Clinical Management of Dialysis Catheter-Related.x

Ann.N.Y.Acad.Sci.ISSN0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue:The Year in Diabetes and ObesityCardiovascular disease and glycemic control in type2 diabetes:now that the dust is settling from largeclinical trialsFrancesco Giorgino,Anna Leonardini,and Luigi LaviolaDepartment of Emergency and Organ Transplantation,Section of Internal Medicine,Endocrinology,Andrology and Metabolic Diseases,University of Bari Aldo Moro,Bari,ItalyAddress for correspondence:Francesco Giorgino,M.D.,Ph.D.,Department of Emergency and Organ Transplantation, Section of Internal Medicine,Endocrinology,Andrology and Metabolic Diseases,University of Bari Aldo Moro,Piazza Giulio Cesare,11,I-70124Bari,Italy.francesco.giorgino@uniba.itThe relationship between glucose control and cardiovascular outcomes in type2diabetes has been a matter of controversy over the years.Although epidemiological evidence exists in favor of an adverse role of poor glucose control on cardiovascular events,intervention trials have been less conclusive.The Action to Control Cardiovascular Risk in Diabetes(ACCORD)study,the Action in Diabetes and Vascular Disease(ADV ANCE)study,and the Veterans Affairs Diabetes Trial(V ADT)have shown no beneficial effect of intensive glucose control on primary cardiovascular endpoints in type2diabetes.However,subgroup analysis has provided evidence suggesting that the potential beneficial effect largely depends on patients’characteristics,including age,diabetes duration,previous glucose control,presence of cardiovascular disease,and risk of hypoglycemia.The benefit of strict glucose control on cardiovascular outcomes and mortality may be indeed hampered by the extent and frequency of hypoglycemic events and could be enhanced if glucose-lowering medications,capable of exerting favorable effects on the cardiovascular system,were used.This review examines the relationship between intensive glucose control and cardiovascular outcomes in type2diabetes,addressing the need for individualization of glucose targets and careful consideration of the benefit/risk profile of antidiabetes medications.Keywords:type2diabetes;HbA1c;macrovascular disease;blood pressure;lipids;hypoglycemia;glucagon-like peptide-1;ADV ANCE;ACCORD;V ADTIntroductionCardiovascular disease(CVD)is the major cause of death in patients with type2diabetes(T2D), as more than60%of T2D patients die of my-ocardial infarction(MI)or stroke,and an even greater proportion of patients have serious burden-some complications.1The impact of glucose low-ering on cardiovascular complications is a hotly debated issue.The United Kingdom Prospective Di-abetes Study(UKPDS)was thefirst clinical trial to provide key evidence of the importance of using in-tensive therapy for diabetes control in individuals with newly diagnosed T2D.However,although the insulin or sulphonylurea-based intensified glucose-control treatment was effective in reducing the risk of major microvascular endpoints,the effects on CVD risk were modest and did not reach statisti-cal significance.2Recent large clinical trials(often referred to as“megatrials”),the Action in Diabetes and Vascular Disease(ADV ANCE),3Action to Con-trol Cardiovascular Risk in Diabetes(ACCORD),4 and the Veterans Affairs Diabetes Trial(V ADT),5 reported no significant decrease in primary cardio-vascular endpoints with intensive glucose control. In the ADV ANCE study,11,140type2diabet-ics were randomly assigned to receive either stan-dard or intensive glucose control,defined as the use of gliclazide plus any other drug required to achieve a glycosylated hemoglobin(HbA1c)level of 6.5%or less(Table1).3After a median follow-up of 5.0years,the mean HbA1c was lower in thedoi:10.1111/nyas.12044Giorgino et al.Intensive glucose control and cardiovascular risk Table1.Age,diabetes duration,median follow-up,HbA1c values,and outcomes in the ACCORD and ADV ANCE studies and the V ADTDiabetes HbA1c(%):duration(year):Median intensive Primary All-cause Age intensive follow-up History versus endpoint HR mortality HR Study(year)versus standard(year)of CVD standard Primary endpoint(95%CI)(95%CI)ACCORD(n=10,251)62.2±6.810vs.10 3.435% 6.4vs.7.5Nonfatal MI,nonfatalstroke,or death fromCVD0.90(0.78–1.04) 1.22(1.01–1.46)ADV ANCE (n=11,140)66±6.08.0±6.4vs.7.9±6.35.032%6.53±0.91vs.7.30±1.26Death fromcardiovascular causes,nonfatal MI,ornonfatal stroke0.94(0.84–1.06)0.93(0.83–1.06)V ADT(n=1,791)60±9.011.5±8vs.11.5±75.640%6.9vs.8.4MI,stroke,death fromCVD,CHF,surgery forvascular disease,inoperable CAD,oramputation forischemic gangrene0.88(0.74–1.05) 1.07(0.81–1.42)intensive control group(6.5%vs.7.3%),with a reduction in the incidence of combined major macrovascular and microvascular