Approximately 70 million individuals in the United States live with ongoing sleep disorders, and nearly 15% of all US adults have insomnia.¹ These are troubling numbers, particularly because insomnia can impact the way an individual functions throughout the day, impairing their ability to work, drive, and perform nearly all daily activities. For patients with insomnia, turning to their pharmacist can be a good first step in combatting sleep disorders and getting the rest they need.

Farah Khorassani, PharmD, an associate clinical professor at the University of California, Irvine School of Pharmacy and Pharmaceutical Sciences, noted that pharmacists play a crucial role in educating patients about good sleep habits—also known as sleep hygiene—as well as in identifying medications or substances that could be contributing to insomnia; recommending medications and doses for insomnia; providing clinician education on the risks, benefits, and evidence on the use of different agents; and counseling patients on the use of these medications.

There are 5 benzodiazepines that are FDA approved for insomnia: estazolam (Prosom), flurazepam (Dalmane), quazpam (Doral), temazepam (Restoril), and triazolam (Halicon). Pharmacists can counsel patients on the use of these prescribed medications, but for many patients, insomnia can be mitigated through lifestyle modifications and appropriate sleep hygiene. “According to the CDC, some examples of good sleep hygiene include going to sleep and waking up at a consistent time every day, removing electronic devices from the bedroom, keeping the a comfortable temperature, exercising during the day—but not too late because that can keep you awake later—and avoiding large meals, caffeine, and alcohol too close to bedtime,” Khorassani explained.

Kathy M. Campbell, PharmD, has been an independent pharmacist for more than 30 years in Owasso, Oklahoma, and has served 4 generations of patients, many of whom have sleep issues and insomnia. Campbell noted that traditionally on the medication side, pharmacists are helping customers manage their prescriptions or triaging the issues even before someone goes to see their primary care provider.

By the Numbers: Shut-Eye Statistics

“They may tell me they have some sleep issues and ask what they should be taking, but I tend to look more at why they are having issues of sleep,” Campbell explained. “When a patient comes to me about that, [I always do] a deeper triage as to what could be the source of the insomnia.” The 2 biggest culprits she sees are low oxygen or sleep apnea keeping the patient awake or glucose irregularities. “There are some tools patients can use, such as sleep apps like a Fitbit, [so] they can see the changes in their sleep and monitor to see if the blood pressure or heart rate accelerates—which are symptoms of not having good oxygenation,” Campbell said. “Nothing freaks the brain out like no oxygen. If you don’t have enough oxygen, your body will wake you up.”

In those instances, Campbell will refer the patient to a sleep study or to their primary care provider to talk more about other options.

Josh Rimany, RPh, FACA, founder and chief wellness officer of Dilworth Wellness Center in Charlotte, North Carolina, likes to be known as the “pharmacist who goes beyond the pill” because he takes a wellness-oriented approach in his practice, focusing on moving away from medication dependency. When he works with a patient who has a sleep issue, his first course of action is to talk about the importance of sleep and ask questions about the “why” and the lifestyle choices that may be contributing to the problem.

“Seventy million people don’t get enough sleep, and the CDC considers it a public health problem, yet only 43% of providers talk to their patients about sleep,” Rimany said. “Sleep is considered one of the No. 1 tools for longevity. If we’re going to bring vibrant life into people, nailing 7 to 8 hours of quality sleep is very important.”

OTC Options

The pharmacist can also advise patients and customers on OTC options to help with sleep—such as melatonin or antihistamines—including the benefits and potential adverse effects of each medication. Counseling is where a pharmacist’s expertise really shines.

The OTC options available to a patient depend on various factors, including their comorbid conditions and the duration of insomnia, Khorassani explained. “In my opinion, melatonin is a good starting point because of its tolerability profile,” she said. “It is an OTC supplement that is safe to use in most patients with insomnia. It is also non–habit forming so can be taken long term and has few adverse effects. The evidence for its efficacy is not very strong, but anecdotally, many patients have told me it helped their insomnia.”

