Beyond High-Risk Lesions: HPV Vaccination and Impact on Invasive Cervical Cancer Risk
BACKGROUND AND PURPOSE:
- HPV vaccine has been shown to be effective at preventing high-grade cervical lesions
- However, direct effect of quadrivalent HPV vaccine on the risk of invasive cervical cancer remains limited
- Lei et al. (NEJM, 2020) used a large cohort to examine the association between HPV vaccination and the risk of invasive cervical cancer
METHODS:
- Cohort study
- Participants
- Girls and women
- 10 to 30 years
- Living in Sweden (from 2006 to 2017)
- Study design
- Received at least one dose of vaccine
- Analysis controlled for
- Age at follow-up | Calendar year | County of residence | Parental characteristics (education, household income, mother’s country of birth, and maternal disease history)
- Primary outcome
- Invasive cervical cancer
RESULTS:
- 1,672,983 girls and women included
- Cervical cancer diagnoses
- Women who received the HPV vaccine: 19 diagnoses
- Women who had not received the HPV vaccine: 538 diagnoses
- Cumulative incidence of cervical cancer
- Received vaccination: 47 cases per 100,000 persons
- Did not receive vaccination: 94 cases per 100,000 persons
- Women who were vaccinated were 0.51 times less likely to experience cervical cancer compared to controls (adjusted for age at follow-up)
- Incidence rate ratio (IRR) 0.51 (95% CI, 0.32 to 0.82)
- After additional adjustment for other covariates, IRR was 0.37 (95% CI, 0.21 to 0.57)
- IRR following adjustment for all covariates
- Vaccinated <17 years
- IRR 0.12 (95% CI, 0.00 to 0.34)
- Vaccinated at 17 to 30 years
- IRR 0.47 (95% CI, 0.27 to 0.75)
- Vaccinated <17 years
CONCLUSION:
- In Sweden, quadrivalent HPV vaccination among women ages 10 to 30 was associated with reduced risk of invasive cervical cancer
- If vaccination initiated <17 years of age, the risk for cervical cancer was 88% lower vs the cohort that had never been vaccinated | Based on the confidence interval, the plausible risk was 66 to 100% lower with vaccination
- The authors conclude
HPV vaccination was associated with a substantially reduced risk of invasive cervical cancer
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HPV Vaccination and the Risk of Invasive Cervical Cancer
Best Strategies for Triage of HPV-Positive Women in Cervical Cancer Screening?
BACKGROUND AND PURPOSE:
- HPV16 and 18 tests can’t determine who has a transient infection vs precancerous lesion
- Pap cytologic testing is limited by variable sensitivity
- A triage method to evaluate which HPV-positive women should receive further work-up is still needed
- A previous study using a p16 (tumor suppressor protein marker)/Ki-67 (cellular proliferation protein marker) dual stain cytology method showed good sensitivity and specificity compared to cytologic triage alone for women who are HPV-positive
- Wentzensen et al. (JAMA Internal Medicine, 2019) evaluated the performance of a p16/Ki-67 dual stain in combination with HPV16/18 genotyping to triage women who are HPV-positive
METHODS:
- Prospective observational study
- Participants
- HPV-positive women undergoing HPV and Pap cytological testing with a dual stain result
- Exposures: Triage for HPV-positive result using 16/18
genotyping plus
- Pap cytology vs
- Dual staining
- Primary outcomes
- CIN2+ and CIN3+ within 3 years after sample collection
RESULTS:
- 3,225 women participated
- Women with dual stain had a higher risk for CIN3+ than Pap (P = .005)
- Dual stain: 12.0% (95% CI, 10.5%-13.5%)
- Pap: 10.3% (95% CI, 9.0%-11.6%)
- Dual stain showed superior risk stratification for CIN3+ vs Pap (regardless of 16 or 18 genotyping result)
- HPV16/18-negative women and negative dual screening had low risk
- low risk and therefore retesting intervals could be extended to 3 years
- Dual stain triage resulted in
- Fewer colposcopies (32.1% reduction) per detection of CIN3+ vs Pap
- Results for CIN2+ were similar to those for CIN3+
- Subset of women undergoing routine screening
- Primary HPV with dual stain showed improved performance compared with Pap including cotesting
CONCLUSION:
- DS was better than Papcytologic testing for the
triage of HPV-positive women
- Equal immediate detection of precancerous lesions
- Fewer colposcopies with dual stain cytology
- Dual cytology can safely replace Pap testing for triage for HPV screening
- In HPV16/18-negative women with negative DS results, retesting intervals can be extended to 3 years
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Cervical Cancer Screening Strategies and Cost-Effectiveness: Which is the Best?
