Category Archives: Lancet

A personalised or procrustean approach to treating hypertension?

A personalised or procrustean approach to treating hypertension?
Lancet. 2017 Jul 01;390(10089):26-27
Authors: Gabb GM, Mol PGM, Arnolda LF
PMID: 28677555 [PubMed – in process]

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Essential medicines are still essential.

Essential medicines are still essential.
Lancet. 2015 Oct 24;386(10004):1601-3
Authors: Gray AL, Wirtz VJ, ‘t Hoen EF, Reich MR, Hogerzeil HV
PMID: 26595616 [PubMed – in process]

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Gestational hypertension and advanced maternal age – Authors’ reply.

Gestational hypertension and advanced maternal age – Authors’ reply.
Lancet. 2015 Oct 24;386(10004):1628
Authors: Broekhuijsen K, Groen H, van den Berg PP, Mol BW, Franssen MT, Langenveld J, HYPITAT-II study group
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Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.

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Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.

Lancet. 2015 Oct 3;386(10001):1353-61

Authors: Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Coleman R, Powles T, Paterson A, Gnant M, Anderson S, Diel I, Gralow J, von Minckwitz G, Moebus V, Bergh J, Pritchard KI, Bliss J, Cameron D, Evans V, Pan H, Peto R, Bradley R, Gray R

Abstract
BACKGROUND: Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.
METHODS: We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).
FINDINGS: We received data on 18,766 women (18,206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02).
INTERPRETATION: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.
FUNDING: Cancer Research UK, Medical Research Council.

PMID: 26211824 [PubMed – indexed for MEDLINE]

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Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.

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Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials.

Lancet. 2015 Oct 3;386(10001):1341-52

Authors: Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Dowsett M, Forbes JF, Bradley R, Ingle J, Aihara T, Bliss J, Boccardo F, Coates A, Coombes RC, Cuzick J, Dubsky P, Gnant M, Kaufmann M, Kilburn L, Perrone F, Rea D, Thürlimann B, van de Velde C, Pan H, Peto R, Davies C, Gray R

Abstract
BACKGROUND: The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.
METHODS: We undertook meta-analyses of individual data on 31,920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).
FINDINGS: In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar.
INTERPRETATION: Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment.
FUNDING: Cancer Research UK, Medical Research Council.

PMID: 26211827 [PubMed – indexed for MEDLINE]

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Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

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Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled…

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Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study.

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Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study.

Lancet. 2015 Oct 16;

Authors: Cleynen…

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Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial.

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Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial.

Lancet. 2015 Sep…

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Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study.

Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study.

Lancet. 2015 Sep 3;

Authors: Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, Hennermann JB, Jameson E, König K, McGregor TL, Font-Montgomery E, Santamaria-Araujo JA, Santra S, Vaidya M, Vierzig A, Wassmer E, Weis I, Wong FY, Veldman A, Schwarz G

Abstract
BACKGROUND: Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor.
METHODS: In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP.
FINDINGS: Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease.
INTERPRETATION: cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit.
FUNDING: German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

PMID: 26343839 [PubMed – as supplied by publisher]

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Identification of novel biomarkers in plasma for prediction of treatment response in patients with heart failure.

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Identification of novel biomarkers in plasma for prediction of treatment response in patients with heart failure.

Lancet. 2015 Feb 26;385 Suppl 1:S26

Authors: Cao TH, Quinn PA, Sandhu JK, Voors AA, Lang CC, Parry HM, Mohan M, Jones DJ, Ng LL