Other agents such as diphenhydramine HCI (Benadryl) and doxylamine (Unisom) are also options, but they come with more adverse effects than melatonin, such as dry mouth and next-day drowsiness. Because of this, these agents are best used for short-term insomnia only.²

It is important for pharmacists to assess the patient’s individual needs and consider any comorbidities or medications that may impact sleep. They can also refer patients to a sleep specialist if necessary.

“I’ve had a few patients who have complained of insomnia because they were taking [the antidepressant bupropion (Wellbutrin)], which can cause insomnia,” Khorassani said. “Several of them were taking it twice daily and were taking the second dose at bedtime. If this medication is taken twice daily, the second dose is ideally given before 4 PM because of its stimulating properties.

“Talking to patients about the timing of their medication helped me uncover a way to improve their insomnia. By suggesting they switch the medication to earlier in the day, their sleep improved, and they didn’t require any additional medication.”

Implementing Lifestyle Changes

Poor sleep is linked to several chronic diseases and can also raise the risk of developing Alzheimer disease, depression, dementia, obesity, anxiety, and more—including premature death.³

“That really gets patients’ attention,” Rimany said. “You can give them tricks and tips for lifestyle habits all day long, but they generally won’t adopt them unless it’s really important to them. When I talk to patients about sleep on a pharmacy level— and this is something I’ve researched quite a bit—there is [an] increase in mortality rate for people who take sleep medication on a regular basis.”⁴

Sleep should be prioritized for a long life, and pharmacists can also help patients manage sleep concerns by recommending nonpharmacological interventions such as cognitive-behavioral therapy for insomnia. Other lifestyle modifications include reducing caffeine intake, avoiding the use of electronics before bedtime, and establishing a consistent sleep routine, all before turning to prescription medications.

Campbell will occasionally recommend melatonin but said she is more concerned about a patient’s sleep hygiene. Before melatonin, she will remind patients to ensure that their bedroom is optimized for sleep and that they aren’t eating too close to bedtime or drinking too much alcohol.

“If they are at the age where they are not producing as much melatonin as they need, I will put them on a very low-dose melatonin,” she said. “I incorporate a lot of nutrition science and a lot of stress science into how I approach and coach patients.”

One factor that has contributed to poor sleep over the past decade is our use of social media. Campbell emphasized the importance of reminding patients to disconnect from their devices well before bedtime.

Another sleep disruptor? Our pets. Individuals who sleep with their pets or who are routinely awoken by their pets during the night experience poor sleep. “Sleep is when the brain and the body recover and rebuild, and sleep is so critical to long-term health,” Campbell said. “Tolerating interruptions is going to alter your long-term health and longevity.”

Rimany offers his customers plenty of options for help and is always looking to educate them more about the benefits of sleep and ways to combat their sleep issues. “A ‘Pharmacy 2.0’ that wants to go beyond dispensing will look at the lifestyle—diet, supplements, and labs—to figure out the best plan,” he said. “Consistency matters [and] quality matters….Cutting out stimulants during the evening and keeping the room at 68 degrees or less [can all help. Some people even use weighted blankets.”

Rimany advises patients to set a cutoff of 2 hours before bedtime for eating or drinking anything other than water, explaining that if the body is digesting, it’s not working toward resting. “Working out is also not a great thing to do before bed,” he said. “Screen time is obviously huge because the blue light and LED lights emitted from these devices are telling your eyeballs that it’s noon, so your brain doesn’t let your body settle down. Blue light–blocking glasses are very important in these cases.” Complete dark—with blackout curtains, if necessary—is also crucial to managing insomnia because any sliver of light can wake up the body’s clock.

For patients who wake up and can’t fall back asleep in 5 minutes, “It’s actually healthier [for them] to get out of bed and read, or do something quiet to get tired,” Rimnay said. “I’m a big fan of meditation and winding myself down. [Putting thoughts down into] a journal can also help [patient’s] get their brain more rested.”

