One hundred years of insulin therapy Mathieu, Chantal; Martens, Pieter-Jan; Vangoitsenhoven, Roman
Nature reviews. Endocrinology,
12/2021, Letnik:
17, Številka:
12
Journal Article
Recenzirano
At the time of its first clinical application 100 years ago, insulin was presented as the cure for people with diabetes mellitus. That transpired to be an overstatement, yet insulin has proven to be ...the lifesaver for people with type 1 diabetes mellitus and an essential therapy for many with type 2 diabetes mellitus or other forms of diabetes mellitus. Since its discovery, insulin (a molecule of only 51 amino acids) has been the subject of pharmaceutical research and development that has paved the way for other protein-based therapies. From purified animal-extracted insulin and human insulin produced by genetically modified organisms to a spectrum of insulin analogues, pharmaceutical laboratories have strived to tailor the preparations to the needs of patients. Nonetheless, overall glycaemic control often remains poor as exogenous insulin is still not able to mimic the physiological insulin profile. Circumventing subcutaneous administration and the design of analogues with profiles that mimic that of physiological insulin are ongoing areas of research. Novel concepts, such as once-weekly insulins or glucose-dependent and oral insulins, are on the horizon but their real-world effectiveness still needs to be proven. Until a true cure for type 1 diabetes mellitus is found and the therapeutic arsenal for other forms of diabetes mellitus is expanded, insulin will remain central in the treatment of many people living with diabetes mellitus.
Ever since its discovery by Windhaus, the importance of the active metabolite of vitamin D (1,25-dihydroxyvitamin D
; 1,25-(OH)2D
) has been ever expanding. In this review, the attention is shifted ...towards the importance of the extra-skeletal effects of vitamin D, with special emphasis on the immune system. The first hint of the significant role of vitamin D on the immune system was made by the discovery of the presence of the vitamin D receptor on almost all cells of the immune system. In vitro, the overwhelming effect of supra-physiological doses of vitamin D on the individual components of the immune system is very clear. Despite these promising pre-clinical results, the translation of the in vitro observations to solid clinical effects has mostly failed. Nevertheless, the evidence of a link between vitamin D deficiency and adverse outcomes is overwhelming and clearly points towards avoidance of vitamin D deficiency especially in early life.
Over the past decade, the detrimental impact of iron deficiency in heart failure with reduced ejection fraction has become abundantly clear, showing a negative impact on functional status, quality of ...life, cardiac function and structure, exercise capacity and an increased risk of hospitalisation due to heart failure. Mechanistic studies have shown the impact of iron deficiency in altering mitochondrial function and negatively affecting the already altered cardiac energetics in heart failure with reduced ejection fraction. Such failing energetics form the basis of the alterations to cellular myocyte shortening, culminating in reduced systolic function and cardiac performance. The IRON-CRT trials show that ferric carboxymaltose is capable of improving cardiac structure and cardiac performance. This article discusses the effect of iron deficiency on cardiac function and structure and how it can be alleviated.
Appropriate interpretation of changes in markers of kidney function is essential during the treatment of acute and chronic heart failure. Historically, kidney function was primarily assessed by serum ...creatinine and the calculation of estimated glomerular filtration rate. An increase in serum creatinine, also termed worsening renal function, commonly occurs in patients with heart failure, especially during acute heart failure episodes. Even though worsening renal function is associated with worse outcome on a population level, the interpretation of such changes within the appropriate clinical context helps to correctly assess risk and determine further treatment strategies. Additionally, it is becoming increasingly recognized that assessment of kidney function is more than just glomerular filtration rate alone. As such, a better evaluation of sodium and water handling by the renal tubules allows to determine the efficiency of loop diuretics (loop diuretic response and efficiency). Also, though neurohumoral blockers may induce modest deteriorations in glomerular filtration rate, their use is associated with improved long‐term outcome. Therefore, a better understanding of the role of cardio–renal interactions in heart failure in symptom development, disease progression and prognosis is essential. Indeed, perhaps even misinterpretation of kidney function is a leading cause of not attaining decongestion in acute heart failure and insufficient dosing of guideline‐directed medical therapy in general. This position paper of the Heart Failure Association Working Group on Cardio‐Renal Dysfunction aims at improving insights into the interpretation of renal function assessment in the different heart failure states, with the goal of improving heart failure care.
•Formulas to calculate plasma volume show moderate to good correlation with directly measured plasma volume.•Estimated plasma volume is widely distributed in heart failure patients receiving ...contemporary heart failure treatment.•Plasma volume expansion is an independent predictor for heart failure readmission and all-cause mortality even on top of established risk factors.•Higher doses of therapy with an ACE-I/ARB or MRA is associated with higher odds for having an optimal plasma volume in HFrEF and HFmrEF but not in HFpEF.
Progressive plasma volume (PV) expansion is a hallmark of chronic heart failure (HF), ultimately contributing to decompensated heart failure. Monitoring PV might offer prognostic information and might be a target for tailored therapy.
