), and B2 (≥ 4 nodules). The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (P < .0001). Significant differences in overall survival (OS) were found between stages A1 and A2 (P = .0118), A2 and A3 (P = .0013), and B1 and B2 (P = .0050), but not between stages A3 and B1 (P = .4742). In stage B1 patients, Child-Pugh B cirrhosis was the only independent prognostic factor for OS. The authors concluded that hepatectomy is beneficial in patients with three or fewer hepatocellular carcinomas and either no or Child-Pugh class A cirrhosis, with the long-term results being comparable to those in patients who underwent a resection of a single HCC. Therefore, resection of up to three HCC is safe and should be considered in clinically appropriate patients.

Many patients with multifocal HCC are not eligible for liver-directed therapies. The standard of care for first-line systemic therapy is the combination of atezolizumab and bevacizumab, as reported in the IMbrave150 clinical trial. Fulgenzi and colleagues published the results of a multicenter prospective observational study, AB-Real, that included 433 patients who received atezolizumab and bevacizumab in routine clinical practice. The investigators confirmed the efficacy of the combination and found that portal vein tumor thrombosis and worse albumin-bilirubin grade were independent prognostic factors for poor OS and were associated with an increased risk for hemorrhagic events. In addition, the authors reported that the overall response rate (ORR) predicted better outcomes, including longer OS. Therefore, atezolizumab and bevacizumab remains a safe and effective first-line treatment for many patients with unresectable HCC.

Finally, Finn and colleagues reported the results of an open-label, noncomparative cohort of the REACH-2 study of ramucirumab in 47 patients with advanced HCC and an alpha-fetoprotein (AFP) level ≥ 400 ng/mL. These patients had previously received one to two lines of systemic therapy, excluding sorafenib or chemotherapy. Lenvatinib was the most common prior systemic therapy (n = 20; 43%). Others included immune checkpoint inhibitor (CPI) monotherapies (n = 11), CPI/antiangiogenic therapy (n = 14), or dual CPI therapy (n = 5). The ORR was 10.6% (95% CI 1.8-19.5) and disease control rate was 46.8% (95% CI 32.5-61.1), with a median duration of response of 8.3 months (95% CI 2.4 to not reached). The grade 3 or more adverse event rate was 57%, with hypertension (11%) being the most common, allowing the authors to conclude that ramucirumab offers clinically significant efficacy with no new safety signals in this setting. Therefore, ramucirumab remains as a safe and effective later-line treatment option for patients with unresectable HCC and an AFP ≥ 400 ng/mL.

Orimo and colleagues addressed the use of liver resection in patients with more than one HCC in the liver. Patients with no or Child-Pugh A/B cirrhosis were included in this single-center retrospective study of 1088 patients who underwent hepatectomy for Barcelona Clinic Liver Cancer (BCLC) stage 0 (n = 88), A (n = 750), or B (n = 250) HCC, with stages A and B subcategorized into A1 (single nodule 2-5 cm or ≤ 3 nodules ≤ 3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥ 10 cm), B1 (2-3 nodules > 3 cm), and B2 (≥ 4 nodules). The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (P < .0001). Significant differences in overall survival (OS) were found between stages A1 and A2 (P = .0118), A2 and A3 (P = .0013), and B1 and B2 (P = .0050), but not between stages A3 and B1 (P = .4742). In stage B1 patients, Child-Pugh B cirrhosis was the only independent prognostic factor for OS. The authors concluded that hepatectomy is beneficial in patients with three or fewer hepatocellular carcinomas and either no or Child-Pugh class A cirrhosis, with the long-term results being comparable to those in patients who underwent a resection of a single HCC. Therefore, resection of up to three HCC is safe and should be considered in clinically appropriate patients.

Many patients with multifocal HCC are not eligible for liver-directed therapies. The standard of care for first-line systemic therapy is the combination of atezolizumab and bevacizumab, as reported in the IMbrave150 clinical trial. Fulgenzi and colleagues published the results of a multicenter prospective observational study, AB-Real, that included 433 patients who received atezolizumab and bevacizumab in routine clinical practice. The investigators confirmed the efficacy of the combination and found that portal vein tumor thrombosis and worse albumin-bilirubin grade were independent prognostic factors for poor OS and were associated with an increased risk for hemorrhagic events. In addition, the authors reported that the overall response rate (ORR) predicted better outcomes, including longer OS. Therefore, atezolizumab and bevacizumab remains a safe and effective first-line treatment for many patients with unresectable HCC.

