Новости эндокринологии, записная книжка

[FilippovaYulia]

Старый и вроде бы хорошо изученный алмаз современной диабетологии открывает все новые грани.
Но сердечно-сосудистый прогноз и метформин - данные все еще несколько противоречивы.

[Korzun]

Сообщение от FilippovaYulia

Но сердечно-сосудистый прогноз и метформин - данные все еще несколько противоречивы.

Противоречия есть, но не при всех сердечно-сосудистых нозологиях.
В целом метформин стоит рассматривать как препарат улучшающий прогноз при ССЗ.

Если идти по ходу сердечно-сосудистого континуума, то:
1. Метформин значимо снижает ЛПНП даже без диабета.
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2. Метформин средне снижает вес и артериальное давление. Но Семаглутид и ингибиторы SGLT-2 делают это лучше.
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3. Метформин по эффективности лечения эректильной дисфункции находится между тадалафилом и вакуумной помпой.
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4. Во время острого инфаркта миокарда может ухудшить прогноз, но принимаемый после инфаркта улучшает его.
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5. Улучшает прогноз при аневризме аорты.
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6. При сердечной недостаточности (финал континуума) немного запутано.
SGLT2 лучше чем метформин при ХСН и делает это и без него.
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Но и с метформином прогноз тоже улучшается.
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Капля дегтя:
Если плясать от СД2, то в общей совокупности в метанализе 29 исследований с 371 смертями в них:
Комбинация метформина с другим гипогликемическим препаратом была связана с более высоким риском смертности от всех причин (ОР: 1,49; 95% ДИ: 1,02, 2,16) и сердечно-сосудистой смертности (ОР: 2,21; 95% ДИ: 1,22, 4,00) по сравнению со схемами приема гипогликемических препаратов без метформина.
Но есть оговорки по дизайну:
Однако вывод должен быть объяснен с осторожностью, учитывая ограничения Британского проспективного исследования диабета (UKPDS).
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Чуть более поздний системный обзор приходит к немного другим выводам:
В целом, несмотря на то, что такие положительные эффекты наблюдались при лечении метформином, необходимы дополнительные РКИ для улучшения нашего понимания его модулирующего воздействия на исходы, связанные с сердечной недостаточностью, особенно у пациентов с сахарным диабетом.
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Вишенка на торте:
Метформин улучшает прогноз при Ковиде-19, а летальность при нем все-таки сердечно-сосудистая (тромбоз, ОРДС, аритмии).
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Т.е. метформин нельзя при остром инфаркте и осторожно при ХСН.
А вот все начальные стадии ССЗ, постинфарктное состояние и аневризма аорты - прямо нужно.
P.S. То, что он лучше ежедневного тадалафила при ЭД, немного удивило.

[ELENA_VLAD]

[Ссылки доступны только зарегистрированным пользователям ] и перевод [Ссылки доступны только зарегистрированным пользователям ]

[Melnichenko]

А здесь можно не быть осторожным ?
The FDA has granted over-the-counter marketing authorization to MED3000 (Eroxon), the first nonprescription topical gel for treating erectile dysfunction (ED), maker Futura Medical announcedopens in a new tab or window on Monday.

According to the company, MED3000 has "a 10-minute onset of action" that sets it apart from prescription PDE5 inhibitors such as sildenafil (Viagra) and tadalafil (Cialis), which typically require a longer period of time to take effect.

The gel was initially tested as the placeboopens in a new tab or window comparator in studies of a nitroglycerin gel the company was developing, but in a large phase III trialopens in a new tab or window it turned out MED3000 worked just as well.

"FDA set a very high standard in evaluating the effectiveness and safety," James Barder, Chief Executive Officer of Futura Medical, said in a statement. "I am delighted that we met this standard with MED3000's submission of 22 clinical, biocompatibility, human factors studies and performance bench tests which were rigorously reviewed and accepted by the FDA."

Last August, the company announced positive results from FM71, a confirmatory 24-week multicenter phase III trialopens in a new tab or window that compared MED3000 to oral tadalafil in 96 ED patients.