BACKGROUND AND PURPOSE:
- There are multiple different strategies available for cervical cancer screening
- Sawaya et al. (JAMA Intern Med., 2019) estimated the cost-effectiveness as well as the quality of life outcomes of 12 cervical cancer screening strategies
METHODS:
- Cross-sectional study and cost-effectiveness analysis
- Participants
- 4 focus groups
- English or Spanish-speaking women aged 21-65 years
- Sociodemographically diverse
- Preferences elicited via interview and questionnaire
- Natural history and test accuracy determined using model-predicted outcomes based on literature
- Overall 12 strategies were evaluated including currently recommended ACOG / USPSTF guidance
- Measures
- Utilities (preferences) for 23 cervical cancer screening associated health states
- Data analysis
- Analyses were conducted from both the societal and health care sector perspectives
- Costs included screening, diagnosis and treatment, including cancer
- Primary outcomes
- Quality-adjusted life-years (QALYs) and total costs for each strategy
RESULTS:
- 451 women helped to determine utilities
- Screening was cost-saving ($1267-$2577 per woman) vs no screening ($2891 per woman)
- Lowest cost strategy
- Cytologic testing every 3 years with hrHPV triage of ASC-US
- Higher cost strategy
- Cytologic testing every 3 years with repeat cytologic testing for ASC-US
- Fewer QALYs at higher costs
- Cotesting and primary hrHPV testing
- Most costly strategy
- Annual cytologic testing
- Fewer QALYs than cytologic testing every 3 years
- Not cost-effective to
- Perform cytologic testing plus hrHPV testing (cotesting) under any condition
- To start primary hrHPV testing prior to age 30 years
- To perform hrHPV testing every 3 years
- To perform cytologic testing annually
CONCLUSION:
- Superior strategy when considering benefits,
harms, and costs were
- Cytologic testing every 3 years for women aged
21 to 29 years with either
- Continued cytologic testing every 3 years
- Switching to a low-cost hrHPV test every 5 years
- Cytologic testing every 3 years for women aged
21 to 29 years with either
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Minimally Invasive vs Abdominal Radical Hysterectomy for Cervical Cancer
BACKGROUND AND PURPOSE:
- Ramirez et al. (NEJM, 2018) compared the efficacy of laparoscopic or robot-assisted radical hysterectomy (minimally invasive surgery) and open abdominal radical hysterectomy (open surgery) among women with early-stage cervical cancer
METHODS:
- Randomized controlled study (RCT)
- Women with stage IA1 (lymphovascular invasion), IA2, or IB1 cervical cancer
- Histologic subtype of squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma
- Patients were randomly assigned to undergo
- Minimally invasive surgery
- Open surgery
- Primary outcome: Rate of disease-free survival at 4.5 years
RESULTS:
- Study did not reach enrollment target
- Stopped due to safety concerns by monitoring committee due to recurrence in minimally invasive group (see results below)
- 319 minimally invasive surgery group | 312 open surgery
- Mean age: 46.0 years
- 91.9% had stage IB1 disease
- In the minimally invasive group
- Laparoscopy: 84.4%
- Robot-assisted surgery: 15.6%
- Two groups were similar with respect to
- Histologic subtypes
- Rate of lymphovascular invasion
- Rates of parametrial and lymph-node involvement
- Tumor size
- Rate of use of adjuvant therapy
- Rate of disease-free survival at 4.5 years
- Minimally invasive surgery: 86.0%
- Open surgery: 96.5%
- Difference: −10.6% (95% CI, −16.4 to −4.7)
- Minimally invasive surgery was associated with
- Lower rate (3 year) of disease-free survival
- Minimally invasive: 91.2%
- Open surgery: 97.1%
- Increased risk of disease recurrence or death from cervical cancer
- Hazard ratio (HR): 3.74 (95% CI, 1.63 to 8.58)
- Lower overall survival (3-year) rate
- Minimally invasive: 93.8%
- Open surgery: 99.0%
- HR for death from any cause: 6.00 (95% CI, 1.77 to 20.30)
- Lower rate (3 year) of disease-free survival
CONCLUSION:
- Compared to open surgery, non-invasive radical surgery for cervical cancer was associated with a lower rate of disease-free survival and overall survival
- These results were reflected in a recent cohort study in the same issue of NEJM (Melamed et al.) that also compared minimally invasive vs laparotomy for the treatment of cervical cancer
- “Adoption of minimally invasive surgery coincided with a decline in the 4-year relative survival rate of 0.8% (95% CI, 0.3 to 1.4) per year (P=0.01 for change of trend)”
- SGO encourages gyn oncologists
…to consider all available data as they counsel individual patients to determine the most appropriate surgical approach. We anticipate additional data to emerge on this important topic.