References

1. Suni E, Truong K. Sleep statistics. Sleep Foundation. Updated May 18, 2023. Accessed June 29, 2023. https:// www.sleepfoundation.org/how-sleep-works/sleep-facts-statistics

2. Olson EJ. Adult health. December 9, 2021. Accessed July 11, 2023. https://www.mayoclinic.org/healthy-lifestyle/adult-health/expert-answers/sleep-aids/faq-20058393

3. What are sleep deprivation and deficiency? National Heart, Lung, and Blood Institute. Updated March 24, 2022. Accessed July 11, 2023. https://www.nhlbi.nih.gov/health/sleep-deprivation

4. Sun Y, Tsai MK, Wen CP. Association of sleep duration and sleeping pill use with mortality and life expectancy: a cohort study of 484,916 adults. Sleep Health. 2023;9(3):354-362. doi:10.1016/j.sleh.2023.01.017

On May 26, 2023, the FDA approved sotagliflozin (Inpefa), a once-daily tablet indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure or type 2 diabetes (T2D), chronic kidney disease, and other cardiovascular risk factors.¹

Sotagliflozin is a first-in-class medication that is a dual inhibitor of sodium-glucose cotransporters 1 and 2. Although the mechanism of action leading to sotagliflozin’s benefits in heart failure has not been fully established, physiologic advantages of reduced renal glucose and sodium reabsorption include both preload and afterload reduction and downregulation of sympathetic activity.¹

Efficacy

Results from 2 studies led to the US approval of sotagliflozin.2,3 The phase 3 SOLOIST-WHF trial (NCT03521934) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study comparing sotagliflozin (n = 608) and placebo (n = 614) in patients with T2D who had been admitted to the hospital, a heart failure unit, infusion center, or emergency department for worsening heart failure.²

Patients in the treatment group demonstrated a significant reduction (33%) in the composite end point of total occurrence of cardiovascular death, hospitalizations for heart failure, and urgent heart failure visits vs placebo (HR, 0.67; 95% CI, 0.53-0.85; P = .001). Within the components of the composite end point, only hospitalization for heart failure showed a significant hazard reduction (HR, 0.65; 95% CI, 0.49-0.87). Of note, there were relatively more events per 100 patient-years for hospitalizations for heart failure than for the other 2 components of the composite end point.²

The phase 3 SCORED trial (NCT03315143) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study examining the effects of sotagliflozin (n = 5292) on the composite total occurrence of cardiovascular death, hospitalizations for heart failure, and urgent heart failure visits versus placebo (n = 5292) in patients with T2D, chronic kidney disease, and additional cardiovascular risk factors.³

Sotagliflozin was superior to placebo in reducing the risk of the primary composite end point (HR, 0.75; 95% CI, 0.63-0.88; P < .001). Of the components in the composite primary end point, only the risk of hospitalization for heart failure was significantly reduced (HR, 0.66, 95% CI, 0.53-0.82). Cardiovascular death (HR, 0.90, 95% CI, 0.73-1.12) and urgent heart failure visits (HR, 0.73, 95% CI, 0.48-1.11) did not show a significant reduction.³

Safety

In the SOLIST-WHF trial, the most common adverse events in the sotagliflozin and placebo groups were hypotension (6% vs 4.6%, respectively), urinary tract infection (4.8% vs 5.1%, respectively), and diarrhea (6.1% vs 3.4%, respectively). Other adverse events that occurred at less than 5% included acute kidney injury, severe hypoglycemia, bone fractures, diabetic ketoacidosis, genital mycotic infections, and adverse events leading to amputation.²

In the SCORED trial, the most common adverse events reported for sotagliflozin were urinary tract infection (11.5%), diarrhea (8.5%), and volume depletion (5.3%). Other adverse events that occurred at a rate of less than 5% included bone fractures, genital mycotic infections, severe hypoglycemia, malignant conditions, venous thrombotic events, adverse events leading to amputation, diabetic ketoacidosis, and pancreatitis.³

Patients were shown to have a transient increase in serum creatinine and a decrease in estimated glomerular filtration rate within 4 weeks of initiation, which then stabilized regardless of baseline kidney function.¹ Sotagliflozin is primarily metabolized by the enzyme UGT1A9 and to a lesser extent CYP3A4.¹