Finally, Finn and colleagues reported the results of an open-label, noncomparative cohort of the REACH-2 study of ramucirumab in 47 patients with advanced HCC and an alpha-fetoprotein (AFP) level ≥ 400 ng/mL. These patients had previously received one to two lines of systemic therapy, excluding sorafenib or chemotherapy. Lenvatinib was the most common prior systemic therapy (n = 20; 43%). Others included immune checkpoint inhibitor (CPI) monotherapies (n = 11), CPI/antiangiogenic therapy (n = 14), or dual CPI therapy (n = 5). The ORR was 10.6% (95% CI 1.8-19.5) and disease control rate was 46.8% (95% CI 32.5-61.1), with a median duration of response of 8.3 months (95% CI 2.4 to not reached). The grade 3 or more adverse event rate was 57%, with hypertension (11%) being the most common, allowing the authors to conclude that ramucirumab offers clinically significant efficacy with no new safety signals in this setting. Therefore, ramucirumab remains as a safe and effective later-line treatment option for patients with unresectable HCC and an AFP ≥ 400 ng/mL.

The effectiveness and safety of advanced therapies for psoriatic arthritis (PsA) was a focus of many published studies last month. Janus kinase inhibitors (JAKi) are a recent class of drugs made available to treat PsA and related diseases, and several clinical trials have been published. Sarabia and colleagues reported the results of a meta-analysis of 15 randomized controlled trials including 6757 patients with psoriasis or PsA who received treatment with a JAKi or placebo. Their analyses revealed that treatment with JAKi vs placebo was associated with higher odds of achieving American College of Rheumatology 20 (ACR20) response (odds ratio [OR] 4.45; 95% CI 3.64-5.44), with similar outcomes observed with tofacitinib vs placebo (OR 2.96; 95% CI 2.01-4.35) and non-tofacitinib JAKi vs placebo (OR 5.41; 95% CI 3.95-7.40). Serious adverse event rates were low (1%-7% in the maximum-dose intervention group).

Interleukin-23i (guselkumab, tildrakizumab, or risankizumab) are another class of biologics recently approved for the treatment of PsA. Preliminary results from a real-world study demonstrate the efficacy of these drugs for PsA. In a retrospective observational study including 80 patients with psoriasis (22 with PsA) who received guselkumab, tildrakizumab, or risankizumab, Elgaard and colleagues demonstrated that 40.9% or 36.4% of the PsA patients achieved complete or partial remission, respectively, compared with only 18.2% of patients with no improvement.

Regarding drug safety, a recent study demonstrated low rates of opportunistic infections with biologic disease-modifying antirheumatic drugs (bDMARD) and targeted synthetic DMARD (tsDMARD). Vassilopoulos and colleagues conducted a meta-analysis of 47 randomized controlled trials and 26 follow-up extension studies that included patients with PsA who received at least one dose of a bDMARD or a tsDMARD (n = 11,790) or placebo (n = 6425) during the placebo-controlled period, and 17,197 patients who received at least one dose of a bDMARD or a tsDMARD in the long-term extension period.

The cumulative incidence of opportunistic infections was < 3% when stratified by the mechanism of action: JAKi (2.72%; 95% CI 1.05%-5.04%), anti-interleukin (IL)-17i (1.18%; 95% CI 0.60%-1.90%), anti-IL-23i (0.24%; 95% CI 0.04%-0.54%), and TNFi (0.01%; 95% CI 0.00%-0.21%). These results are consistent with my own observations in my clinic. Thus, currently available advanced therapies, including JAKi and IL-23i, are effective and safe for the management of patients with PsA when used as monotherapy with or without conventional synthetic DMARD (csDMARD). Ongoing studies on combination therapy will provide us with guidance on the efficacy and safety of combining these drugs for the treatment of resistant disease.

Many patients do not respond to treatment, however. Actionable risk factors for lack of response are of clinical interest. One such factor is obesity. In an observational study of 774 adult PsA patients who started their first b/tsDMARD, Vallejo-Yague and colleagues reported that the odds of achieving minimal disease activity (adjusted OR [aOR] 0.45; 95% CI 0.24-0.82) and Disease Activity Index for Psoriatic Arthritis (DAPSA)-remission (aOR 0.42; 95% CI 0.21-0.85) were lower in the obese vs normal-weight group within the first year. Thus, obese patients had ~50% lower likelihood of achieving a state of low disease activity. Comprehensive management of PsA must include management of obesity and other comorbid conditions to achieve optimal outcomes.

