Evolocumab plus statin potentially reduces atherosclerosis progression in GLAGOV study


The addition of evolocumab to statin therapy in individuals with angiographic coronary disease appeared to encourage coronary atherosclerosis regression, as demonstrated in the GLAGOV* trial presented at the Scientific Sessions of the American Heart Association (AHA 2016) held in New Orleans, Louisiana, US.

In comparison with patients on statin alone who experienced a nonsignificant 0.05 percent increase in percent atheroma volume (PAV), those on combined therapy of statin and evolocumab had a 0.95 percent reduction in PAV (difference, -1.0 percent, 95 percent confidence interval [CI], -1.8 to -0.64 percent; p<0.001). Normalized total atheroma volume (TAV) decreased by 0.9 mm3 (nonsignificant) in those on statin alone compared with 5.8 mm3 in those on statin and evolocumab (difference, -4.9 mm3, 95 percent CI, -7.3 to -2.5; p<0.001). [AHA 2016, LBCT 03; JAMA 2016;doi:10.1001/jama.2016.16951]

Plaque regression occurred in a greater number of patients on evolocumab and statin compared with those on statin alone (64.3 percent vs 47.3 percent; difference, 17.0 percent, 95 percent CI, 10.4 to 23.6 percent; p<0.001 for PAV and 61.5 percent vs 48.9 percent; difference, 12.5 percent, 95 percent CI, 5.9 to 19.2 percent; p<0.001 for TAV).

“We are really reducing plaque burden in the coronaries if we can get [low-density lipoprotein cholesterol (LDL-C)] down to these very low levels,” said study chair Dr Steven Nissen from the Department of Cardiovascular Medicine at the Cleveland Clinic, Cleveland, Ohio, US, who presented the findings. “It turns out that a little bit of change in plaque volume translates into a very big change in plaque behaviour.”

“[These findings] suggest a new era in lipid management,” said discussant Dr Raul Santos from the University of São Paulo, Brazil.

Evolocumab appeared to be well tolerated with comparable incidences of injection site reactions (0.4 percent vs 0 percent), myalgia (7.0 percent vs 5.8 percent), neurocognitive events (1.4 percent vs 1.2 percent), and new onset diabetes (3.6 percent vs 3.7 percent) for evolocumab plus statin vs statin monotherapy, respectively.

In this double-blind, placebo-controlled, multicentre trial, participants (n=968, mean age 59.8 years; 72 percent male) with angiographic coronary disease, LDL-C levels ≥80 mg/dL or 60–80 mg/dL with additional high-risk features, and on stable statin therapy were randomized to receive monthly subcutaneous injections of the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab (420 mg) or placebo for 76 weeks. After angiography, participants underwent intravascular ultrasound (IVUS) of the same artery at baseline and at week 78.

“Both the primary and secondary IVUS efficacy measures showed atherosclerosis regression … in patients treated with the combination of evolocumab and statins and absence of regression in patients treated with a statin alone,” said study lead investigator Dr Steven Nicholls, also from the Cleveland Clinic. “These findings provide evidence that PCSK9 inhibition produces incremental benefits on coronary disease progression in statin-treated patients.”

“Over the last 4 decades, evidence has accumulated suggesting that optimal LDL levels for patients with coronary disease may be much lower than commonly achieved. While we await large outcome trials for PCSK9 inhibitors, the GLAGOV trial provides intriguing evidence that clinical benefits may extend to LDL-C levels as low as 20 mg/dL,” said Nissen, who acknowledged the limitations of the trial such as the small number of patients and short treatment period. “IVUS is a useful measure of disease activity, but the critical determination of benefit and risk will require completion of large outcome trials currently underway,” he said.

Other factors that could potentially influence disease progression in the setting of very low LDL-C levels also need to be investigated, said Nicholls.

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Dapagliflozin drives HbA1c, SBP, and weight down in DERIVE


Dr Siew-Pheng Chan.

The use of the sodium/glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin in patients with type 2 diabetes (T2D) and moderate renal impairment provides benefits beyond glucose lowering, with no new safety signals, in the phase III DERIVE* study.

At 6 months, the primary endpoint of mean reduction in HbA1c level was greater by 0.34 percent in patients treated with dapagliflozin vs placebo (p< 0.001). There were also greater reductions in systolic blood pressure (SBP, 3.1 mm Hg; p<0.05) and mean body weight (1.25 percent, p< 0.001) with dapagliflozin. (APSC 2018, abstract S105-01)

“Dapagliflozin induces glycosuria and lowers blood glucose. However, the glycaemic efficacy of dapagliflozin is attenuated in patients with moderate renal impairment, for example in stage 3 CKD, because less glucose is cleared in the kidney in this group,” said Dr Siew-Pheng Chan, consultant endocrinologist at Subang Jaya Medical Centre in Subang Jaya, Malaysia, who is unaffiliated with the study.

