Navigating the Literature

November 2024

“Tirzepatide for Obesity Treatment and Diabetes Prevention”

Plain Text Summary

Summary: Reports on 3-year safety outcomes of tirzepatide (dual GIP/GLP-1 receptor agonist) and its efficacy in reducing weight and delaying progression of DMII in patients with obesity and prediabetes

Method: Phase 3, double-blind, randomized, controlled trial in which patients with obesity and prediabetes were assigned in 1:1:1:1 ratio to receive tirzepatide (once-weekly) 5 mg, 10 mg, or 15 mg or placebo for 176 weeks with a 17-week washout

Results

• No significant differences in safety profiles between tirzepatide doses and placebo
• Mean percent change in body weight among the participants who received tirzepatide was −12.3% (5 mg), −18.7% (10 mg), and −19.7% (15 mg) versus −1.3% among those who received placebo (P<0.001)
• Fewer participants progressed to DMII in tirzepatide groups than in placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001)

Analysis              

Pros

• Small number needed to treat (NNT) (9)
  • A NNT of 9 suggests a greater treatment effect size

Cons

• Problematic inclusion criteria
  • Mean baseline HbA1c was 5.76, merely qualifying for prediabetes, which calls into question participants’ true risk for development of diabetes
• Pharmaceutical company involvement
  • Eli Lilly, manufacturer of tirzepatide, was substantially involved in study, which introduces potential bias

Bottom Line: As dual GIP/GLP-1 receptor agonists are already a part of most primary care practices, the data presented will not fundamentally change our current clinical practice.

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October 2024

“Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction"

Plain Text Summary

Question: Should I prescribe finerenone to patients with heart failure with preserved ejection fraction (HFpEF)?

Answer: No, we do not recommend prescribing finerenone to patients with HFpEF, but we will not be surprised to see an increase in patients prescribed the medication.

Background: The article “Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction,” published in The New England Journal of Medicine on October 24, 2024, presents data from a larger international, double-blind, randomized control trial of finerenone, a non-steroidal mineralocorticoid receptor antagonist, for its potential benefits in heart failure patients with mildly reduced or preserved ejection fraction (HFpEF), where steroidal options have shown limited benefit.

Study Summary: The trial enrolled HF patients with an ejection fraction of 40% or greater, randomly assigning them to finerenone or placebo plus standard treatment. The primary outcome measured a composite of worsening HF events and death from cardiovascular (CV) events. Findings indicated that primary outcomes were less frequent in the finerenone group than in the placebo group (rate ratio = 0.84; 95% CI 0.74–0.95; p = 0.007) with consistent support from subgroup analysis.

Key Considerations

• Efficacy: Despite the reduced rate of primary outcomes, the actual difference in affected patients was only 3.2% lower in the finerenone group.
• Safety Profile: Hyperkalemia occurred more frequently in the finerenone group (9.7%) compared to placebo (4.2%), which may influence clinical decision-making.
• Potential Bias: The study was funded by Bayer, with one author employed by the sponsor, which could introduce bias.

Bottom Line: Given finenerone’s limited efficacy and side effect profile, we are unlikely to prescribe finerenone for patients with HFpEF; however, we will be unsurprised to see an increase in patients placed on this medication.

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September 2024

“Electronic Nicotine-Delivery Systems for Smoking Cessation” 

Plain Text Summary

Question: Should I recommend that patients use electronic cigarettes (“e-cigarettes”) as a tool to complete smoking cessation?

Answer: No, we do not recommend the use of e-cigarettes as a tool to complete smoking cessation.

Background

• Article Title: “Electronic Nicotine-Delivery Systems for Smoking Cessation”
• Journal: The New England Journal of Medicine
• Publication Date: February 15, 2024
• Abstract Summary: With funding from the Swiss government, an open-label randomized controlled trial concluded that the use of e-cigarettes as a tool for complete smoking cessation alongside standard smoking cessation treatment was more effective than standard treatment alone. At six months, biochemically validated continuous abstinence from smoking was 28.9% in the intervention group and 16.3% in the control group (RR = 1.77; 95% CI = 1.43-2.20) with similar serious adverse event profiles in both groups.