events primarily because of a reduction in the incidence of nephropa-thy.There were no significant effects of the inten-sive glucose control on major macrovascular events, death from cardiovascular causes,or death from any cause.Similarly,in the V ADT,1,791suboptimally controlled type2diabetics,40%with established CVD,were randomized to receive either intensive glucose control,targeting an absolute reduction of 1.5%in HbA1c levels,or standard glucose control (Table1).5After a median follow-up of5.6years, HbA1c was lower in the intensive-therapy group (6.9%vs.8.4%).Nevertheless,there was no sig-nificant difference between the two groups in the incidence of major cardiovascular events,or in the rate of death from any cause.ACCORD was another study designed to determine whether intensive glu-cose control would reduce the rate of cardiovas-cular events(Table1).4In this study,10,251type 2diabetics with median baseline HbA1c of8.1% were randomly assigned to receive either intensive therapy targeting an HbA1c level within the normal range,that is,below6.0%,or standard therapy tar-geting HbA1c between7.0%and7.9%.The primary outcome was a composite of nonfatal MI,nonfatal stroke,or death from cardiovascular causes.Even though the rate of nonfatal MI was significantly lower in the intensive therapy arm,thefinding of higher all-cause and cardiovascular cause mortal-ity in this group led to discontinuation of the in-tensive therapy after a mean follow-up of3.5years (Fig.1).Notably,hypoglycemia requiring assistance and weight gain of more than10kg were more fre-quent in the intensive therapy group.The results of the ACCORD study raised concern about not only the effectiveness but also the safety of inten-sive glycemic control in type2diabetics.Prespec-ified subgroup analysis of the participants in this trial suggested that patients in the intensive group without history of cardiovascular event before ran-domization or whose baseline HbA1c level was8.0% or less may have had fewer fatal or nonfatal car-diovascular events than did patients in the standard therapy group.Several recent meta-analyses of randomized con-trolled trials have also investigated the effects of intensive glucose lowering on all-cause mortal-ity,cardiovascular death,and vascular events in T2D.6–10In the largest and most recent meta-analysis by Boussageon et al.,13studies were in-cluded.6Of the34,533patients evaluated,18,315 received intensive glucose-lowering treatment and 16,218standard treatment.Intensive treatment did not significantly affect all-cause mortality or cardiovascular death.The results of this meta-analysis showed limited benefit of intensive glucose-lowering therapy on all-cause mortality and deaths from cardiovascular causes,and a10%reduction in the risk of microalbuminuria.6Results from other meta-analyses have also shown no effects ofIntensive glucose control and cardiovascular risk Giorgino etal.Figure 1.Effects of intensive glucose control on all-cause and cardiovascular mortality and myocardial infarction in the ACCORD study.CV,cardiovascular.∗P<0.05.Adapted from Ref.4.intensive glucose control on all-cause or cardiovas-cular mortality,while indicating a modest15–17% reduction in the incidence of nonfatal MI in these cohorts.7–10Several potential factors could have contributed to limit the potential benefit of intensive glucose-lowering therapies on CVD prevention in T2D in-dividuals in studies such as the ACCORD and AD-V ANCE and the V ADT:(1)Concomitant targeting of other potentiallymore potent cardiovascular risk factors,suchas blood pressure and lipids,might havedampened the favorable effects of controllinghyperglycemia.(2)Intensive control of hyperglycemia could havebeen directed to patients unable to exhibit theexpected benefit due to their specific clinicalcharacteristics(“wrong”patients).(3)Limited benefit might have derived from usingglucose-lowering drugs with no favorable im-pact on the global cardiovascular risk profile.(4)Glucose-lowering drugs might have producedadverse effects on the cardiovascular systemby inducing weight gain and hypoglycemicevents,resulting in somewhat increased riskfor CVD and mortality(“imperfect”drugs).