Abstract
BACKGROUND: Heart failure is a complex clinical syndrome that occurs at the end stage of heart disease. Despite advances in therapy for heart failure, improvement of clinical outcomes remains a challenge for physicians. The identification of treatment response early in the course of disease would be useful to improve management of these patients. The aim of this study was to identify novel biomarkers in plasma that could predict treatment response in patients with heart failure.
METHODS: Patients with heart failure who met inclusion and exclusion criteria according to the guidelines of the European Society of Cardiology were recruited. Uptitration of angiotensin-converting enzyme inhibitors and β blockers was performed over 6 months. Patients were followed up for clinical events within the next 24 months. Plasma proteins in patients who responded to standard treatment (responders) were compared with patients who died or were re-admitted for heart failure (non-responders). Plasma samples were depleted of 14 high abundance proteins with a multiple affinity removal system column (MARS). Then plasma samples were analysed on two-dimensional liquid chromatography coupled to a tandem mass spectrometry (2D LC-ESI-MS/MS) in high definition mode (HDMS(E)) to identify and quantify the different expression of proteins in plasma. Finally, ELISA was used to verify candidate biomarkers.
FINDINGS: Participants were 100 patients with heart failure matched for sex and age (50 responders [25 women], 50 non-responders [25 women], mean age 76·6 years [SD 8·1]). Of the non-responders, 18 died and 32 were re-admitted to hospital. 2D LC-ESI-MS/MS showed that the expression of neurotrimin (NTM) was highly upregulated, by 26·5 times (p<0·0001), in the responder group compared with the non-responder group. ELISA in the verification phase showed that the concentrations of NTM in plasma were significantly higher in the responders and lower in the non-responders (mean 4·73 log10 relative light units [SD 0·07] vs 4·70 [0·08], p=0·036). When ANOVA with Bonferroni post-hoc comparisons was used in three outcome subgroups (responders, patients re-admitted to hospital, and deaths), NTM concentrations were significantly different between death and the other groups (higher in responder vs death group, p<0·0001; higher in re-admission vs death group, p=0·001).
INTERPRETATION: Our findings suggest that NTM as a novel biomarker in heart failure will not only add information to understand the pathophysiological mechanisms of heart failure better, but also might provide a more accurate prediction of treatment response to guide medical therapy. In addition, a novel therapeutic target could be identified for design of drugs to improve outcomes. Futher work is required in larger populations to confirm this biomarker.
FUNDING: European Union’s Seventh Framework Programme (BIOSTAT-CHF), John and Lucille van Geest Foundation.

PMID: 26312848 [PubMed – as supplied by publisher]

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ISAT: end of the debate on coiling versus clipping?

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ISAT: end of the debate on coiling versus clipping?
Lancet. 2015 Jun 6;385(9984):2251
Authors: Bakker NA, Veeger NJ, Van Dijk JM
PMID: 26088494 [PubMed – in process]

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Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial.

Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial.

Lancet. 2015 Mar 24;

Authors: Broekhuijsen K, van Baaren GJ, van Pampus MG, Ganzevoort W, Sikkema JM, Woiski MD, Oudijk MA, Bloemenkamp KW, Scheepers HC, Bremer HA, Rijnders RJ, van Loon AJ, Perquin DA, Sporken JM, Papatsonis DN, van Huizen ME, Vredevoogd CB, Brons JT, Kaplan M, van Kaam AH, Groen H, Porath MM, van den Berg PP, Mol BW, Franssen MT, Langenveld J, HYPITAT-II study group

Abstract
BACKGROUND: There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women.
METHODS: We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792).
FINDINGS: Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred.
INTERPRETATION: For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered.
FUNDING: ZonMw.

PMID: 25817374 [PubMed – as supplied by publisher]

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2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial.

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2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial.

Lancet. 2015 Mar 4;

Authors: Lees CC, Marlow N, van Wassenaer-Leemhuis A, Arabin B, Bilardo CM, Brezinka C, Calvert S, Derks JB, Diemert A, Duvekot JJ, Ferrazzi E, Frusca T, Ganzevoort W, Hecher K, Martinelli P, Ostermayer E, Papageorghiou AT, Schlembach D, Schneider KT, Thilaganathan B, Todros T, Valcamonico A, Visser GH, Wolf H, for the TRUFFLE study group

Abstract
BACKGROUND: No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction. We aimed to assess whether changes in the fetal ductus venosus Doppler waveform (DV) could be used as indications for delivery instead of cardiotocography short-term variation (STV).
METHODS: In this prospective, European multicentre, unblinded, randomised study, we included women with singleton fetuses at 26-32 weeks of gestation who had very preterm fetal growth restriction (ie, low abdominal circumference [<10th percentile] and a high umbilical artery Doppler pulsatility index [>95th percentile]). We randomly allocated women 1:1:1, with randomly sized blocks and stratified by participating centre and gestational age (<29 weeks vs ≥29 weeks), to three timing of delivery plans, which differed according to antenatal monitoring strategies: reduced cardiotocograph fetal heart rate STV (CTG STV), early DV changes (pulsatility index >95th percentile; DV p95), or late DV changes (A wave [the deflection within the venous waveform signifying atrial contraction] at or below baseline; DV no A). The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85, at 2 years of age. We assessed outcomes in surviving infants with known outcomes at 2 years. We did an intention to treat study for all participants for whom we had data. Safety outcomes were deaths in utero and neonatal deaths and were assessed in all randomly allocated women. This study is registered with ISRCTN, number 56204499.
FINDINGS: Between Jan 1, 2005 and Oct 1, 2010, 503 of 542 eligible women were randomly allocated to monitoring groups (166 to CTG STV, 167 to DV p95, and 170 to DV no A). The median gestational age at delivery was 30·7 weeks (IQR 26·1-40·6) and mean birthweight was 1019 g (SD 322). The proportion of infants surviving without neuroimpairment did not differ between the CTG STV (111 [77%] of 144 infants with known outcome), DV p95 (119 [84%] of 142), and DV no A (133 [85%] of 157) groups (ptrend=0·09). 12 fetuses (2%) died in utero and 27 (6%) neonatal deaths occurred. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes (133 [95%] of 144, 95%, 95% CI 90-98) were free of neuroimpairment when compared with those randomly assigned to CTG (111 [85%] of 131, 95% CI 78-90; p=0.005), but this was accompanied by a non-significant increase in perinatal and infant mortality.
INTERPRETATION: Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age.
FUNDING: ZonMw, The Netherlands and Dr Hans Ludwig Geisenhofer Foundation, Germany.