Drug Administration

Sotagliflozin is supplied as a 200-mg or 400-mg film-coated tablet to be taken once daily and not more than 1 hour before the first meal of the day.1 Initial dosing is 200 mg once daily after assessing the patient’s volume status, baseline renal function, and hemodynamic stability in decompensated heart failure. Up-titration to a maximum of 400 mg daily may occur after at least 2 weeks, as tolerated.¹

References

1. Inpefa. Package insert. Lexicon Pharmaceuticals Inc; 2023. https://www. accessdata.fda.gov/drugsatfda_docs/label/2023/216203s000lbl.pdf

2. Bhatt DL, Szarek M, Steg PG, et al; SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117-128. doi:10.1056/NEJMoa2030183

3. Bhatt DL, Szarek M, Pitt B, et al; SCORED Investigators. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129-139. doi:10.1056/NEJMoa2030186

Triple-negative breast cancer (TNBC) has long presented treatment challenges, but evolving literature and new data show significant promise for this patient population, according to presenter Erika P. Hamilton, MD, in a session at the 2023 Community Oncology Alliance (COA) meeting.

Drugs such as pembrolizumab, sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd) all have growing bodies of evidence illustrating which patients are most likely to benefit and in which settings. For example, the KEYNOTE 355 trial of pembrolizumab in first-line TNBC provided insight into both the setting and metastatic site, as well as how much these considerations matter, according to Hamilton.

In that trial, three-quarters of the patients had programmed death-ligand 1 (PD-L1) expression; however, with a more stringent cutoff of a combined positive score (CPS) of at least 10, that number fell to 35% to 40%. In the intent-to-treat (ITT) population, there was no significant benefit, and this was the same in the CPS cutoff of 1 or greater. However, in those with a CPS score of at least 10, there was a significant benefit in progression-free survival (PFS) with the addition of pembrolizumab. Based on this, the FDA approved pembrolizumab plus chemotherapy for metastatic TNBC with a CPS score of at least 10.

Hamilton noted that immune-mediated adverse events (AEs) are the main reason that this is not indicated in patients with a CPS score of less than 10. These can include hypothyroidism, hyperthyroidism, pneumonitis, colitis, and severe skin reactions, all of which tend to occur in approximately one-quarter of patients receiving pembrolizumab, Hamilton said.

Hamilton noted that the KEYNOTE 355 trial showed no real difference in overall survival (OS) in the ITT group and the patient population with a CPS score of at least 1. However, improvement was seen in those with a CPS score of at least 10, going from 16.1 months to 23 months.

Hamilton did point out, however, that this trial did not include the use of antibody drug conjugates (ADCs).

“I think we really are doing better than this now, but still, triple-negative has the worst prognosis or our three [breast cancer] types,” Hamilton said.

ADCs have significant potential, an example of which is SG. The ASCENT trial investigated SG in the third- and fourth-line settings, which showed a 5.6-month PFS with SG versus 1.7 months with chemotherapy only. In April 2021, Hamilton said the FDA granted regular approval to SG for patients with metastatic PFS who have received 2 or more prior systemic therapies, at least 1 of which was for metastatic disease.

Additionally, OS was increased by up to a year in patients receiving SG in the ASCENT trial, demonstrating an improvement of approximately 6 months. Hamilton said these findings raised questions about whether clinicians should test for Trop2 expression.

“Patients that have high Trop2 [expression] certainly get great benefit from sacituzumab, but even those patients that have low expression—although they don’t do as well—are still outperforming chemotherapy,” Hamilton explained. “And so, this really led to the idea that we don’t need to be testing for Trop2.”

Several upcoming trials are aiming to further the data supporting SG, including the ASCENT-03 trial examining it in the first line setting for metastatic TNBC and the ASCENT-04 trial of SG in addition to immunotherapy in the first-line setting. With these ongoing trials, Hamilton said she anticipates that SG will eventually move into the first-line setting.