Researchers led by Dr Paola Fioretto of the University of Padova in Padua, Italy conducted the DERIVE study to compare the efficacy and safety of dapagliflozin vs placebo in 321 patients with T2D (HbA1c of 7 –11 percent) and moderate renal impairment (stage 3A chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR), 45 to <60 mL/min/1.73m2). Patients were randomized to either dapagliflozin 10 mg (n=160) or placebo (n=161) over 6 months. Randomization was stratified by background glucose-lowering medication. Both groups had similar baseline characteristics.

At 6 months, treatment with dapagliflozin resulted in a significant reduction in mean HbA1c (-0.37 percent vs -0.03 percent for placebo) and mean body weight (-3.17 vs -1.92 kg, respectively) from baseline. The mean fasting plasma glucose was also significantly reduced with dapagliflozin (-21.46 vs -4.87 mg/dL for placebo) as was mean SBP (-4.8 vs -1.7 mm Hg, respectively) from baseline to 6 months.

In terms of safety, mean eGFR was reduced with dapagliflozin (-3.23 mL/min/1.73m2) vs placebo (-0.63 mL/min/1.73m2). Urinary tract infection and genital infection were the most common adverse events of interest reported. Overall, the safety profile of dapagliflozin was consistent with previous reports seen for T2D. No bone fractures or amputations were reported.

Dapagliflozin is currently indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2D. Dapagliflozin remains contraindicated in patients with an eGFR <30 mL/min/1.73 m².

 

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Low ankle-brachial index tied to cognitive decline


Even in the absence of peripheral arterial disease, a lower ankle-brachial index (ABI) is significantly associated with larger declines in cognitive function, according to a poster presented at the 2018 Congress of the Asian Pacific Society of Cardiology (APSC 2018) in Taipei, Taiwan.

“The present study aimed to investigate whether a graded association between ABI and cognitive function exists, and whether this association is independent of artery stiffness, which is a recognized predictor of cognitive impairment,” said researchers.

Categorizing 708 participants according to quartiles of ABI, researchers found that there was a significant and inverse correlation between ABI values and global cognitive function, represented as scores in the Mini-Mental Short Examination (MMSE; p=0.0011 for trend). [APSC 2018, abstract P006]

Specifically, mean MMSE scores were lowest in the first ABI quartile (27.4±3.1) and increased in the second (27.8±2.8), third (28.2±2.3) and fourth (28.4±2.0) quartiles.

The significant relationship between ABI and global cognitive function was confirmed in general linear (β, –0.137; p=0.0007) and fully adjusted multivariable logistic regression models (Q4 vs Q1: adjusted odds ratio [OR], 3.623; 95 percent CI, 1.096–11.972).

Researchers likewise found a significant and positive relationship between MMSE scores and carotid-femoral pulse wave velocity (CF-PWV; β, 0.114; p=0.0044).

Notably, using patients with both high ABI and low PWV as reference, the odds of cognitive function decline was elevated in those with high PWV only (OR, 2.34) and low ABI only (OR, 2.28). The effect was substantially more pronounced in those with both low ABI and high PWV (OR, 8.19).

ABI also showed a significant and inverse association with mean brachial pulse pressure (Q1: 58.3±11.8; Q2: 56.6±13.2; Q3: 54.7±10.6; Q4: 54.9±10.6 mm Hg; p=0.0094 for trend). There was a significantly higher proportion of male patients in the third (58.52 percent) and fourth (57.30 percent) ABI quartiles than in the first (35.16 percent) and second (42.42 percent; p<0.0001 for trend).

The findings of the present study show that a lower ABI value is significantly associated with a greater decline in global cognitive function, said researchers. In addition, the relationship was independent of and additive to the effect of arterial stiffness.

For the study, researchers recruited 708 adults without peripheral arterial disease (ABI >0.9; mean age 69.0±7.0 years; 48.35 percent male). Volume-plethysmographic apparatus was used to measure ABI, while CF-PWV was used as a measure of arterial stiffness.

Of the participants, 182 had ABI from 0.9–1.10 and were placed in the lowest quartile (mean age 69.3±7.1 years) while 165 had ABI from 1.10–1.14 and fell within the second quartile (mean age 69.1±6.9 years). The third (ABI 1.14–1.19; mean age 68.8±7.3 years) and fourth (ABI ≥1.19; mean age 68.9±6.6 years) quartiles included 176 and 185 participants, respectively.

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Lp(a) Levels May Modulate CV Benefits of Evolocumab: FOURIER


Patients treated with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) may experience a greater reduction in cardiovascular events if they have higher baseline levels of lipoprotein(a) [Lp(a)], US investigators have shown.