- GOC also emphasizes the importance of counseling and in addition
- Recommends that gyn oncologists should “proceed with caution” as the results of these studies “cannot be ignored”
- Lists strategies that have been suggested including
…placing a suture on the unaffected cervix at the beginning of surgery for easy retrieval and if possible to cover the tumour, using a vaginal vault cup without intrauterine manipulator, performing a colpotomy circumferentially intra-abdominally (rather than across the vagina) or via the vaginal route, and using specimen extraction techniques that mitigate intra-abdominal spillage
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Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer (Ramirez et al.)
What is the Most Efficient Method for Cervical Cancer Screening?
BACKGROUND:
- As part of the evidence report for the new USPSTF recommendations for cervical cancer screening recently released (see ‘Related ObG Topics’ below), a decision analysis using a disease simulation model was constructed
- Kim et al. (JAMA, 2018) modeled the benefits and harms of various cervical cancer screening strategies
METHODS:
- Microsimulation model of a hypothetical cohort of women initiating screening at age 21 years
- The models looked at 19 strategies for cervical cancer screening, including 2 previous guideline-based strategies
- Previous guideline strategy 1: Cytology alone every 3 years from ages 21 to 65 years
- Previous guideline strategy 2: Cytology alone every 3 years from ages 21 to 29 years, with a switch to cytology and hrHPV cotesting every 5 years from ages 30 to 65 years
- Primary HPV testing strategies
- Outcomes assessed risks and benefits
- Harms: Total number of cytology and hrHPV tests (including screening, triage, and surveillance) | Colposcopies | FP screening results
- Benefits: CIN 2 and CIN 3 detected | CIN 3 or worse (CIN 3+) detected (including CIN 3 and cervical cancers detected through screening) | Cervical cancer cases and deaths averted | Life-years gained
- Efficient strategies
- More benefit and less harm than another strategy or
- Lower harm to benefit ratio than a strategy with less harms
RESULTS:
- Compared with no screening, all modeled cervical cancer screening strategies were estimated to result in substantial reductions in cancer cases and deaths and gains in life-years
- The effectiveness of screening across the different strategies was estimated to be similar
- Primary hrHPV-based and alternative cotesting strategies have slightly higher effectiveness and greater harms than current guidelines-based cytology testing
- In all analyses, primary hrHPV testing strategies occurring at 5-year intervals were efficient
- In contrast, strategies involving 3-year hrHPV testing was less efficient with much higher harm/benefit ratios, ranging from 2188 to 3822 colposcopies per life-year gained
- In most analyses, strategies involving cotesting were not efficient
CONCLUSION:
- From modeling, it was estimated that primary hrHPV screening demonstrated a reasonable balance of harms and benefits when performed every 5 years
- The most efficient harm/benefit strategy was converting from cytology to hrHPV at age 30
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Classifying Cervical Cancer: A Genomic and Molecular Approach
PURPOSE:
This study by the Cancer Genome Atlas Research Network (Nature, 2017) sought to characterize endometrial cancers using molecular and genomic information. This, to date, is the largest genomic study of cervical cancer and involved 303 investigators.
METHODS:
Basic Science – Genomic Study
RESULTS:
228 primary cervical cancers were identified. Novel genes such as SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 were identified. In addition, the authors discovered potential targets for newer therapies, including drugs such as lapatinib (already in use against breast cancer). Also of note, the important role of HPV in cervical cancer was again demonstrated, with the integration of HPV in all HPV18 cases and 76% of HPV16 cases. A unique set of endometrial-like cervical cancers were identified. These were almost exclusively HPV-negative. These results are critical for the future development of cervical cancer therapies.
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Integrated genomic and molecular characterization of cervical cancer
Does the Primary Care Physician Gender Wage Gap Differ Based on Compensation Method?