Dato-DXd is another promising Trop2-targeting ADC. In the TROPION PanTumor01 study, treatment with Dato-DXd showed encouraging OS data, with an overall response rate of 32% in all patients and 44% in topoisomerase I inhibitor-naïve patients. Additionally, the median duration of response was 16.8 in both treatment arms; the median PFS was 4.4 months in all patients and 7.3 months in topoisomerase I inhibitor-naïve patients; and the median OS was a little over 1 year in both groups.

The BEGONIA trial is also investigating Dato-DXd in addition to durvalumab and has shown impressive tumor shrinkage. Hamilton said 82% of patients were still on treatment at the time of data disclosure, with a follow-up of about 7 months. This treatment also looks quite durable in the first-line setting, and response was seen in both PD-L1 high and PD-L1 low tumors.

Finally, the DAISY trial is examining the efficacy of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer, and particularly those with an immunohistochemistry score of 0 or greater. Response rates are encouraging, with a median PFS of 4.5 months in the hormone receptor (HR)-positive group and 2.1 months in the HR-negative group. Additionally, the trial has seen a median OS of 11.6 months in the treatment arm.

Next, Hamilton discussed developments in early breast cancer. The KEYNOTE 522 study investigated pembrolizumab for this patient population, including a broad population of anyone with at least a 2 cm tumor or any known positivity. Notably, the primary endpoint, pathologic complete response, showed an improvement from 51% to 65%.

“Even for those patients that are node-negative, so they qualify [for the trial] based on the fact that they had a 2 cm tumor or greater, the benefit is almost 6.5%,” Hamilton said. “And so, especially for [TNBC], this really is quite meaningful for us.”

Finally, Hamilton reviewed data around adjuvant olaparib in early TNBC. The OlympiA trial investigated olaparib in early germline BRCA breast cancer, and about 80% of patients in the trial did have TNBC disease, including approximately 70% BRCA1 and 30% BRCA2. With 3.5 years of median follow up, the study found improved OS of approximately 3.4% at the second interim analysis, including a 7.4% benefit with both invasive and distant disease-free survival.

As more studies develop and new data are released, Hamilton said patients with early-stage and TNBC will continue to have improved outcomes. Key studies to watch include the SASCIA and ASCENT-05 trials for SG in residual disease post-neoadjuvant therapy, as well as the TROPION Breast03 trial of Dato-DXd with or without durvalumab for residual disease post-neoadjuvant chemotherapy.

REFERENCE

Hamilton EP. Current Advances: Triple Negative & Locally Advanced Breast Cancer. Presented at: Community Oncology Alliance 2023 Meeting. March 23, 2023.

Patients of the female sex who are hospitalized with COVID-19 are less likely to have cardiovascular (CV) complications than male patients, according to a recent study published in the journal BMJ Medicine. Females were also found to be 35% less likely than males to die in the hospital.

“Sex differences exist in the risk of admission to hospital and death from COVID-19, with female individuals reportedly having better outcomes, on average, than male individuals,” the study authors wrote in the article. “We [also] found clear sex differences in the risk of cardiovascular disease (CVD) associated with COVID-19.”

The most prevalent COVID-19 complications include arrhythmia, heart failure, and thromboembolic events, despite the illness being respiratory. Previous studies suggest that patients with CVD have a greater risk of severe COVID-19 or death after contracting the virus, and other reports suggest that female patients have a lower risk of hospitalization or death from COVID-19.

However, few studies have evaluated the link between the interaction between sex and CVD on the risk of severe COVID-19. Further, few studies have examined the risk of CV complications from COVID-19 because of sex, according to the current study. The investigators conducted the current study to evaluate the risk of CV complications from COVID-19 between the sexes, and whether risks based on sex were associated with pre-existing CVD.

Data were collected on 11,167 adults who were hospitalized due to COVID-19 illness between March 2020 and May 2021. Patients were taken from the Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY (CAPACITY-COVID). Among the patients evaluated, 3423 had pre-existing CVD.

The primary outcome was any CV complication during hospitalization, and secondary outcomes were defined as in-hospital mortality or CV complication subtypes.

After investigators performed a subgroup analysis of age, ethnicity, pre-existing CVD, and CVD risk factors, they found that females were less likely to have a CV complication or die from COVID-19. Additionally, female patients admitted to the hospital with COVID-19 were independently associated with a reduced risk of complications including arrhythmia, cardiac ischemia, pulmonary embolism, or death.