The results are from a preplanned analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, published in March 2017 in the New England Journal of Medicine.

As reported by theheart.org | Medscape Cardiology at that time, main FOURIER results showed that evolocumab was associated with a 15% reduced risk for a composite of myocardial infarction (MI), stroke, cardiovascular disease (CVD), coronary revascularization, and unstable angina hospitalization at 22 months compared with placebo (P < .001).

Moreover, treatment was associated with a 20% reduction in a composite of CVD, MI, and stroke vs placebo (P < .001), which occurred in tandem with large reductions in low-density lipoprotein (LDL) cholesterol levels.

The current analysis, presented here at the European Atherosclerosis Society (EAS) 2018 meeting, shows evolocumab also achieves significant reductions in Lp(a) levels of more than 25%.

The researchers found that the greatest effect of the drug compared with placebo on the risk for cardiovascular death, MI, and stroke was in patients with higher baseline Lp(a) levels, at 24% vs 15% in those with lower levels, at a twofold increase in the absolute risk reduction.

Study presenter Michelle L. O’Donoghue, MD, Brigham and Women’s Hospital, Boston, Massachusetts, told theheart.org | Medscape Cardiology that whether or not the benefits offered by Lp(a) reduction are “above and beyond” the LDL reduction is an area of ongoing study.

“But I think it’s worthwhile that we were able to see that baseline Lp(a) concentration appears to help identify individuals who derive greater benefit from treatment with evolocumab,” she added.

“So if those individuals have a larger magnitude of benefit and a smaller number needed to treat, then that’s perfect, as we’re trying to think about different high-risk features that might help to identify individuals who get the greatest benefit from the drug in a cost-effective manner.”

For O’Donoghue, one of the key aspects of their results is that they suggest that evolocumab affects both Lp(a) and LDL separately to lower the risk for cardiovascular outcomes. This was underlined by data showing that the greatest benefit was seen in individuals who achieved both their Lp(a) and LDL cholesterol target.

“With a drug like evolocumab, you’ve got multiple effects, and it becomes almost like a pleiotropic effect, because you’ve got LDL lowering, which is obviously very compelling, in addition to the effects on Lp(a),” she said.

“I think there’s a lot of work to be done to figure out whether or not the Lp(a) reduction on its own offers as much, or greater, or less benefit than LDL reduction on its own,” she added. “It’s interesting to see, though, that those who achieved the dual targets of lower levels of both are those who do best.”

Evolocumab and Lp(a)

The FOURIER trial involved 27,564 patients with stable atherosclerotic CVD and LDL cholesterol levels of 1.8 mmol/L (70 mg/dL) or higher who were receiving statin therapy and were randomly assigned to evolocumab, 140-mg injections every other week or 420-mg injections monthly, or to placebo.

After a mean follow-up of 2.2 years, evolocumab treatment was associated with a 59% relative reduction (P < .00001), or a 56-mg/dL absolute reduction, in LDL levels down to a median of 30 mg/dL, alongside the observed clinical benefits.

Previous Mendelian randomization data suggested that Lp(a) plays a causal role in the risk for coronary heart disease (CHD), and PCSK9 inhibitors have been shown to significantly reduce Lp(a) levels, so the team examined the impact of evolocumab on Lp(a) in FOURIER.

As part of the trial, Lp(a) levels were measured at baseline and weeks 12 and 58, with results available for 25,096 participants. The median Lp(a) level was 37 nmol/L (interquartile range [IQR], 13 – 165 nmol/L).

Individuals in the highest quartile of Lp(a) levels were, compared with those in the lower quartiles, significantly less likely to be male, to have ischemic stroke and diabetes mellitus, and to currently use tobacco (P < .001 for trend).

In contrast, individuals in the highest quartile were significantly more likely to have had a MI, to have peripheral artery disease, and to have higher baseline LDL cholesterol levels than those in the lower quartiles (P < .001 for trend).

As expected, higher baseline Lp(a) levels were associated in the placebo group with a significantly higher risk for CHD death or MI, cardiovascular death, MI or stroke, and MI and coronary death individually on multivariate analyses taking into account a range of potential confounding factors.

For example, the adjusted hazard ratio of CHD death or MI in participants with an Lp(a) in quartile 4 vs those in quartile 1 was 1.26 (95% CI, 1.02 – 1.56).

Among 11,864 participants given evolocumab, treatment was associated with a mean absolute change in Lp(a) levels at week 48 of –11 nmol/L (IQR, –31 nmol/L to –1 nmol/L), or a median percentage change of –26.9% (IQR, –46.7% to –6.2%).