BACKGROUND AND PURPOSE:
- Female physicians continue to be paid less than their male counterparts
- Ganguli et al. (Ann Intern Med, 2022) determined how Primary Care Physician (PCP) compensation by gender differs when applying existing productivity-based and alternative compensation models
METHODS:
- Microsimulation study
- Data from national clinical registry of 1222 primary care practices (2016 to 2019)
- Population
- Male and female PCPs were matched by
- Specialty | Years since medical school graduation | Practice site | Sessions worked
- Male and female PCPs were matched by
- Simulations
- Productivity-based fee-for-service | Panel size–based capitation
- Without or with risk adjustment
- Hybrid payment models
- Productivity-based fee-for-service | Panel size–based capitation
- Study design
- Microsimulation inputs included patient and visit characteristics and overhead expenses
- Primary outcome
- Net annual, full-time-equivalent compensation for male versus female PCPs under the different simulations
RESULTS:
- Male PCPs: 881 | Female PCPs: 554
- Female PCP panels included patients who, on average
- Were younger
- Had lower diagnosis-based risk scores
- Were more often female
- Were more often uninsured or insured by Medicaid rather than by Medicare
- Female PCP panels included patients who, on average
- Under productivity-based payment
- Female PCPs earned 21% less than male PCPs
- Median income difference: $58,829 (IQR, $39,553 to $120,353)
- Gap was similar under capitation without adjustment
- Median income difference: $58,723 (IQR, $42,141 to $140,192)
- Wage gap was larger under capitation risk-adjusted for
- Age alone
- Median income difference: $74,695 (IQR, $42,884 to $152,423)
- Diagnosis-based scores alone (Charlson Comorbidity Index [CCI])
- Median income difference: $114,792 (IQR, $49,080 to $215,3260)
- Age-, sex-, and diagnosis-based scores (CCI): Median income difference: $83,438 (IQR, $28,927 to $129,414)
- Age alone
- The wage gap was small and nonsignificant under capitation risk-adjusted for age and sex
- Median income difference: $36,631 (IQR, $12,743 to $73,898)
CONCLUSION:
- Within a productivity-based model, female Primary Care physicians earned 21% less vs male colleagues
- The authors state
We found that despite female PCPs likely working similar hours to or even more hours than their male counterparts, female PCPs received less compensation under productivity-based payment due to conducting fewer visits
These lower visit rates may be explained by female PCPs spending more time per visit, or being less likely to work with nurse practitioners or physician assistants billing under their NPIs
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Does the Primary Care Physician Gender Wage Gap Differ Based on Compensation Method?
BACKGROUND AND PURPOSE:
- Female physicians continue to be paid less than their male counterparts
- Ganguli et al. (Ann Intern Med, 2022) determined how Primary Care Physician (PCP) compensation by gender differs when applying existing productivity-based and alternative compensation models
METHODS:
- Microsimulation study
- Data from national clinical registry of 1222 primary care practices (2016 to 2019)
- Population
- Male and female PCPs were matched by
- Specialty | Years since medical school graduation | Practice site | Sessions worked
- Male and female PCPs were matched by
- Simulations
- Productivity-based fee-for-service | Panel size–based capitation
- Without or with risk adjustment
- Hybrid payment models
- Productivity-based fee-for-service | Panel size–based capitation
- Study design
- Microsimulation inputs included patient and visit characteristics and overhead expenses
- Primary outcome
- Net annual, full-time-equivalent compensation for male versus female PCPs under the different simulations
RESULTS:
- Male PCPs: 881 | Female PCPs: 554
- Female PCP panels included patients who, on average
- Were younger
- Had lower diagnosis-based risk scores
- Were more often female
- Were more often uninsured or insured by Medicaid rather than by Medicare
- Female PCP panels included patients who, on average
- Under productivity-based payment
- Female PCPs earned 21% less than male PCPs
- Median income difference: $58,829 (IQR, $39,553 to $120,353)
- Gap was similar under capitation without adjustment
- Median income difference: $58,723 (IQR, $42,141 to $140,192)
- Wage gap was larger under capitation risk-adjusted for
- Age alone
- Median income difference: $74,695 (IQR, $42,884 to $152,423)
- Diagnosis-based scores alone (Charlson Comorbidity Index [CCI])
- Median income difference: $114,792 (IQR, $49,080 to $215,3260)
- Age-, sex-, and diagnosis-based scores (CCI): Median income difference: $83,438 (IQR, $28,927 to $129,414)
- Age alone
- The wage gap was small and nonsignificant under capitation risk-adjusted for age and sex
- Median income difference: $36,631 (IQR, $12,743 to $73,898)
CONCLUSION:
- Within a productivity-based model, female Primary Care physicians earned 21% less vs male colleagues
- The authors state
We found that despite female PCPs likely working similar hours to or even more hours than their male counterparts, female PCPs received less compensation under productivity-based payment due to conducting fewer visits
These lower visit rates may be explained by female PCPs spending more time per visit, or being less likely to work with nurse practitioners or physician assistants billing under their NPIs
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Meta-Analysis: Do Daily Multivitamins Have Beneficial Effects on Cognitive Health in Older Adults?