Finally, an interesting study by Freuer and colleagues used bidirectional two-sample Mendelian randomization in 12,882 patients with inflammatory bowel disease (IBD), 21,770 matched controls, 5621 patients with psoriasis, 2063 patients with PsA, and 252,323 controls. The study found that genetically predicted IBD was associated with a higher risk for PsA (pooled OR 1.11; P = .003) with the risk being majorly mediated by Crohn's disease (OR 1.12; P = .002) and not ulcerative colitis (P = .70). Thus, patients with Crohn's disease need to be carefully evaluated for the development of PsA.

The effectiveness and safety of advanced therapies for psoriatic arthritis (PsA) was a focus of many published studies last month. Janus kinase inhibitors (JAKi) are a recent class of drugs made available to treat PsA and related diseases, and several clinical trials have been published. Sarabia and colleagues reported the results of a meta-analysis of 15 randomized controlled trials including 6757 patients with psoriasis or PsA who received treatment with a JAKi or placebo. Their analyses revealed that treatment with JAKi vs placebo was associated with higher odds of achieving American College of Rheumatology 20 (ACR20) response (odds ratio [OR] 4.45; 95% CI 3.64-5.44), with similar outcomes observed with tofacitinib vs placebo (OR 2.96; 95% CI 2.01-4.35) and non-tofacitinib JAKi vs placebo (OR 5.41; 95% CI 3.95-7.40). Serious adverse event rates were low (1%-7% in the maximum-dose intervention group).

Interleukin-23i (guselkumab, tildrakizumab, or risankizumab) are another class of biologics recently approved for the treatment of PsA. Preliminary results from a real-world study demonstrate the efficacy of these drugs for PsA. In a retrospective observational study including 80 patients with psoriasis (22 with PsA) who received guselkumab, tildrakizumab, or risankizumab, Elgaard and colleagues demonstrated that 40.9% or 36.4% of the PsA patients achieved complete or partial remission, respectively, compared with only 18.2% of patients with no improvement.

Regarding drug safety, a recent study demonstrated low rates of opportunistic infections with biologic disease-modifying antirheumatic drugs (bDMARD) and targeted synthetic DMARD (tsDMARD). Vassilopoulos and colleagues conducted a meta-analysis of 47 randomized controlled trials and 26 follow-up extension studies that included patients with PsA who received at least one dose of a bDMARD or a tsDMARD (n = 11,790) or placebo (n = 6425) during the placebo-controlled period, and 17,197 patients who received at least one dose of a bDMARD or a tsDMARD in the long-term extension period.

The cumulative incidence of opportunistic infections was < 3% when stratified by the mechanism of action: JAKi (2.72%; 95% CI 1.05%-5.04%), anti-interleukin (IL)-17i (1.18%; 95% CI 0.60%-1.90%), anti-IL-23i (0.24%; 95% CI 0.04%-0.54%), and TNFi (0.01%; 95% CI 0.00%-0.21%). These results are consistent with my own observations in my clinic. Thus, currently available advanced therapies, including JAKi and IL-23i, are effective and safe for the management of patients with PsA when used as monotherapy with or without conventional synthetic DMARD (csDMARD). Ongoing studies on combination therapy will provide us with guidance on the efficacy and safety of combining these drugs for the treatment of resistant disease.

Many patients do not respond to treatment, however. Actionable risk factors for lack of response are of clinical interest. One such factor is obesity. In an observational study of 774 adult PsA patients who started their first b/tsDMARD, Vallejo-Yague and colleagues reported that the odds of achieving minimal disease activity (adjusted OR [aOR] 0.45; 95% CI 0.24-0.82) and Disease Activity Index for Psoriatic Arthritis (DAPSA)-remission (aOR 0.42; 95% CI 0.21-0.85) were lower in the obese vs normal-weight group within the first year. Thus, obese patients had ~50% lower likelihood of achieving a state of low disease activity. Comprehensive management of PsA must include management of obesity and other comorbid conditions to achieve optimal outcomes.

Finally, an interesting study by Freuer and colleagues used bidirectional two-sample Mendelian randomization in 12,882 patients with inflammatory bowel disease (IBD), 21,770 matched controls, 5621 patients with psoriasis, 2063 patients with PsA, and 252,323 controls. The study found that genetically predicted IBD was associated with a higher risk for PsA (pooled OR 1.11; P = .003) with the risk being majorly mediated by Crohn's disease (OR 1.12; P = .002) and not ulcerative colitis (P = .70). Thus, patients with Crohn's disease need to be carefully evaluated for the development of PsA.