The correlation between percentage change in Lp(a) and change in LDL cholesterol at 48 weeks in treated patients was r = 0.37 (P < .001), while that for absolute change was r = 0.21.

When the team divided the patients into those whose baseline Lp(a) level was above the median and those whose level was at or below the median, they found a difference in the impact of evolocumab on cardiovascular outcomes vs placebo.

Specifically, patients with a baseline Lp(a) level above the median had a hazard ratio of cardiovascular death, MI, or stroke with evolocumab vs placebo of 0.76 (95% CI, 0.66 – 0.86), or an absolute risk reduction of 2.8% and a number needed to treat of 36.

This compares with a hazard ratio for evolocumab vs placebo among patients with a baseline Lp(a) level at or below the median of 0.85 (95% CI, 0.73 – 0.97), or an absolute risk reduction of 1.28% and a number needed to treat of 79.

Next, the team looked at Lp(a) and LDL cholesterol together in terms of the impact of evolocumab treatment on the risk for combined cardiovascular events after week 12.

The risk was lower in patients who achieved a reduction of Lp(a) and LDL cholesterol to at or below the median at baseline (6.57%) than in those who achieved that milestone only with Lp(a) (7.88%), those who got there only with LDL cholesterol (8.45%), and those who achieved that for neither measure (9.43%) (P < .001 overall).

Concluding her presentation, O’Donoghue said their findings show that evolocumab significantly reduces Lp(a) levels and that “patients starting with higher Lp(a) levels appear to derive greater absolute benefit.”

Moreover, individuals “who achieve lower levels of both LDL cholesterol and Lp(a) have the lowest subsequent risk of CV events.”

Speaking after the session in an interview, she said that this latter finding is particularly interesting when one thinks of the individuals who have a reduction in Lp(a) levels “but a rise in LDL cholesterol levels at the same time.”

“What are those genetic predictors that help to identify those individuals? It’s not completely clear,” she said.

Completely Different Story

Commenting on the findings, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, Italy, and past president of the EAS, told theheart.org | Medscape Cardiology that “it’s a completely different story” between Lp(a) and LDL cholesterol.

He explained that with LDL cholesterol, the greater the reduction in plasma levels, the greater the benefit, while with Lp(a), “there’s always been a struggle” to demonstrate a similar relationship.

“Lp(a) is related to cardiovascular disease, but the strongest relationship is with calcification of the aortic wall, or aortic stenosis,” he said.

However, Catapano noted that the “exact mechanism is still not completely clear,” unlike the situation with LDL.

“Of course, we’ll never know everything for sure but we have robust evidence with LDL,” he said. “With Lp(a), it’s not clear whether it’s coagulation, whether it’s atherosclerosis and the buildup of cholesterol, or both together.”

“Having said that,” he added, “there is clearly a relationship that is not linear but sort-of hyperbolic, so that above a certain level, the correlation gets stronger and the risk becomes higher.”

Catapano pointed out, however, that the median Lp(a) levels seen in the FOURIER trial were lower than those seen in the general population and lower than the 50 mg/dL that has been linked to a substantially increased cardiovascular risk, “so you would not expect a huge benefit” with Lp(a) reduction in this population.

“The second point is they saw a benefit that was larger in absolute terms according to the levels of Lp(a), [which] is entirely in line with what we know,” he said. “We know that Lp(a) contributes to the risk and we know that we have a higher risk if we have higher Lp(a), and that reducing LDL cholesterol for sure reduces the risk.”

“Whether the contribution of Lp(a) to that reduction of risk is important, we do not know; it would be almost impossible to disentangle from the data,” he said. “That’s my personal view.”

However, Catapano believes, these answers may be provided  with the results of ongoing studies into antisense nucleotides, which target Lp(a) specifically.

FOURIER was funded by Amgen. O’ Donoghue reports receiving research grant support from GlaxoSmithKline, Eisai, Merck & Co, Janssen, Amgen, The Medicines Company, and AstraZeneca. Catapano reports being a consultant for and receiving honoraria from Pfizer, Sanofi, Genzyme, Merck, Akcea, and Amgen; receiving honoraria from Kowa, Mediolanum, Farmaceuti, Menarini, Bayer, Eli Lilly, Recordati, and Genzyme; and receiving research grants from Pfizer, Merck, Sanofi, Menarini, Regeneron, Mediolanum, and Farmaceutici.

 

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First Trial of Three Aromatase Inhibitors: Similar Efficacy, Safety


The first-ever direct comparison of three adjuvant aromatase inhibitors for the treatment of postmenopausal hormone receptor–positive early breast cancer shows no significant differences in clinical efficacy or safety, according to an Italian research team.