Analysis

• Positive Findings: E-cigarette usage decreased total nicotine usage.
• Study Concerns: Experimental and control groups were not suitably matched (e.g., the experimental group was given free e-cigarettes with optional, not-free nicotine replacement therapy while the control group was given $50 that could be used towards nicotine replacement therapy). Additionally, nicotine abstinence rates (i.e., no use of tobacco cigarettes, e-cigarettes with nicotine, and nicotine-replacement therapy) were higher in the control group.
• Other Concerns: Long-term data on safety of e-cigarettes remains unknown.

Bottom Line: A large Swiss study found that e-cigarettes increased smoking cessation, but due to the study’s potential methodological bias and the overall lack of long-term safety data on e-cigarettes, we are unlikely to recommend the use of e-cigarettes as a tool for patients looking to quit smoking.

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May 2024

“Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity"

Plain Text Summary

Question: Is intermittent fasting more effective for weight loss than a typical eating pattern when calorie intake is held constant?

Answer: No, intermittent fasting without caloric adjustment does not appear more effective for weight loss.

Background: Published in Annals of Internal Medicine, “Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity” (published on April 19, 2024) investigates whether time-restricted eating (TRE) promotes weight loss and improves glucose metabolism independently of calorie reduction in adults with obesity and prediabetes or diet-controlled diabetes.

Study Summary: In a controlled, isocaloric feeding experiment, 41 participants were assigned to either a TRE regimen (10-hour eating window with 80% of calories consumed before 1 PM) or a usual eating pattern (UEP) (≤ 16-hour window with ≥50% of calories consumed after 5 PM). Over 12 weeks, both groups consumed the same number of calories from meals prepared at the research facility. Results showed no significant difference in weight loss between the TRE (-2.3 kg (95% CI, 1.0 to 3.5 kg)) and UEP (-2.6 kg (95% CI, 1.5 to 3.7 kg)) groups or glycemic profiles between the TRE and UEP groups.

Key Considerations

• Limited Generalizability: Study composed of only 41 participants, the majority of whom were Black women, with noticeably differing starting weights (TRE = 95.6 kg (95% CI, 89.6 to 101.6 kg), UEP = 103.7 kg (95% CI, 95.3 to 112.0 kg)), and all study participants were given meals prepared by registered dieticians in the research facility.

Bottom Line: A controlled study revealed that intermittent fasting was no more effective for weight loss than a regular eating pattern when calorie intake was equal. However, in practice, real-world studies, intermittent fasting has shown greater effectiveness compared to a standard eating pattern.

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April 2024

“Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease"

Plain Text Summary

Question: Should I prescribe gabapentinoids to patients with chronic obstructive pulmonary disease (COPD)?

Answer: We recommend caution in prescribing gabapentinoids to patients with COPD, especially if moderate to severe.

Background: The article “Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease,” published in Annals of Internal Medicine on January 16, 2024, reports on a large, population-based, retrospective cohort study conducted in Quebec, Canada, which investigated the relationship between the use of gabapentinoids (gabapentin and pregabalin) and the risk of severe exacerbations in patients with COPD. Amid international warnings about the respiratory risks of gabapentinoids, this research provides key insights into their safety in a vulnerable population.

Study Summary: The study included patients with COPD who were ≥ 55 years of age and initiated gabapentinoid therapy (gabapentin or pregabalin) or received no such treatment. They were propensity-matched 1:1 based on clinical and demographic factors. The primary outcome was severe COPD exacerbations requiring hospitalization or resulting in death. Results showed that severe exacerbations occurred more frequently in the gabapentinoid group than in the nonuser group (hazard ratio = 1.39; 95% CI 1.29–1.50). Subgroup analyses supported these findings across different indications, including epilepsy, neuropathic pain, and other chronic pain.

Key Considerations

• Methodology: Despite its use of propensity matching, the study is retrospective, not prospective, which limits its ability to infer causality.
• Data: The absolute increase in severe COPD exacerbations, while modest, was significant and aligns with data from prior observational studies.
• Analysis: Multiple sensitivity analyses did not change results.

Bottom Line: Considering the findings of this study alongside other observational research, caution is warranted when prescribing gabapentinoids to patients with COPD, particularly those with severe disease.

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