BACKGROUND AND PURPOSE:
- Vyas et al. (American Journal of Clinical Nutrition, 2024) assessed the effects of multivitamin-mineral (MVM) supplementation on cognitive change
METHODS:
- 2×2 factorial trial and meta-analysis
- COcoa Supplement and Multivitamin Outcomes Study (COSMOS)
- Participants
- US adults aged ≥60 years who completed all cognitive tests administered at baseline
- Interventions
- Cocoa extract [500 mg flavanols/day]
- Daily multivitamin-mineral supplement
- Placebo
- Primary outcomes
- Cardiovascular disease
- Cancer
- Meta-analysis inclusion criteria
- Non-overlapping participants across three COSMOS cognitive sub-studies
- Meta-Analysis review of patients from different substudies
- COSMOS-Clinic: n=573 | COSMOS-Mind: n=2158 | COSMOS-Web: n=2472
RESULTS:
- 573 participants from COSMOS-Clinic study
- Compared to placebo, there was a modest nonsignificant benefit of MVM on global cognition over 2 years
- Mean difference (MD) 0.06 (95% CI, -0.003 to 0.13) standard deviation units
- MVM was associated with better episodic memory
- MD 0.12 (95% CI, 0.002 to 0.23) standard deviation units
- There was no difference in executive function/attention with MVM
- MD 0.04 (95% CI, –0.04 to 0.11) standard deviation units
- Meta-analysis showed a benefit of MVM on
- Global cognition: MD 0.07 (95% CI, 0.03 to 0.11) | P=0.0009
- Episodic memory: MD 0.06 (95% CI, 0.03 to 0.10) | P=0.0007
- The effect on global cognition was equivalent to reducing cognitive aging by 2 years
CONCLUSION:
- Daily MVM supplementation in older adults had a beneficial effect on episodic memory after 2 years
- Meta-analysis revealed that daily MVM supplements are beneficial for both global cognition and episodic memory
- The authors state
These findings within the COSMOS trial support the benefits of a daily MVM in preventing cognitive decline among older adults
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Do Regular Primary Care Visits Reduce Medicare Costs and Acute Care Utilization?
BACKGROUND AND PURPOSE:
- Sonmez et al. (JAMA Network Open, 2023) examined the association between Medicare savings and primary care visit patterns
METHODS:
- Retrospective cohort study
- Population
- A 5% sample of traditional Medicare claims from 2016 to 2019
- Claims included in this sample came from participants with
- ≥3 primary care visits with ≥180 days between the first and the last visit | Who were not enrolled in Medicare Advantage | Who did not have end-stage kidney disease | Who were not institutionalized
- Exposures
- Primary care visit patterns
- Visit frequency | Regularity | Continuity of care (saw the most responsible primary care clinician or organization vs other primary care clinicians or organizations)
- Primary care visit patterns
- Primary outcomes
- Savings in Medicare expenditures
- Risk-adjusted Medicare expenditures | Number of emergency department (ED) visits | Hospitalizations
RESULTS:
- 504,471 beneficiaries
- Compared to the irregular noncontinuous group, the group with a regular and highly continuous pattern was associated with
- Greater savings
- 175.87% (95% CI, 167.40 to 184.33) | P<0.001
- Lower risk-adjusted expenditures
- −16.61% (95% CI, –16.73 to –16.48) | P<0.001
- Fewer risk-adjusted ED visits
- −40.49% (95% CI, –40.55 to −40.43) | P<0.001
- Fewer risk-adjusted hospitalizations
- −53.32% (95% CI, –53.49 to –53.14) | P<0.001
- Greater savings
- Regular visits with higher continuity were associated with the highest savings
- Savings increased with increasing visit frequencies
- Peak savings were observed at higher visit frequencies as clinical complexity increased
- As regularity and continuity decreased, the association between savings and visit frequencies progressively inverted
CONCLUSION:
- Medicare savings were maximized when primary care visits were frequent, regular, and continuous regardless of demographics and clinical characteristics
- The authors state
Proactive approaches to primary care, defined by temporally regular visits with a continuity-of-care clinician at a frequency optimized for clinical complexity, may offer benefits to payers, clinicians, and patients by decreasing expenditures, reducing ED visits, and reducing hospitalizations
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Primary Care Continuity, Frequency, and Regularity Associated With Medicare Savings
RCT Results: Oral Orforglipron for the Treatment of Obesity
BACKGROUND AND PURPOSE:
- Glucagon-like peptide-1 (GLP-1) receptor agonists appear to be effective for the treatment of obesity, but injection as a mode of delivery may prevent patient uptake
- Wharton et al. (NEJM, 2023) evaluated the efficacy and safety of oral orforglipron in adults with obesity or with overweight plus at least one weight-related coexisting condition
METHODS:
- Phase 2, randomized, double-blind trial
- Participants
- Obesity or overweight and ≥1 weight-related coexisting condition
- Exclusion: Diabetes
- Intervention