Both primary endpoints were achieved in the open-label study. At 24 weeks, scores on the International Index of Erectile Function – Erectile Function (IIEF-EF) scale were significantly improved across mild, moderate, and severe ED (P<0.001), with a demonstrated durability of response beyond 12 weeks. And patients assigned to the gel experienced an average 5.73-unit change from baseline in IIEF-EF score at 24 weeks, exceeding the 4-unit difference required by the FDA and defined as the minimal clinically important difference.

MED3000 also met FDA criteria for rapid onset, a secondary endpoint of the trial, with a significant improvement in erectile function at 10 minutes; tadalafil did not meet the criteria at that time.

Headache was reported in 19% of those randomized to tadalafil versus 4% of those assigned to the topical gel, while noncardiac chest pain and back pain were only reported in the PDE5 inhibitor group (4% for each). Nausea was reported in 4% of those using MED3000, along with one instance of "mild local burning," the company said. No local side effects were reported among sexual partners.

[Korzun]

Как в старом анекдоте.
Средство для потенции - Три богатыря.
Три - это глагол.

[Dr.Vad]

Слышал в свою бытность молодым врачом, что до виагры доктора использовали гель с нитроглицерином (что ранее использовался для лечения стенокардии) как топическое эректильное средство, прошло более 25 лет и опять приходят "натирания"

[Dr.Vad]

PS. ой, его предшественник по номеру и был нитратом

MED2005, a 0.2% glyceryl trinitrate topical gel, formulated into an enhanced absorption topical delivery system (DermaSys), administered on demand, in the treatment of ED.

[Ссылки доступны только зарегистрированным пользователям ]

[Dr.Vad]

ох, и детективная история - опять случайные находки: плацебо гель работал также хорошо, как и нитрат на гелевой плацебо-основе

The gel was initially used as a placebo in studies of a nitroglycerin gel called MED2005. Early trial results of MED2005 in 2018 spawned media buzz, with headlines playing on the word "dynamite" ... However, a 2019 phase III trial of 1,000 men with ED in Europe found that the nitroglycerin gel didn't reach primary endpoints versus the placebo. In fact, the placebo's effectiveness was roughly equal to that of the active treatment per multiple measurements.

Futura Medical has declined to identify the components of the placebo gel, now called MED3000... Futura Medical said the product "gently evaporates to create a unique cooling effect followed by a warming effect. This stimulates nerve sensors in the highly innervated glans penis, leading to smooth muscle relaxation, tumescence and erection."

[Korzun]

Посмотрел состав MED3000 - спирт, глицерил - точно за счет массажа весь эффект.
После покупки 5 тюбиков вакуумная помпа в подарок

[Melnichenko]

Personalized recombinant leptin treatment helped reverse severe, early-onset obesity in two children carrying rare antagonistic leptin genetic variants, a study showed.

In the double case report, two unrelated children -- a 14-year-old boy and a 2-year-old girl -- presented with what appeared to be leptin dysfunction, marked by intense hyperphagia, lack of satiety, and severe obesity, Martin Wabitsch, MD, PhD, of Ulm University Medical Center in Germany, and colleagues detailed in a New England Journal of Medicineopens in a new tab or window (NEJM) brief report.

Of note, the parents of the boy were second-degree cousins and parents of the girl were first-degree cousins.

The researchers confirmed that both patients had abnormally high levels of circulating leptin. Conditions like Prader-Willi and Bardet-Biedl syndromes were both ruled out.

Based on in vitro experiments they performed, Wabitsch's group found that these patients had impaired binding between leptin proteins and leptin receptors. Treatment was started at the recommended dose of 0.03 mg/kg of lean body weight, but because of the agonist activity, the initial metreleptin treatment -- a recombinant human leptin -- given to these patients flopped, having virtually no effect.

Following the in vitro results, the researchers opted to bump up the doses for both patients.

For the boy (a carrier of leptin variant P64S), the dose was increased to 0.14 mg/kg on day 2 of treatment, to 0.70 mg/kg on day 5, and was tapered down starting on day 131, reaching an end dose of 0.15 mg/kg.

For the girl (a carrier of leptin variant G59S), the dose was increased to 0.15 mg/kg on day 2 of treatment, and tapered down starting on day 264, with an ending dose of 0.07 mg/kg.