The effectiveness and safety of advanced therapies for psoriatic arthritis (PsA) was a focus of many published studies last month. Janus kinase inhibitors (JAKi) are a recent class of drugs made available to treat PsA and related diseases, and several clinical trials have been published. Sarabia and colleagues reported the results of a meta-analysis of 15 randomized controlled trials including 6757 patients with psoriasis or PsA who received treatment with a JAKi or placebo. Their analyses revealed that treatment with JAKi vs placebo was associated with higher odds of achieving American College of Rheumatology 20 (ACR20) response (odds ratio [OR] 4.45; 95% CI 3.64-5.44), with similar outcomes observed with tofacitinib vs placebo (OR 2.96; 95% CI 2.01-4.35) and non-tofacitinib JAKi vs placebo (OR 5.41; 95% CI 3.95-7.40). Serious adverse event rates were low (1%-7% in the maximum-dose intervention group).

Interleukin-23i (guselkumab, tildrakizumab, or risankizumab) are another class of biologics recently approved for the treatment of PsA. Preliminary results from a real-world study demonstrate the efficacy of these drugs for PsA. In a retrospective observational study including 80 patients with psoriasis (22 with PsA) who received guselkumab, tildrakizumab, or risankizumab, Elgaard and colleagues demonstrated that 40.9% or 36.4% of the PsA patients achieved complete or partial remission, respectively, compared with only 18.2% of patients with no improvement.

Regarding drug safety, a recent study demonstrated low rates of opportunistic infections with biologic disease-modifying antirheumatic drugs (bDMARD) and targeted synthetic DMARD (tsDMARD). Vassilopoulos and colleagues conducted a meta-analysis of 47 randomized controlled trials and 26 follow-up extension studies that included patients with PsA who received at least one dose of a bDMARD or a tsDMARD (n = 11,790) or placebo (n = 6425) during the placebo-controlled period, and 17,197 patients who received at least one dose of a bDMARD or a tsDMARD in the long-term extension period.

The cumulative incidence of opportunistic infections was < 3% when stratified by the mechanism of action: JAKi (2.72%; 95% CI 1.05%-5.04%), anti-interleukin (IL)-17i (1.18%; 95% CI 0.60%-1.90%), anti-IL-23i (0.24%; 95% CI 0.04%-0.54%), and TNFi (0.01%; 95% CI 0.00%-0.21%). These results are consistent with my own observations in my clinic. Thus, currently available advanced therapies, including JAKi and IL-23i, are effective and safe for the management of patients with PsA when used as monotherapy with or without conventional synthetic DMARD (csDMARD). Ongoing studies on combination therapy will provide us with guidance on the efficacy and safety of combining these drugs for the treatment of resistant disease.

Many patients do not respond to treatment, however. Actionable risk factors for lack of response are of clinical interest. One such factor is obesity. In an observational study of 774 adult PsA patients who started their first b/tsDMARD, Vallejo-Yague and colleagues reported that the odds of achieving minimal disease activity (adjusted OR [aOR] 0.45; 95% CI 0.24-0.82) and Disease Activity Index for Psoriatic Arthritis (DAPSA)-remission (aOR 0.42; 95% CI 0.21-0.85) were lower in the obese vs normal-weight group within the first year. Thus, obese patients had ~50% lower likelihood of achieving a state of low disease activity. Comprehensive management of PsA must include management of obesity and other comorbid conditions to achieve optimal outcomes.

Finally, an interesting study by Freuer and colleagues used bidirectional two-sample Mendelian randomization in 12,882 patients with inflammatory bowel disease (IBD), 21,770 matched controls, 5621 patients with psoriasis, 2063 patients with PsA, and 252,323 controls. The study found that genetically predicted IBD was associated with a higher risk for PsA (pooled OR 1.11; P = .003) with the risk being majorly mediated by Crohn's disease (OR 1.12; P = .002) and not ulcerative colitis (P = .70). Thus, patients with Crohn's disease need to be carefully evaluated for the development of PsA.