In the randomized, open-label phase 3 FATA-GIM3 trial of almost 3700 women, the 5-year disease-free survival for patients treated with anastrozole (Arimidex, Novartis), exemestane (Aromasin, Pfizer), or letrozole (Femara, Novartis) was 90.0%, 88.0% and 89.4%, respectively.

There were no unexpected serious adverse reactions or treatment-related deaths, say Francesco Perrone, MD, of the Istituto Nazionale per lo Studio e la Cura dei Tumori, in Naples, Italy, and colleagues. No differences were observed between patient subgroups, even though more than 50% of patients were overweight or obese.

The study was published online February 23 in the Lancet Oncology.

This is also the first trial to compare an up-front treatment schedule with a switch schedule using anastrozole, the study authors note. The up-front schedule consisted of 5 years of treatment with aromatase inhibitors; the switch schedule consisted of 2 years of treatment with tamoxifen followed by 3 years of treatment with aromatase inhibitors.

The study shows that both treatment schedules were clinically relevant. There was only a 1.6% difference in disease-free survival after 2 years. After 5 years, the disease-free survival was 88.5% with the switch strategy and 89.8% with the up-front regimen (hazard ratio [HR], 0.89; P = .23).

“FATA-GIM3 is the only trial to compare upfront treatment with a switch strategy using anastrozole, and the first trial to directly compare the three aromatase inhibitors; thus, contributing to the knowledge base, which is currently limited to indirect comparisons of the EBCTCG [Early Breast Cancer Trialists’ Collaborative Group] meta-analysis and two head-to-head trials, one of which was limited to node-positive patients,” Perrone and colleagues write.

“The number of deaths and other breast-related events was too low to allow reliable conclusions to be drawn on endpoints other than disease-free survival,” the investigators add. The 5-year overall survival was 95.3% with the switch schedule and 96.8% with the up-front schedule (HR, 0.72; P = .052).

Tamoxifen vs AIs: Clear Differences

The researchers suggest that clinicians consider patient preferences, tolerability, and cost when determining the best treatment approach.

“Clinical benefits and tolerability are particularly important in the choice between aromatase inhibitors and tamoxifen,” Perrone told Medscape Medical News. The safety profile is “clearly different,” he added. He noted that musculoskeletal side effects are seen more frequently with aromatase inhibitors.

“We should still consider tamoxifen a good option,” Perrone emphasized.

Findings from the earlier ATAC study suggested that less costly switch therapy might be more effective than up-front therapy, state the investigators, who conducted a literature search through August 30, 2017. ATAC findings also indicated that longer exposure to aromatase inhibitors could be associated with a greater risk for cardiac and musculoskeletal toxicity.

When FATA-GIM3 was designed in 2006, the up-front aromatase inhibitor treatment strategy was about to become standard practice, the study authors say.

In an accompanying comment, Luc Y. Dirix, MD, of the University of Antwerp, Belgium, called the FATA-GIM3 trial “an important confirmatory study.

“These data are the first for the switch approach with anastrozole,” he confirmed. “Patients and clinicians can be confident that any aromatase inhibitor is acceptable in this treatment strategy.”

FATA-GIM3 reinforces results from the EBCTGC meta-analysis, which demonstrated a small absolute benefit with up-front therapy after 5 years of follow-up, Dirix notes. Two large international trials established the clinical relevance of the up-front and switch regimens while the FATA-GIM2 trial was still underway, he points out.

The BIG1-98 trial found that tamoxifen followed by letrozole was more effective then letrozole alone. Similarly, the TEAM trial showed that tamoxifen followed by exemestane was more effective than exemestane alone.

“The duration of adjuvant endocrine therapy is now considered a more crucial factor in treatment outcomes,” Dirix says.

The editorialist also says that “even if the upfront strategy is preferred, FATA-GIM3 confirms the absence of a relevant difference between the aromatase inhibitors (with only small differences in toxicities but not in efficacy), giving clinicians the freedom to exchange one aromatase inhibitor for another.”

For the study, 3697 postsurgical patients with invasive hormone receptor–positive breast cancer were enrolled from 76 Italian public healthcare institutions between March 9, 2007, and July 31, 2012. Participants were randomly assigned to one of six treatment groups.

A total of 1847 participants received up-front treatment. These patients took oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 5 years. A total of 1850 patients were assigned to switch therapy. These patients received oral tamoxifen 20 mg once daily for 2 years followed by oral anastrozole 1 mg, exemestane 25 mg, or letrozole 2.5 mg once daily for 3 years.

The median time on tamoxifen was 24 months. The median time on the three aromatase inhibitors was 32 to 35 months in the switch group and 54 to 56 months in the up-front group.

Toxicity was the main reason for early treatment interruption. This was seen more frequently in patients treated with tamoxifen (11%) than in those treated with aromatase inhibitors (5% in the switch group and 7% in the up-front group).