- 36 weeks of orforglipron at one of four doses: 12 mg | 24 mg | 36 mg | 45 mg
- Placebo
- Primary outcome
- Percentage change from baseline in body weight at week 26
- Secondary outcome
- Percentage change from baseline in body weight at week 36
RESULTS:
- 242 participants
- At week 26, the mean change from baseline in body weight was higher in all orforglipron dose cohorts
- The mean change in body weight increased linearly with increasing dose
- Orforglipron 12 mg: −8.6 (95% CI, −10.2 to −6.9)
- Orforglipron 45 mg: −12.6 (95% CI, −14.1 to −11.1)
- Placebo: −2.0 (95% CI, −3.6 to −0.4)
- The mean change from baseline was higher in all orforglipron dose cohorts at week 36
- A weight reduction of at least 10% by week 36 occurred in more participants in the orforglipron groups
- Orforglipron 12 mg: 46% (95% CI, 32 to 61)
- Orforglipron 45 mg: 69% (95% CI, 57 to 81)
- Placebo: 9% (95% CI, 1 to 17)
- The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures
- Adverse events
- Most common adverse events: Mild to moderate gastrointestinal events
- Typically occurred during dose escalation
- Discontinuation of orforglipron occurred in 10% to 17% of participants across dose cohort
- The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class
CONCLUSION:
- Compared to placebo, the daily use of oral orforglipron was associated with greater weight loss in participants with obesity and overweight with similar outcomes to injectables
- The safety profile of orforglipron is similar to that of other GLP-1 receptor agonists
- The authors state
Daily oral orforglipron was associated with weight reduction and related benefits that appeared to be similar to the efficacy outcomes observed with injectable GLP-1 receptor agonists that have already been approved for weight management
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Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity
Meta-Analysis: Metformin for PCOS Weight Management
BACKGROUND AND PURPOSE:
- Melin et al. (European Journal of Endocrinology, 2023) examined the effectiveness of metformin and lifestyle modification for the management of PCOS
METHODS:
- Systematic review and meta-analysis
- Inclusion criteria
- Randomized controlled trials
- Studies that assessed the effectiveness of metformin and lifestyle compared to placebo for the management of hormonal and clinical features of PCOS
- Primary outcomes
- Outcomes related to weight management and insulin sensitivity
RESULTS:
- 32 RCTs
- There was moderate certainty evidence that metformin vs placebo improved
- BMI with or without lifestyle change
- MD −0.53 kg/m2 (95% CI, −0.95 to −0.12)
- MD −0.50 (95% CI, −0.91 to −0.09)
- Fasting glucose
- MD −0.13 mmol/L (95% CI, −0.19 to −0.07)
- BMI with or without lifestyle change
- Compared to placebo, there were increased mild gastrointestinal adverse effects with metformin
- OR 7.67 (95% CI, 2.74 to 21.46)
- There was low certainty evidence to support metformin improving
- Reduction of waist-hip ratio
- MD −0.02 (95% CI, −0.03 to −0.00)
- Total cholesterol
- MD −0.24 mmol/L (95% CI, −0.43 to −0.05)
- Low-density lipoprotein
- MD −0.16 mmol/L (95% CI, −0.30 to −0.01)
- Triglycerides
- MD −0.11 mmol/L (95% CI, −0.20 to −0.02)
- Reduction of waist-hip ratio
CONCLUSION:
- For individuals with PCOS, metformin can effectively improve weight management, insulin tolerance, and lipids
- The authors state
Metformin should be considered in adult women with PCOS and BMI ≥25 kg/m2 for prevention of weight gain and management of weight and metabolic disorders
Metformin may be considered in adults with BMI < 25 kg/m2 and adolescents with PCOS, acknowledging more limited evidence
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Is Non-Erosive GERD Linked to an Increased Incidence of Esophageal Adenocarcinoma?
BACKGROUND AND PURPOSE:
- Gastroesophageal reflux disease (GERD) with erosive esophagitis is a risk factor for esophageal adenocarcinoma
- Holmberg et al. (BMJ, 2023) assessed the incidence rate of esophageal adenocarcinoma among patients with non-erosive GERD compared with the general population
METHODS:
- Population based cohort study
- Population
- Adults undergoing endoscopy in Denmark, Finland, and Sweden from 1987 through 2019
- Exposures
- Non-erosive GERD: absence of esophagitis and any other esophageal diagnosis at endoscopy
- Erosive GERD: presence of esophagitis at endoscopy
- Study design
- Follow-up: Up to 31 years
- Standardized incidence ratios with 95% CIs were calculated by dividing the observed number of esophageal adenocarcinomas in each of the GERD cohorts by the expected number
- Expected number derived from the general populations in Denmark, Finland, and Sweden of the corresponding age, sex, and calendar period
- Primary outcome
- Incidence rate of esophageal adenocarcinoma
RESULTS:
- Non-erosive GERD: 285,811 patients | Erosive GERD: 200,745 patients
- Non-erosive GERD: 2,081,051 person-years of follow-up | Erosive GERD: 1,750,249 person-years
- Incidence of esophageal adenocarcinomas