In addition to the increased metreleptin doses, both patients participated in exercise programs and "vigorous" fasts in order to magnify the effect of exogenous leptin. After achieving a therapeutic response, patients lost weight, normalized food intake, and achieved satiety. Both also developed antibodies against metreleptin.

After 1,188 days of treatment, the 14-year-old boy achieved a near-normal weight of 94.1 kg (207.5 lb). He lost 49.9 kg (110 lb) -- a weight loss of 27.8% -- by day 131, and lost 72.9 kg (160.7 lb) -- a weight loss of 40.5% -- by day 264. The boy's body mass index (BMI) also dropped from 54.3 at baseline to 26.9 by day 1,188.

After 1,260 days of treatment, the 2-year-old girl achieved a near-normal weight of 23.2 kg (51.1 lb). She lost 9.6 kg (21.2 lb) -- a weight loss of 36.5% -- by day 238 of treatment. The girl's BMI dropped from 31.6 at baseline to 17.6 on day 1,260.

"To be honest, after our initial descriptionopens in a new tab or window of biologically inactive leptin variants in 2015, we had expected that sooner or later a patient would present at our Centre for Genetic Obesity who had an antagonizing leptin variant," Wabitsch told MedPage Today. "Based on the knowledge of the molecular ligand-receptor interaction of leptin and its receptor, the existence of antagonizing variants of leptin in humans was likely."

"We hypothesized that specific rare human gene variants in the leptin gene will result in leptin molecules with an impaired interaction with interaction site III of the leptin receptor responsible for receptor activation but with high affinity to the interaction site II responsible for receptor binding. We further hypothesized that these leptin variants would block the receptor when metreleptin treatment is initiated and behave as antagonizing ligands at the receptor level," he explained. "The fact that we were then presented with two patients within a short period of time with two different variants that had these characteristics was a surprise."

"But that was only the first step," Wabitsch added. "Our elaborate in vitro experiments then paved the way for a successful therapy. Based on the in vitro results, we were able to calculate the dose we needed to overcome the antagonism in vivo by substituting metreleptin."

"This was the basis for a successful treatment," he said, noting that this was the first time this had been done in humans. "This is exciting and a novelty for human medicine."

In an accompanying editorialopens in a new tab or window, Clifford J. Rosen, MD, of the MaineHealth Institute for Research in Scarborough and an associate editor for NEJM, pointed out how leptin "was once hailed as a treatment for most cases of childhood obesity but quickly lost favor when resistance to leptin was noted."

"It is apparent that there is a narrow appropriate dose-response effect of leptin on leptin-receptor signaling in the hypothalamus. Further research into the use of monoclonal antibodies as a potential therapeutic tool for obesity is warranted," he suggested, also noting that these findings have implications for more general treatments of obesity.

Wabitsch advised that clinicians "should first think of and look for a genetic cause in children with extreme obesity and hyperphagia."

"In the rare case of a pathogenic leptin gene variant, the effects of this variant should be examined in detail. Colleagues are welcome to contact our center," he added. "If necessary, in vitro experiments can help to determine the therapy with leptin."

[Melnichenko]

CHICAGO -- Some of the latest research in the field of endocrinology presented at ENDO 2023opens in a new tab or window, the annual meeting of the Endocrine Society, included studies on testosterone-replacement therapyopens in a new tab or window and the risk of major cardiac events, the incongruence between BMI and body fat percentageopens in a new tab or window, and the glucose benefits of time-restricted eatingopens in a new tab or window. Below are a few more highlights.

Treatment for Hypothalamic Obesity Shows Promise

In an extension of a phase II trial including 13 patients with hypothalamic obesity, treatment with setmelanotide (Imcivree) was associated with an average reduction in body mass index (BMI) of 21% after 6 months, reported Christian Roth, MD, of the University of Washington in Seattle, and colleagues.

Most of this weight loss was achieved within the first 16 weeks of treatment, with an average BMI reduction of 16.8%. All participants achieved a BMI reduction of at least 5%, while 10 of the 13 participants were able to achieve at least a 10% reduction.