Endometrial side effects were the most frequent reason for tamoxifen interruption (4%). Three percent of patients in the switch group and 4% in the up-front group experienced grade 3-4 musculoskeletal side effects.

A total of 85 patients were diagnosed with a second nonbreast cancer. Five patients were diagnosed after breast cancer recurrence.

There were 138 deaths, including 80 participants treated using the switch schedule and 58 patients treated using the up-front schedule. Breast cancer was the most frequent cause of death in both groups: 55 participants (3%) in the switch group, and 30 (2%) in the up-front group.

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Acne in Adolescents Linked With Dairy Intake–Again


The association between acne in adolescents and dairy consumption is supported by 2 recent studies, bringing renewed interest in the long-established hypothesis of this link.

The association between dairy intake and acne in teenagers has gained renewed interest with 2 new studies supporting the hypothesis that acne is linked with diet. Conflicting accounts exist about the significance of different types of milk as contributing factors, however, and the cause of acne is still unknown despite several studies.1,2 Dermatologists are still somewhat polarized in their opinion on the role of diet in acne, and it remains a controversial topic.3

A new study by Professor Maria Ulvestad and colleagues of Oslo University Hospital, Norway, published in the March 2017 issue of the Journal of the European Academy of Dermatology and Venereology, supports the argument for a connection between high consumption of milk and moderate-to-severe acne in adolescents.

According to the researchers, acne affects a significant percentage of adolescents. It leads to a reduced quality of life similar to chronic conditions like diabetes and arthritis, so it is of scientific and economic importance to understand the underlying cause.4

“Considering the extensiveness of acne, a great interest exists to reveal and comprehend its possible causative factors,” the authors point out. “Much is known about the pathophysiology of acne that eventually leads to a chronic inflammation in pilosebaceous units. What provokes these events to happen, however, is not fully understood. During the last decade, the acne-diet connection has been brought back to credibility, after being considered a myth for a long time. This hypothesis suggests that consumption of different foods influence the occurrence of acne.”4

In this latest study, adolescent participants were provided with a questionnaire for the self-assessment of their acne, and analyses of the results were done by separating the adolescents into 2 groups: those with no-to-little acne vs those with moderate-to-severe acne. The researchers then compared the level of dairy product consumption between the 2 groups, with further subgroup analyses differentiating the dairy consumed based on fat content, whether intake was low or high, as well as on gender.4

The investigators were unable to establish a link between low-fat or skim milk and acne, but instead, found that a correlation exists between high intakes of full-fat dairy products, defined as greater than or equal to 2 glasses per day, and moderate-to-severe acne.4

Low-fat dairy and acne

A slightly earlier study by Andrea Zaenglein, MD, and colleagues from the Pennsylvania State University College of Medicine, “Consumption of dairy in teenagers with and without acne,” was published in the August 2016 issue of the Journal of the American Academy of Dermatology. This study, which was supported by the American Acne and Rosacea Society, also showed a positive link with acne when including milk in the diet, but the association was only found with low-fat or skim milk, not full-fat milk or other dairy products.3 In this study, a dermatologist classified acne using the Global Acne Assessment Scale and, as with the 2017 study, self-reporting of dairy intake was included.3

“There are 4 main factors in the pathogenesis of acne: increased sebum (or oil) production from the glands in the skin, increased hyperkeratinization where the skin cells at the pores get sticky and build up blocking the pore outlet, an increase bacteria in the pore called Propionibacterium acnes, and inflammation. All of these factors are intertwined, each making the other worse. They are also influenced by such factors as diet and genetics,” Dr. Zaenglein told MedPage Today.

“The discussion was quiescent for years until a study found virtually no acne in select non-Westernized populations, leading researchers to infer that a Western diet may be to blame. Subsequent studies suggested an association between dairy, particularly skim milk and acne,” the authors also report.3

These contradictory findings in the literature may be a direct result of methodological limitations, and this should be given consideration when interpreting the results. However, whether full-fat or low-fat/fat-free dairy plays a significant role in the prevalence of acne in adolescents, both recent studies support the previous data linking milk intake with acne.1,5

“This is very controversial and the data is mixed to be sure. There are known differences in skim versus whole milk, however. Whole milk has natural Vitamin A and D. In skim milk, it is removed and replaced after the fat is skimmed off. So, absorption might be affected. Whole milk contains some additional beneficial components such as medium chain fatty acids that promote healthy metabolism and decrease insulin resistance, as well as conjugated linoleic acid and monounsaturated fatty acids,” said Dr. Zaenglein.