- Non-erosive GERD: 228
- Incidence rate: 11.0 per 100,000 person-years
- Erosive GERD: 542
- Incidence rate: 31.0 per 100,000 person-years
- Non-erosive GERD: 228
- The incidence of esophageal adenocarcinomas in the non-erosive GERD cohort was similar to that of the general population
- Standardized incidence ratio 1.04 (95% CI, 0.91 to 1.18)
- The incidence in the non-erosive GERD cohort did not increase with longer follow-up
- For 15 to 31 years of follow-up: IR 1.07 (95% CI, 0.65 to 1.65)
- Erosive GERD cohort had an increased incidence of esophageal adenocarcinomas compared to the general population
- Effect more pronounced with longer follow-up
- Standardized incidence ratio 2.36 (95% CI, 2.17 to 2.57)
CONCLUSION:
- Patients with non-erosive GERD experience esophageal adenocarcinomas at similar rates to patients in the general population
- The authors state
This finding suggests that patients with confirmed non-erosive GORD are not susceptible to develop oesophageal adenocarcinoma and may not require repeated endoscopic examinations regarding assessment of cancer risk
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GLP-1 Agonist Use for Weight Loss and Gastrointestinal Complications
BACKGROUND AND PURPOSE:
- Sodhi et al. (JAMA, 2023) examined gastrointestinal adverse events associated with Glucagon-like peptide 1 (GLP-1) agonists used for weight loss in a clinical setting
METHODS:
- Cohort study
- Population
- A random sample of a large health claims database
- Exposures
- New users of semaglutide or liraglutide
- New users of active comparator bupropion-naltrexone (weight loss agent unrelated to GLP-1 agonists)
- Study design
- Cox proportional hazards regression model was used to estimate hazard ratios (HR)
- Adjustments: Age | Sex | Alcohol use | Smoking | Hyperlipidemia | Abdominal surgery in the previous 30 days | Geographic location
- Primary outcome
- Incidence of biliary disease | Pancreatitis | Bowel obstruction | Gastroparesis
RESULTS:
- Liraglutide: 4144 | Semaglutide: 613 | Bupropion-naltrexone: 654
- Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of
- Pancreatitis: Adjusted HR 9.09 (95% CI, 1.25 to 66.00)
- Bowel obstruction: HR, 4.22 (95% CI, 1.02 to 17.40)
- Gastroparesis: HR, 3.67 (95% CI, 1.15 to 11.90)
- Use of GLP-1 agonists did not increase the risk of biliary disease
- HR 1.50 (95% CI, 0.89 to 2.53)
- Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results
CONCLUSION:
- The use of GLP-1 agonists for weight loss was linked to an increased risk of pancreatitis, gastroparesis, and bowel obstruction
- The authors state
Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes
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RCT Results: To What Extent Does the Wrong BP Cuff Size Impact the Accuracy of BP Readings?
BACKGROUND AND PURPOSE:
- The effect of incorrect cuff size has not been systematically measured
- Ishigami et al. (JAMA Internal Medicine, 2023) determined the effect of using a regular BP cuff vs an appropriately sized BP cuff on automated BP readings
METHODS:
- Randomized crossover trial
- Baltimore, MD
- Participants
- Adults in the community
- Interventions
- 4 sets of triplicate BP measurements
- Initial 3 sets used an appropriate, too-small, or too-large BP cuff in random order
- The fourth set always used repeated measurements obtained with an appropriate BP cuff (to determine reproducibility of the reference measurement)
- 4 sets of triplicate BP measurements
- Study design
- 4 cuff sizes: Small | Regular | Large | Extra large
- Automated BP devices
- All participants had ≥1 set of BP measurements with the regular cuff regardless of whether size was appropriate based on arm circumference
- Results were stratified by
- Systolic BP: ≥130 mm Hg vs <130 mm Hg
- BMI: ≥30 vs <30
- Primary outcome
- The difference in mean BP when measured with a regular BP cuff compared with an appropriate BP cuff
- Secondary outcome
- The difference in BP when using too-small or too-large BP cuffs vs an appropriate BP cuff across all cuff sizes
RESULTS:
- 195 adults
- Patients who require a small BP cuff
- Use of a regular BP cuff resulted in a significant lower BP reading
- Mean systolic BP difference −3.6 (95% CI, −5.6 to −1.7) mm Hg
- Patients who require a large or extra-large BP cuff
- BP differences were greater among those requiring larger BP cuffs
- These results were consistent when stratified by systolic BP and BMI
CONCLUSION:
- Using the wrong BP cuff size resulted in significantly inaccurate BP readings especially among patients requiring a large or extra-large BP cuff size
- The authors state
…using a regular BP cuff size for all individuals regardless of arm size resulted in strikingly inaccurate BP readings. A renewed emphasis on individualized BP cuff selection is warranted, particularly in individuals with larger arm sizes
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Are Direct Oral Anticoagulants or Warfarin a Better Choice for Extended VTE Therapy?