The most commonly reported adverse events were nausea (69.2%), skin hyperpigmentation (38.5%), and vomiting (30.8%). The most common cause of hypothalamic obesity was treatment of craniopharyngioma, followed by hypothalamic hamartoma, and juvenile pilocytic astrocytoma.

"This impressive response adds to the evidence suggesting setmelanotide may provide a meaningful clinical benefit for patients with this disease who currently have no approved therapeutic options," said Roth in a statement.

Setmelanotide is currently FDA-approved for certain genetic causes of obesity.

New Scientific Statement on Aging

During the meeting, the Endocrine Society released a scientific statement -- also published in the Journal of Clinical Endocrinology & Metabolismopens in a new tab or window -- outlining the differences between normal aging and treatable conditions.

Menopause was one of the highlighted conditions in the new statement, as many women experience bothersome symptoms but few actually receive treatment for it. The statement suggested that hormone therapy is safest for women within a 10-year window of the menopause transition or those younger than 60. New non-hormonal hot flash treatments have also shown promise for this population.

"The statement discusses how menopausal symptoms and osteoporosis are often undertreated in the older population, despite evidence that the treatments are both safe and effective," said lead author Anne Cappola, MD, ScM, of the University of Pennsylvania in Philadelphia, in a statement. "Treating these symptoms and screening for common endocrine conditions that develop or worsen with age could really improve the quality of life for older people."

Eneboparatide for Chronic Hypoparathyroidism

In a phase II trial, eneboparatide, an investigational long-acting parathyroid hormone 1 receptor agonist, helped patients with chronic hypoparathyroidism achieve independence from conventional therapy.

In the 14-person trial, more than 90% of patients were off active vitamin D and oral calcium therapy after 3 months of eneboparatide treatment, according to Peter Kamenický, MD, PhD, of Le Kremlin-Bicêtre in France, and colleagues.

While nearly half of patients had osteopenia or osteoporosis in at least one site at baseline, bone mineral density scores didn't significantly change during the trial. On top of that, in the half of patients who had hypercalciuria at baseline, mean 24-hour urinary excretion of calcium dropped by 49%.

No patients in the trial experienced a serious adverse event.

Based on these positive findings, developer Amolyt Pharma said it was initiating a 165-participant phase III trialopens in a new tab or window.

[FilippovaYulia]

Интересно.
Но, боюсь, буде сетмеланотид зарегистрирован в России, им тут же начнут лечить "гипоталамический синдром пубертатного возраста"...
Отлично, что есть перспективы по гипопаратиреозу. Очень часто "агонисты рецепторов" оказываются перспективнее, чем аналог нативного гормона.

[Melnichenko]

Юля, очень правильная мысль насчет агонистов...

[ghrh44]

Психиатры долго искали метаболичесие маркеры шизофрении и депрессии. Все их попытки были безуспешны. Но относительно недавно новые методы обнаружили пониженные уровни глютамина и глютамата в мозгу и крови у больных с биполярной болезнью. Кетамин, агонист GABA, ворвался в психиатрию буквально в последние несколько лет и показал высокий и быстрый эффект на депрессию. Но он требует периодических в/венных инфузий. Но вот недавно появилась новая таблетка, Auvelity, агонист GABA с крохотной дозой бупропиона, эффективная при депрессии, с быстрым (1-2 недели) действием у больных с резистентностью к обычным препаратам , кроме бупропиона. Но причинно-следственная связь глютамина и депрессии еще не была доказана.

В последнм выпуске JCEM есть статья из Китая со сложнейшим и дотошнейшим статистическим анализом возможной связи между уровнем глютамина крови и ожирением ( состоянием пониженного глютамина в крови) и депрессией.
Эта группа выявила тесную связь уровня глютамина и ожирения как факторов риска депрессии.

Неужто найден молекулярный маркер депрессии? Если так, то это первый прорыв в диагностику и патогенез биполярного расстройства, и идея психонейроэндокринологии как легитимной области эндокринологии в целом, получает поддержку.


Скрещивам пальцы и плюем три раза через левое плечо.



The Journal of Clinical Endocrinology & Metabolism, Volume 108, Issue 6, June 2023, Pages 1370–1375, [Ссылки доступны только зарегистрированным пользователям ]

[Melnichenko]

плюем строго в рамках ЕВМ!