The more recent results from the 2017 study suggest there may be gender differences. Data indicate an association between acne and high total dairy consumption in female adolescents, compared with a greater magnitude of association between acne and high consumption of exclusively full-fat dairy in male adolescents. It is stated though, that any gender differences observed may be confounded by other gender-specific variables such as diet preferences or some behavioral or environmental factors like smoking or exercise.4

Data support dairy intake link with acne

It appears that the role of dairy in our overall health is a complex issue. Earlier studies report that milk causes an elevated insulinemic response and promotes an increase in insulin-like growth factor-1. It may be possible that this spike in insulin encourages phosphorylation of the transcription factor Foxhead box protein O1 (Fox01), thereby resulting in the activation of the mammalian target of rapamycin complex 1 (mTORC1) receptor and thus the stimulation of the sebaceous glands. These findings reveal a common mechanism of action for antiacne treatments and may provide a route to the development of new medication.3,6

“We have no explanation for why we solely found association with full-fat dairy products, and not with semi-skimmed or skimmed products. It has been proposed that different manufacturing processes of cow’s milk might alter the composition of other bioactive substances, as well as the intended change in fat content. Milk is a complex fluid, containing different proteins, carbohydrates and steroid hormones etc., which are likely to influence endogenic and possibly acne-promoting pathways. Lately, the ability of cow’s milk to increase IGF-1 and insulin levels in vivo has received much attention,” reported the authors of the 2017 study.

Although there were certain limitations of the 2017 study, the authors did highlight that their consistent results for full-fat dairy association support the hypothesis that dairy intake may be a relevant, contributing factor to acne.4

Future directions

The manufacturing process of skim milk where fat-soluble vitamins A and D are removed from full-fat milk and reintroduced later to the low-fat product may warrant further investigation to study the bioavailability and distribution of essential vitamins compared with full-fat milk.3

“Since I am a dermatologist and not a nutritionist, important next steps in research that need to be done before we make firm dietary recommendations to patients would be to see if switching from skim milk to whole milk actually makes a difference in acne,” Dr. Zaenglein concluded.

 

In Insane Coffee-Drinking Study, Coffee Appears to Be the Anti-Cannabis


Coffee has been the world’s favorite stimulant for hundreds of years, yet scientists are only now figuring out its impact on human health. In a new Journal of Internal Medicine study, scientists report that the addictive beverage has a unique impact on a person’s metabolism. In particular, coffee changes the metabolism of steroids and neurotransmitters that are usually associated with another of our favorite drugs — cannabis.

At the base level, the international team of researchers reported on Thursday, coffee shifts the levels of certain metabolites, which are chemicals in the blood that spike or drop after we eat or drink. Extremely heavy coffee drinking caused neurotransmitters related to the stress-regulating endocannabinoid system to decrease — which is the opposite of what happens after a person smokes marijuana. The researchers reasoned that the decrease in metabolites could be the body’s way of trying to get stress levels back to equilibrium after getting so hyped up on coffee.

“These are entirely new pathways by which coffee might affect health,” lead author Marilyn Cornelis, Ph.D., an assistant professor of preventative medicine at Northwestern University, explained in a statement released Thursday. “Now we want to delve deeper and study how these changes affect the body.”

Math explains how to make the perfect cup of coffee.
Scientists are still learning exactly how coffee impacts health.

For three months, the 47 study participants willingly let the scientists screw with their coffee schedule. In the first month, they didn’t drink any coffee; in the second month, they moved up to four cups a day; and in the third month, they slurped down eight cups a day (four more than what’s recommended as the healthy limit). Then, the scientists examined the hundreds of metabolites floating around in the blood samples collected after each stage of the study.

Heavy coffee drinking appeared to raise the number of metabolites linked to the androsteroid system, which helps the body get rid of steroid molecules. But the scientists also found that the blood metabolites related to the endocannabinoid system metabolic pathway decreased with coffee consumption, especially when participants were drinking eight cups of coffee a day. The endocannabinoid system regulates a wide range of functions in the body, including stress.

The body naturally produces endocannabinoids, which mimic the cannabinoid activity caused by chemicals in marijuana. But when a person smokes weed, endocannabinoid blood metabolites increase in the system — the opposite of what happens when you drink coffee.

What happens when you drink weed-infused coffee is a whole other question scientists have yet to figure out — and with the rapid legalization of marijuana, it may have to be a scientific puzzle they need to figure out soon.

Impact Study


Understanding injuries on the basketball court

Wearable sensors will give researchers data on impact loading in real-world game and practice situations.

Whether players are crashing the boards on rebounds, sprinting down court on a fast break or taking a charge on defense, basketball is a physically demanding sport that can take a toll on athletes’ bodies.