Females had a 29% lower risk of developing a CV complication, although they shared a similar complication profile to males. And despite a female’s reduced CV risk, it cannot be attributed to a lower prevalence of pre-existing CVD.

“The persistence of the female advantage in those with pre-existing cardiovascular disease suggests that the pathophysiological mechanisms of COVID-19 itself might differentially affect the sexes,” the study authors wrote.

The study includes limitations, the first of which being that the population was limited to patients hospitalized with COVID-19. The findings are also generalized to older patients. Additionally, the COVID-19 landscape is constantly changing—at 1 part of the study period, a vaccine was not available.

“Further research is needed to better understand the male disadvantage in COVID-19, specifically whether the pathophysiological mechanisms of COVID-19 itself affect female and male individuals differentially,” the study authors wrote in the report.

Reference

Hockham C, Linschoten M, Asselbergs F, et al. Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study. BMJ Medicine. 2023. doi: 10.1136/bmjmed-2022-000245

It is estimated that 5% of patients with metastatic colorectal cancer (MCRC) have microsatellite instability (MSI) and/or deficiency in the mismatch repair pathway (DMMR), according to authors of a recently published study in JAMA Network Open. MCRCs with MSI are often presented with high tumor mutational burden (TMB), which creates an enhanced response to immune checkpoint inhibitors (ICIs).

Investigators recently discovered that MCRC patients with high microsatellite instability (MSI-H)—assessed by next-generation sequencing (NGS)—and/or DMMR appeared to have more favorable outcomes with first-line ICIs than chemotherapy. However, MSI appeared to anticipate ICI outcomes better than DMMR.

“Herein we have extended the study of MMR or MSI in MCRC and report, to our knowledge, the first comparison of outcomes between patients with MSI-H MCRC receiving first-line therapy with ICIs vs chemotherapy in standard practice settings,” wrote study authors. “Our findings support MSI assessed by NGS as a biomarker of outcomes of first-line ICIs in patients with MCRC.”

MSI is caused by a sequence variation of an MMR gene that results in lost protein expression—immunohistochemistry (IHC) is a method that can detect MMR deficiency. Like NGS and polymerase chain reaction (PCR), IHC detects MSI, but studies are limited on their ability to be a biomarker of ICI response.

In this trial, investigators evaluated MSI determined by NGS as a biomarker for ICI treatment outcomes for patients with MCRC with MSI-H tumors receiving first-line ICIs vs chemotherapy. The primary endpoints were time to next treatment (TTNT), PFS, and OS. Investigators identified 138 patients with MSI-H MCRC to received first-line ICIs or chemotherapy. In a second cohort, 182 patients received ICIs in any line of therapy (LOT) for biomarker examination.

“We asked a question not about optimal detection method but rather about best performing biomarker in anticipating outcomes,” study authors wrote in the article.

The results showed that MMR and MSI could similarly anticipate ICI outcomes. However, when comparing NGS-derived MSI assessments with IHC, NGS was found to be a superior method. This could be because NGS addresses multiple MMR biomarkers. Additionally, first-line ICIs led to a PFS of 24.87 months compared to 5.65 months in the control group, while the median OS for ICI patients was 24 months.

There are a few limitations in the study. First, the patient population is rare, therefore the relative sample size is small, which may limit biomarker comparisons. The data also did not include presence or absence of liver metastases.

In the prior trial KEYNOTE-177, investigators had compared first-line ICI therapy pembrolizumab (Keytruda; Merck) with chemotherapy in a randomized cohort of MSI-H and/or DMMR MCRC patients, which also determined that ICIs are a first-line treatment option for this patient population.

“Detection of MSI by NGS may be favored for evaluating patients with MCRC for ICI-based treatments when the biomarkers are discordant,” study authors wrote.

Reference

Quintanilha J, Graf R, Fisher V, et al. Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden. JAMA Netw Open. 2023;6(1):e2252244. doi:10.1001/jamanetworkopen.2022.52244