PMID: 25747582 [PubMed – as supplied by publisher]

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β blockers, atrial fibrillation, and heart failure.

β blockers, atrial fibrillation, and heart failure.

Lancet. 2015 Dec 20;384(9961):2181-2183

Authors: McMurray JJ, van Veldhuisen DJ

PMID: 25625384 [PubMed – as supplied by publisher]

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Prosopometamorphopsia and facial hallucinations.

Prosopometamorphopsia and facial hallucinations.
Lancet. 2014 Nov 29;384(9958):1998
Authors: Blom JD, Sommer IE, Koops S, Sacks OW
PMID: 25435453 [PubMed – in process]

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Chronic whiplash-associated disorders.

Chronic whiplash-associated disorders.
Lancet. 2014 Oct 11;384(9951):1346
Authors: Otte A, Garcia DV, Dierckx RA, Holstege G
PMID: 25307840 [PubMed – in process]

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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

Lancet. 2014 Sep 24;

Authors: Swerdlow DI, Preiss D, Kuchenbaecker KB, Holmes MV, Engmann JE, Shah T, Sofat R, Stender S, Johnson PC, Scott RA, Leusink M, Verweij N, Sharp SJ, Guo Y, Giambartolomei C, Chung C, Peasey A, Amuzu A, Li K, Palmen J, Howard P, Cooper JA, Drenos F, Li YR, Lowe G, Gallacher J, Stewart MC, Tzoulaki I, Buxbaum SG, van der A DL, Forouhi NG, Onland-Moret NC, van der Schouw YT, Schnabel RB, Hubacek JA, Kubinova R, Baceviciene M, Tamosiunas A, Pajak A, Topor-Madry R, Stepaniak U, Malyutina S, Baldassarre D, Sennblad B, Tremoli E, de Faire U, Veglia F, Ford I, Jukema JW, Westendorp RG, de Borst GJ, de Jong PA, Algra A, Spiering W, der Zee AH, Klungel OH, de Boer A, Doevendans PA, Eaton CB, Robinson JG, Duggan D, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, Kjekshus J, Downs JR, Gotto AM, Keech AC, Marchioli R, Tognoni G, Sever PS, Poulter NR, Waters DD, Pedersen TR, Amarenco P, Nakamura H, McMurray JJ, Lewsey JD, Chasman DI, Ridker PM, Maggioni AP, Tavazzi L, Ray KK, Seshasai SR, Manson JE, Price JF, Whincup PH, Morris RW, Lawlor DA, Smith GD, Ben-Shlomo Y, Schreiner PJ, Fornage M, Siscovick DS, Cushman M, Kumari M, Wareham NJ, Verschuren WM, Redline S, Patel SR, Whittaker JC, Hamsten A, Delaney JA, Dale C, Gaunt TR, Wong A, Kuh D, Hardy R, Kathiresan S, Castillo BA, van der Harst P, Brunner EJ, Tybjaerg-Hansen A, Marmot MG, Krauss RM, Tsai M, Coresh J, Hoogeveen RC, Psaty BM, Lange LA, Hakonarson H, Dudbridge F, Humphries SE, Talmud PJ, Kivimäki M, Timpson NJ, Langenberg C, Asselbergs FW, Voevoda M, Bobak M, Pikhart H, Wilson JG, Reiner AP, Keating BJ, Hingorani AD, Sattar N

Abstract
BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).
INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
FUNDING: The funding sources are cited at the end of the paper.

PMID: 25262344 [PubMed – as supplied by publisher]

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Cognitive therapy for patients with schizophrenia.

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Cognitive therapy for patients with schizophrenia.
Lancet. 2014 Aug 2;384(9941):400
Authors: Coyne JC, van Linschoten HS
PMID: 25088854 [PubMed – indexed for MEDLINE]

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Risk factors and early origins of chronic obstructive pulmonary disease.

Risk factors and early origins of chronic obstructive pulmonary disease.
Lancet. 2014 Aug 11;
Authors: Postma DS, Bush A, van den Berge M
Abstract
Chronic obstructive pulmonary disease is mainly a smo… Continue reading

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Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

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