In particular, basketball players experience a large number of high-impact loading events during their career and these repetitive loading events are thought to be related to the high incidence of lower-limb injury that elite players experience, including bone-stress injury. Unfortunately, the relationship between mechanical loading and injury is not clear because until now it has been difficult to measure impact loads during practice and games.

A new study led by Irene Davis, Harvard Medical School professor of physical medicine and rehabilitation and the director of the Spaulding National Running Center plans to examine the role of fatigue on landing impacts and bone-stress injuries in basketball players.

The research team will be using small devices, called wearable sensors, that can be secured to the lower leg to measure these loads while players are on the court. The relationship between load and injury is affected by other factors such as sleep, nutrition, bony anatomy and the current state of bone health. To prevent bone-stress injury and help athletes recover from bone-stress injury, we must first have a better understanding of these mechanical and biological factors and how they relate to bone health, the researchers said.

“Ultimately, we want to understand the factors that affect the foot-bone loading a basketball player sustains over the course of a season,” Davis said.

The study is funded by the National Basketball Association and GE Orthopedics and Sports Medicine Collaboration.

Davis and her team will focus on foot-bone stress injuries as these are the most common in basketball players. They plan to first collect baseline measures of foot-bone anatomy and bone health using various types of imagining techniques. They will also gather data on nutrition and diet, such as the amount of vitamin D in the blood and daily caloric intake. The study team will then monitor how hard the players are landing with each step across practices and games throughout the season and also monitor sleep over the course of the season. Finally, the team will image the foot again to determine if any injuries are developing.

“Bone-stress injuries can progress to small cracks in the bone, and ultimately, complete fractures. These injuries can be season ending and sometimes career ending. Therefore, preventing them from happening is the best approach. We believe this study will provide important information for sports medicine professionals who oversee these athletes’ care,” Davis said.

The advent of wearable sensors that can accurately measure and monitor impact loads provides an opportunity to characterize the physical demands of the game in unprecedented ways, Davis said. This new form of data has the potential to influence the understanding of lower-limb injury, as well as provide crucial insight on how to alter training to mitigate injury risk and how to improve return-to-play decisions.

Understanding the role of mechanical loading in maintaining bone health is particularly relevant to young elite basketball athletes whose skeletons are still undergoing a modeling process and to freshman college athletes who might receive a dramatic increase in impact load exposure during preseason training that their skeletons have not yet adapted to.

By including both college and elite basketball athletes in this cohort, Davis said that her research will address several interesting research questions: How does lower-limb load exposure due to training differ between college and elite level basketball athletes? What is the impact load exposure during a game and how does this compare to training? How do lower-limb impact loads change during a game and throughout the season (i.e., is there a fatigue-related change in impact load)? And ultimately, does impact load exposure predict bone health and possibly, bone-stress injury?

The findings of the study should also provide insight that will be helpful for the health of people who happen not to be elite athletes, Davis said.

“Ultimately, measuring and monitoring the mechanical loads experienced by musculoskeletal tissue is critical to improve our understanding of musculoskeletal injury and health,” Davis said.

Preventing Overweight Using Novel Dietary Strategies Study (POUNDS LOST)


Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) study was a clinical trial designed to test the effects of four heart-healthy diets varying in fat, protein, and carbohydrate composition on the weight loss and its long term maintenance. Participants were assigned to one of four diets and asked to record their food intake in a diary or an online tool that showed how intake compared with goals. The diets were low or high in total fat (20 or 40 percent of calories) with average or high protein (15 or 25 percent of calories). Carbohydrate content ranged from 35 to 65 percent of calories. The diets all used the same calorie reduction goals and were heart-healthy—low in saturated fat and cholesterol while high in dietary fiber. Study participants were 811 free-living overweight or obese adults ages 30-70 from Boston, MA and Baton Rouge, LA. All participants were offered group and individual counseling sessions over two years.

Weight loss after six months and two years was similar among participants assigned to the four diets. On average, participants lost 13 pounds at six months and maintained a 9 pound loss at two years. Participants also reduced their waistlines by 1 to 3 inches by the end of the study. Craving, fullness, hunger, and diet satisfaction were all similar across the four diets. All diets improved risk factors for cardiovascular disease at both six months and two years in ways consistent with previous studies. Improved risk factors include reduced levels of triglycerides, LDL (bad) cholesterol, lowered blood pressure, and increased HDL (good) cholesterol. The results indicate that heart-healthy, reduced-calorie diets, regardless of which macronutrients they emphasize, can help overweight and obese adults achieve and maintain weight loss.

Selected References:

Sacks FM, Bray GA, Carey VJ, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009;360:859-73.

Souuurce:www.nhlbi.nih.gov

Metformin during pregnancy safer than insulin : Study


https://speciality.medicaldialogues.in/metformin-during-pregnancy-safer-than-insulin/

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