BACKGROUND AND PURPOSE:
- It is not clear whether warfarin or more recently developed direct oral anticoagulants (DOACs) are the better treatment option for extended VTE therapy
- Fang et al. (JAMA Network Open, 2023) compared DOACs vs warfarin for anticoagulant treatment beyond 6 months after acute VTE
METHODS:
- Cohort study
- Data derived from Kaiser Permanente Virtual Data Warehouse
- Sampling time period: January 1, 2010, to December 31, 2018
- Population
- ≥18 years
- Received a diagnosis of incident VTE
- Completed a 6-month initial treatment for VTE
- Exposures
- DOACs
- Warfarin
- Study design
- Follow-up: End of the initial 6-month treatment period until discontinuation of anticoagulation | Occurrence of an outcome event | Health plan disenrollment | End of the study follow-up period
- Comparison of DOAC and warfarin outcomes performed using multivariable Cox proportional hazards regression
- Primary outcomes
- Recurrent VTE | Hospitalizations for hemorrhage | All-cause death
RESULTS:
- 18,495 patients
- DOAC: 11.5% | Warfarin: 88.5%
- Aged ≥75 years: 29.6% | Women: 48.5%
- Predominant DOAC was dabigatran
- Unadjusted event rates were lower for patients receiving DOAC therapy than warfarin therapy for (per 100 person-years)
- Recurrent VTE
- DOACs: 2.92 (95% CI, 2.29 to 3.54)
- Warfarin: 4.14 (95% CI, 3.90 to 4.38)
- Hospitalizations for hemorrhage
- DOACs: 1.02 (95% CI, 0.66 to 1.39]
- Warfarin: 1.81 (95% CI, 1.66 to 1.97)
- All-cause death
- DOACs: 3.79 (95% CI, 3.09 to 4.49)
- Warfarin: 5.40 (95% CI, 5.13 to 5.66)
- Recurrent VTE
- After adjustment, DOAC treatment was associated with a lower risk of recurrent VTE
- Adjusted hazard ratio (aHR) 0.66 (95% CI, 0.52 to 0.82)
- There were no significant differences between the groups in the risk of
- Hospitalization for hemorrhage: aHR 0.79 (95% CI, 0.54 to 1.17)
- All-cause death: aHR 0.96 (95% CI, 0.78 to 1.19)
CONCLUSION:
- Patients who continued anticoagulation treatment beyond 6 months experienced a lower risk of recurrent VTE with DOACs vs warfarin
- The authors state
Our study contributes to the growing evidence supporting the use of DOACs for both initial and extended treatment of VTE in terms of clinical outcomes as well as treatment satisfaction
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RCT Results: Does a Low-Dose Tricyclic Antidepressant Improve Irritable Bowel Syndrome?
BACKGROUND AND PURPOSE:
- When first-line treatments for irritable bowel syndrome (IBS) are ineffective, guidelines suggest low-dose tricyclic antidepressants as a second-line treatment
- Despite most IBS cases being managed in primary care, very few primary care practitioners prescribe tricyclic antidepressants for IBS
- Ford et al. (The Lancet, 2023) examines the impact of amitriptyline on IBS at 6 months
METHODS:
- Randomized, double-blind, placebo-controlled trial
- Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment (ATLANTIS)
- Participants
- ≥18 years
- Rome IV IBS Criteria: Recurrent abdominal pain, on average, at least 1 day per week associated with stool changes
- Ongoing symptoms despite first-line treatment
- Normal full blood count and C-reactive protein | Negative celiac serology | No evidence of suicidal ideation
- Interventions
- Low-dose oral amitriptyline (10 mg once daily) for 6 months
- Placebo
- Study design
- Amitriptyline dose titration occurred over 3 weeks (up to 30 mg daily)
- Participants, their general practitioners, investigators, and analysis team were all masked to allocation throughout the trial
- Analysis by intention-to-treat
- Safety analyses were conducted with all participants who took at least one dose of the trial drug
- Primary outcome
- IBS- Severity Scoring System (SSS) score at 6 months
RESULTS:
- Low-dose amitriptyline: 232 participants | Placebo: 231
- There was a significant improvement in IBS-SSS score at 6 months among the low-dose amitriptyline
- Difference: –27.0 (95% CI, –46.9 to –7.10) | P=0.0079
- Discontinuation due to adverse events before 6 months
- Low-dose amitriptyline: 13% | Placebo: 9%
- There were 5 serious adverse reactions
- Amitriptyline group: 2 | Placebo: 3
CONCLUSION:
- As a second-line treatment, low-dose amitriptyline, 10 mg to 30 mg daily, significantly improved IBS symptoms at 6 months vs placebo
- Treatment was well-tolerated
- The authors state
General practitioners should offer low-dose amitriptyline to patients with IBS in whom first-line therapies are ineffective, with appropriate support to guide patient-led dose titration, such as the self-titration document we developed
Management guidelines should be updated to reflect these findings