The correlation between technetium-99 (99Tc)–labeled red blood cell measured PV and calculated PV was first determined in a validation cohort. The relationship between PV status (PVS; a marker how much actual PV deviated from the ideal PV) and outcome was analyzed with the use of Cox proportional modeling in a prospective chronic HF (CHF) population (the outcome cohort). Thirty-one HF patients were included in the validation cohort. Calculated PV correlated well with 99Tc-measured PV (r = 0.714; P = .001). A total of 1173 patients (HF with reduced ejection fraction HFrEF: n = 872; HF with mid-range EF HFmrEF: n = 229; HF with preserved EF HFpEF: n = 72) were prospectively included in the outcome cohort. The mean PVS in the outcome cohort was −6.7% ± 10%, indicating slight PV contraction. Higher PVS was independently associated with increased risk for HF hospitalization and all-cause mortality (hazard ratio 1.016; 95% confidence interval 1.006–1.027 per 1% increase in PVS; P = .002). Receiver operating characteristic curve analysis indicated that a PVS of −6.5% optimally predicted absence of adverse outcome. Hazard ratio analysis indicated that CHF patients were less equipped in tolerating PV expansion in comparison to PV contraction. The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and mineralocorticoid receptor antagonists were independently associated with a higher odds of having an optimal PVS in HFrEF and HFmrEF (all P < .05), but not in HFpEF.
Calculated PV correlates well with measured PV in HF patients. An increase in PV is independently associated with a higher risk of adverse outcome, and a slight contraction of the predicted PV seems to be related to less adverse events. Higher dosages of renin-angiotensin-aldosterone blockers are associated with higher odds of having an optimal PV status.
Budd-Chiari syndrome Martens, Pieter; Nevens, Frederik
United European Gastroenterology Journal,
December 2015, Letnik:
3, Številka:
6
Book Review, Journal Article
Recenzirano
Odprti dostop
Budd-Chiari syndrome (BCS) is a rare and potentially life-threatening disorder characterized by obstruction of the hepatic outflow tract at any level between the junction of the inferior vena cava ...with the right atrium and the small hepatic veins. In the West, BCS is a rare hepatic manifestation of one or more underlying prothrombotic risk factors. The most common underlying prothrombotic risk factor is a myeloproliferative disorder, although it is now recognized that almost half of patients have multiple underlying prothrombotic risk factors. Clinical manifestations can be diverse, making BCS a possible differential diagnosis of many acute and chronic liver diseases. The index of suspicion should be very low if there is a known underlying prothrombotic risk factor and new onset of liver disease. Doppler ultrasound is sufficient for confirming the diagnosis, although tomographic imaging (computed tomography (CT) or magnetic resonance imaging (MRI)) is often necessary for further treatment and discussion with a multidisciplinary team. Anticoagulation is the cornerstone of the treatment. Despite the use of anticoagulation, the majority of patients need additional (more invasive) treatment strategies. Algorithms consisting of local angioplasty, TIPS and liver transplantation have been proposed, with treatment choice dictated by a lack of response to a less-invasive treatment regimen. The application of these treatment strategies allows for a five-year survival rate of 90%. In the long term the disease course of BCS can sometimes be complicated by recurrence, progression of the underlying myeloproliferative disorder, or development of post-transplant lymphoma in transplant patients.
Aims
To investigate the effects of acetazolamide on natriuresis, decongestion, kidney function and neurohumoral activation in acute heart failure (AHF).
Methods and results
This prospective, ...two‐centre study included 34 AHF patients on loop diuretics with volume overload. All had a serum sodium concentration < 135 mmol/L and/or serum urea/creatinine ratio > 50 and/or an admission serum creatinine increase of > 0.3 mg/dL compared to baseline. Patients were randomised towards acetazolamide 250–500 mg daily plus bumetanide 1–2 mg bid vs. high‐dose loop diuretics (bumetanide bid with daily dose twice the oral maintenance dose). The primary endpoint was natriuresis after 24 h. Natriuresis after 24 h was similar in the combinational treatment vs. loop diuretic only arm (264 ± 126 vs. 234 ± 133 mmol; P = 0.515). Loop diuretic efficiency, defined as natriuresis corrected for loop diuretic dose, was higher in the group receiving acetazolamide (84 ± 46 vs. 52 ± 42 mmol/mg bumetanide; P = 0.048). More patients in the combinational treatment arm had an increase in serum creatinine levels > 0.3 mg/dL (P = 0.046). N‐terminal pro‐B‐type natriuretic peptide reduction and peak neurohumoral activation within 72 h were comparable among treatment arms. There was a non‐significant trend towards lower all‐cause mortality or heart failure readmissions in the group receiving acetazolamide with low‐dose loop diuretics vs. high‐dose loop diuretic monotherapy (P = 0.098).
Conclusion
Addition of acetazolamide increases the natriuretic response to loop diuretics compared to an increase in loop diuretic dose in AHF at high risk for diuretic resistance.
Trial registration: ClinicalTrials.gov NCT01973335.
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