Medical Bulletin 15/ May/ 2024

According to a study published in the journal JAMA Internal Medicine, in patients with sepsis, the use of a combination of vancomycin and piperacillin-tazobactam is associated with increased mortality risk compared with a combination of vancomycin and cefepime.

Piperacillin/tazobactam is a broad-spectrum antibiotic that is commonly administered for sepsis, a life-threatening complication from infection. In its absence, clinicians commonly use another antibiotic, cefepime, which has similar activity against common sepsis pathogens but, unlike piperacillin/tazobactam, has minimal effects on anaerobic gut bacteria.

In health, the gut microbiome is largely populated by anaerobic bacteria that rarely cause disease. Prior research has revealed that even a single dose of piperacillin/tazobactam kills most of these anaerobic gut bacteria, which play important roles in the body’s metabolism, immunity, and prevention of infections.

In their study, Dr. Rishi Chanderraj and his multidisciplinary team from the University of Michigan's Division of Infectious Disease analysed patient records from a cohort of 7,569 individuals. They compared outcomes between 4,523 patients treated with piperacillin/tazobactam and 3,046 patients who received cefepime.

Their findings revealed significant disparities: patients treated with piperacillin-tazobactam experienced a 5 percent rise in 90-day mortality, longer durations on ventilators, and increased instances of organ failure. Moreover, opting for piperacillin/tazobactam over cefepime could potentially result in one additional fatality for every 20 septic patients treated.

“These are powerful antibiotics that are administered to patients every day in every hospital nationwide. Clinicians use them because they are trying to treat every possible pathogen that might be causing their patients’ illnesses. But our results suggest that their effects on the microbiome might also have important effects on patient outcomes,” said Chanderraj. “Our previous research hinted at potential harm associated with piperacillin/tazobactam, but it was based on observational data with limitations. The drug shortage presented a unique opportunity, acting as a nearly perfect natural experiment to rigorously compare the outcomes of patients treated with these two drugs. Physicians should carefully consider the necessity of prescribing anti-anaerobic antibiotics.”

Reference: Chanderraj R, Admon AJ, He Y, et al. Mortality of Patients With Sepsis Administered Piperacillin-Tazobactam vs Cefepime. JAMA Intern Med. Published online May 13, 2024. doi:10.1001/jamainternmed.2024.0581

In the Women’s Health Initiative (WHI) randomized trial, adopting a low-fat diet was found to decrease breast cancer mortality, particularly among women with multiple metabolic syndrome components such as obesity, high blood pressure, elevated blood sugar, and abnormal cholesterol levels.

The analysis, published in the journal Cancer, indicated that metabolic syndrome and obesity each have different associations with breast cancer subtypes and mortality risk.

Obesity is a prevalent health concern among women worldwide, with its incidence steadily rising in recent years. Alongside its association with various metabolic disorders, including type 2 diabetes and cardiovascular disease, obesity has also been closely linked to an increased risk of cancer. In particular, obese women face a heightened likelihood of developing breast cancer, among other malignancies, due to the complex interplay of hormonal imbalances, chronic inflammation, and metabolic dysregulation associated with excess adiposity.

Metabolic syndrome, characterized by a cluster of metabolic abnormalities including hypertension and hyperglycemia, poses a significant risk factor for cancer-related deaths in women. This syndrome contributes to a systemic environment conducive to tumor growth and progression. Insulin resistance, a hallmark feature of metabolic syndrome, leads to elevated levels of insulin and insulin-like growth factor 1 (IGF-1), both of which promote cell proliferation and inhibit apoptosis, thereby fostering the development and spread of cancer cells.

In the study, researchers analyzed data from 63,330 postmenopausal participants of the WHI clinical trial who had no history of breast cancer, along with normal entry mammograms and MetS scores ranging from 0 to 4. Following a median follow-up period of 23.2 years, the analysis revealed 4,562 new cases of breast cancer and 659 deaths attributed to breast cancer (breast cancer mortality).

The study found that a higher metabolic syndrome score, regardless of obesity, was linked to poorer prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative breast cancers, and a 44% higher risk of breast cancer mortality. Obesity, irrespective of the metabolic syndrome score, was associated with better-prognosis, ER-positive, and PR-positive cancers. Only women with severe obesity faced a higher risk of breast cancer mortality.

Reference: Rowan T. Chlebowski MD, PhD, Aaron K. Aragaki MS, Kathy Pan MD, Michael S. Simon MD, MPH, et al.; Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women’s Health Initiative; CANCER; https://doi.org/10.1002/cncr.35318

Two studies presented at the European Congress on Obesity investigated the long-term effects of semaglutide on weight loss and explored the relationship between cardiovascular benefits and initial weight or extent of weight loss.

Semaglutide, a GLP-1 medication typically prescribed for adults with type 2 diabetes, is also approved for weight management in individuals with obesity or overweight who have at least one comorbidity. This medication class mimics the actions of the body's natural incretin hormones, aiding in post-meal blood sugar regulation. By modulating these hormone levels, semaglutide can induce a feeling of fullness, thereby reducing daily calorie consumption.

In the SELECT trial spanning from October 2018 to June 2023, 17,604 adults aged 45 or older from 41 countries were given semaglutide (2.4mg) or placebo for an average of 40 months. They had overweight or obesity but no diabetes and a history of cardiovascular events.

The findings are as follow:

1. Semaglutide users saw a 20% lower risk of heart attack, stroke, or cardiovascular death and lost an average of 9.4% body weight.

2. In the semaglutide group, weight loss persisted up to week 65 and was maintained for four years, with participants achieving an average body weight reduction of 10.2% and a waistline decrease of 7.7cm, compared to 1.5% and 1.3cm respectively in the placebo group.

3. The semaglutide group experienced a significant 6.9% reduction in average waist circumference-to-height ratio, compared to 1% in the placebo group. After two years, over half (52%) of semaglutide-treated participants shifted to a lower BMI category, compared to 16% of those receiving placebo.

4. Semaglutide treatment provided cardiovascular benefits regardless of initial weight or the extent of weight loss. This implies that even individuals with mild obesity or modest weight loss may experience improved cardiovascular outcomes with semaglutide therapy.

“Our findings show that the magnitude of this treatment effect with semaglutide is independent of the amount of weight lost, suggesting that the drug has other actions which lower cardiovascular risk beyond reducing unhealthy body fat. These alternative mechanisms may include positive impacts on blood sugar, blood pressure, or inflammation, as well as direct effects on the heart muscle and blood vessels, or a combination of one or more of these,” said Professor John Deanfield from University College London, UK.

Reference: Ryan, D.H., Lingvay, I., Deanfield, J. et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-02996-7