Agents proven to reduce major kidney issues in type 2 diabetes include renin-angiotensin system blockers, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid inhibitors, but there are few data on the renal effects of the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. In a post-hoc analysis of the SURPASS-4 trial, Heerspink and colleagues reported that tirzepatide slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (ACR) compared with insulin glargine U100. There was also a reduction (≥ 40% decline) in the composite kidney outcome of eGFR, end-stage kidney disease (ESKD), death due to kidney failure, and new-onset macroalbuminuria, and this was driven by the reduction in new-onset macroalbuminuria. Although this was a post-hoc, exploratory analysis, the benefit of tirzepatide on kidney effects suggests that this agent should be studied in type 2 diabetes patients at high risk for kidney disease progression to determine whether indeed there will be a kidney protective effect.

Diabetes is the leading cause of ESKD, and recognizing patients at high risk for progression to ESKD is paramount. Abnormal glycolipid metabolism contributes to the development and progression of diabetic kidney disease (DKD). Bile acids, by regulating glycolipid metabolism, may indirectly provide renoprotective effects. Xiao and colleagues have published a retrospective cohort study of 184 Chinese patients with type 2 diabetes and biopsy-proven DKD. They found that low levels of bile acids (≤2.8 mmol/L) were associated with an over fivefold risk for ESKD after adjusting for known factors associated with ESKD. This is the first study suggesting a link between low bile acid levels and adverse kidney outcomes in DKD, and it provides a rationale for studying bile acid analogs as therapeutic agents for the treatment of DKD.

SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiorenal benefits in type 2 diabetes, and each is recommended in guidelines for patients at higher risk for cardiorenal complications. There are no head-to-head randomized trials of SGLT2 inhibitors vs GLP-1 receptor agonists, and studies suggesting an increased risk for lower-extremity amputation with SGLT2 inhibitors have shown inconsistent results. Lee and colleagues conducted a retrospective cohort study in Taiwan, and, after propensity score-matching patients with type 2 diabetes treated with SGLT inhibitors or GLP-1 receptor agonists, they found no significant difference in major adverse limb events between the two groups. Although limited by retrospective design, short follow-up, and a low number of events, this study suggests that SGLT2 inhibitors and GLP-1 receptor agonists should continue to be used as indicated and according to diabetes guidelines, with no difference in amputation rates between these two classes of antihyperglycemic agents.

Gastrointestinal adverse events are the most common side effects related to metformin use. Many clinicians choose an extended-release metformin preparation over immediate-release, believing that there may be better tolerability, but studies have shown inconsistent results. In a systematic review, meta-analysis, and meta-regression of randomized controlled trials, Nabrdalik and colleagues demonstrated an increased risk for abdominal pain, nausea, and diarrhea with metformin compared with other antidiabetic drugs or placebo, as well as a reduced risk for bloating and diarrhea with extended-release metformin compared with immediate-release formulations. These findings reinforce the practice for considering metformin extended-release over immediate-release formulations to reduce the chance of gastrointestinal side effects.

Agents proven to reduce major kidney issues in type 2 diabetes include renin-angiotensin system blockers, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid inhibitors, but there are few data on the renal effects of the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. In a post-hoc analysis of the SURPASS-4 trial, Heerspink and colleagues reported that tirzepatide slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (ACR) compared with insulin glargine U100. There was also a reduction (≥ 40% decline) in the composite kidney outcome of eGFR, end-stage kidney disease (ESKD), death due to kidney failure, and new-onset macroalbuminuria, and this was driven by the reduction in new-onset macroalbuminuria. Although this was a post-hoc, exploratory analysis, the benefit of tirzepatide on kidney effects suggests that this agent should be studied in type 2 diabetes patients at high risk for kidney disease progression to determine whether indeed there will be a kidney protective effect.

Diabetes is the leading cause of ESKD, and recognizing patients at high risk for progression to ESKD is paramount. Abnormal glycolipid metabolism contributes to the development and progression of diabetic kidney disease (DKD). Bile acids, by regulating glycolipid metabolism, may indirectly provide renoprotective effects. Xiao and colleagues have published a retrospective cohort study of 184 Chinese patients with type 2 diabetes and biopsy-proven DKD. They found that low levels of bile acids (≤2.8 mmol/L) were associated with an over fivefold risk for ESKD after adjusting for known factors associated with ESKD. This is the first study suggesting a link between low bile acid levels and adverse kidney outcomes in DKD, and it provides a rationale for studying bile acid analogs as therapeutic agents for the treatment of DKD.

SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiorenal benefits in type 2 diabetes, and each is recommended in guidelines for patients at higher risk for cardiorenal complications. There are no head-to-head randomized trials of SGLT2 inhibitors vs GLP-1 receptor agonists, and studies suggesting an increased risk for lower-extremity amputation with SGLT2 inhibitors have shown inconsistent results. Lee and colleagues conducted a retrospective cohort study in Taiwan, and, after propensity score-matching patients with type 2 diabetes treated with SGLT inhibitors or GLP-1 receptor agonists, they found no significant difference in major adverse limb events between the two groups. Although limited by retrospective design, short follow-up, and a low number of events, this study suggests that SGLT2 inhibitors and GLP-1 receptor agonists should continue to be used as indicated and according to diabetes guidelines, with no difference in amputation rates between these two classes of antihyperglycemic agents.

Gastrointestinal adverse events are the most common side effects related to metformin use. Many clinicians choose an extended-release metformin preparation over immediate-release, believing that there may be better tolerability, but studies have shown inconsistent results. In a systematic review, meta-analysis, and meta-regression of randomized controlled trials, Nabrdalik and colleagues demonstrated an increased risk for abdominal pain, nausea, and diarrhea with metformin compared with other antidiabetic drugs or placebo, as well as a reduced risk for bloating and diarrhea with extended-release metformin compared with immediate-release formulations. These findings reinforce the practice for considering metformin extended-release over immediate-release formulations to reduce the chance of gastrointestinal side effects.

Agents proven to reduce major kidney issues in type 2 diabetes include renin-angiotensin system blockers, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid inhibitors, but there are few data on the renal effects of the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. In a post-hoc analysis of the SURPASS-4 trial, Heerspink and colleagues reported that tirzepatide slowed the rate of estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (ACR) compared with insulin glargine U100. There was also a reduction (≥ 40% decline) in the composite kidney outcome of eGFR, end-stage kidney disease (ESKD), death due to kidney failure, and new-onset macroalbuminuria, and this was driven by the reduction in new-onset macroalbuminuria. Although this was a post-hoc, exploratory analysis, the benefit of tirzepatide on kidney effects suggests that this agent should be studied in type 2 diabetes patients at high risk for kidney disease progression to determine whether indeed there will be a kidney protective effect.

Diabetes is the leading cause of ESKD, and recognizing patients at high risk for progression to ESKD is paramount. Abnormal glycolipid metabolism contributes to the development and progression of diabetic kidney disease (DKD). Bile acids, by regulating glycolipid metabolism, may indirectly provide renoprotective effects. Xiao and colleagues have published a retrospective cohort study of 184 Chinese patients with type 2 diabetes and biopsy-proven DKD. They found that low levels of bile acids (≤2.8 mmol/L) were associated with an over fivefold risk for ESKD after adjusting for known factors associated with ESKD. This is the first study suggesting a link between low bile acid levels and adverse kidney outcomes in DKD, and it provides a rationale for studying bile acid analogs as therapeutic agents for the treatment of DKD.

SGLT2 inhibitors and GLP-1 receptor agonists have proven cardiorenal benefits in type 2 diabetes, and each is recommended in guidelines for patients at higher risk for cardiorenal complications. There are no head-to-head randomized trials of SGLT2 inhibitors vs GLP-1 receptor agonists, and studies suggesting an increased risk for lower-extremity amputation with SGLT2 inhibitors have shown inconsistent results. Lee and colleagues conducted a retrospective cohort study in Taiwan, and, after propensity score-matching patients with type 2 diabetes treated with SGLT inhibitors or GLP-1 receptor agonists, they found no significant difference in major adverse limb events between the two groups. Although limited by retrospective design, short follow-up, and a low number of events, this study suggests that SGLT2 inhibitors and GLP-1 receptor agonists should continue to be used as indicated and according to diabetes guidelines, with no difference in amputation rates between these two classes of antihyperglycemic agents.

Gastrointestinal adverse events are the most common side effects related to metformin use. Many clinicians choose an extended-release metformin preparation over immediate-release, believing that there may be better tolerability, but studies have shown inconsistent results. In a systematic review, meta-analysis, and meta-regression of randomized controlled trials, Nabrdalik and colleagues demonstrated an increased risk for abdominal pain, nausea, and diarrhea with metformin compared with other antidiabetic drugs or placebo, as well as a reduced risk for bloating and diarrhea with extended-release metformin compared with immediate-release formulations. These findings reinforce the practice for considering metformin extended-release over immediate-release formulations to reduce the chance of gastrointestinal side effects.