(5)Excess mortality might have potentially re-sulted from using too many drugs and/or toocomplex drug regimens,leading to undesir-able drug–drug interactions with a potentiallyharmful impact on patients’health.These diverse factors and their potential role in the relationship between intensive glucose control and CVD/mortality are outlined in Figure2,and will be discussed individually below.Limited benefit due to other therapies Although several studies have focused on intensive glycemic control to decrease the risks of macrovas-cular and microvascular diseases in T2D,glucose control is only one of the factors to be considered. Comprehensive risk factor management,including blood pressure control,lipid management,weight reduction in overweight or obese individuals,and smoking cessation,are also needed.The results of the ACCORD and ADV ANCE studies and the V ADT should be interpreted in the context of comprehen-sive care of patients with diabetes.Interventions for simultaneous optimal control of comorbidities of-ten present in type2diabetics,such as hyperten-sion and hyperlipidemia,have been shown to be a more effective strategy in reducing cardiovascular risk than targeting only blood glucose levels per se.11 Evidence for an aggressive approach to lipid and blood pressure control was supported by the re-sults from the Steno-2study.11,12In Steno-2,inves-tigators used intensified multifactorial intervention with improved glycemia,renin–angiotensin system blockers,aspirin,and lipid-lowering agents and evaluated whether this approach would have an ef-fect on the rates of death from cardiovascular causes and from any cause.11,12The primary endpoint at 13.3years of follow-up was the time to death from any cause.Intensive therapy was also associated with a significantly lower risk of death from cardiovascu-lar causes and of cardiovascular events.The Steno-2study did demonstrate a difference in levels of glycemia achieved when compared with the AC-CORD study:4,11HbA1c was a mean of8.4%at study entry and7.9%at end of study intervention for the intensively treated group,whereas it was8.8%at baseline and9.0%at study end for conventional treatment.In addition,only a limited proportion of subjects in the intensively treated group reached an HbA1c level of less than6.5%(i.e.,∼15%),and this proportion was not statistically different than in the conventionally treated group,indicating poor success in achieving the prespecified glucose target and somewhat reducing the relevance of the spe-cific intervention on the hyperglycemia component for CVD and microvascular disease prevention.The observational study has continued,and the differ-ences observed in glycemia between intensive andGiorgino et al.Intensive glucose control and cardiovascularriskFigure2.Relationship between intensive glucose control and cardiovascular outcomes and mortality in the ACCORD study and other megatrials.The potential mechanisms affecting this relationship and limiting the clinical benefit are outlined in the box on the left.CV,cardiovascular;CVD,cardiovascular disease.conventional treatments are much less than at endof intervention.Nevertheless,over the long-termperiod of follow-up,intensive intervention with avaried drug regimen and lifestyle modification hadsustained beneficial effects with respect to vascularcomplications and rates of death from any cause andfrom cardiovascular causes.12Blood pressureThe ACCORD study also had an embedded bloodpressure trial that examined whether blood pressurelowering to systolic blood pressure(SBP)less than120mm Hg provided greater cardiovascular protec-tion than a SBP of130–140mm Hg in T2D patientsat high risk for CVD.13A total of4,733participantswere randomly assigned to intensive therapy(SBP <120mm Hg)or standard therapy(SBP<140mm Hg),with the mean follow-up being4.7years.Theblood pressure levels achieved in the intensive andstandard groups were119/64mm Hg and133/70mm Hg,respectively;this difference was attainedwith an average of3.4medications per participantin the intensive group and2.1in the standard ther-apy group.The intensive antihypertensive therapyin the ACCORD blood pressure trial did not consid-erably reduce the primary cardiovascular outcomeor the rate of death from any cause.However,theintensive arm of blood pressure control reduced therate of total stroke and nonfatal stroke,with the estimated number needed to treat with intensive blood pressure therapy to prevent one stroke over five years being89.There were indicators of possi-ble harm associated with intensive blood pressure lowering(SBP<120mm Hg),including a rate of serious adverse events in the intensive arm.It should be noted that of the subjects investigated in the ACCORD glucose control trial∼85%were on antihypertensive medications,and their blood pres-sure levels were126.4/66.9and127.4/67.7in the intensive and standard groups,respectively,a differ-ence that was statistically significant(P<0.001) (Table2).4Thus,the effects of intensive glucose lowering on the CVD and other outcomes were ex-amined in a context in which blood pressure was being actively targeted,with possible differences between the intensively and conventionally treated cohorts.The ADV ANCE study also included a blood pres-sure intervention trial.In this study,treatment with an angiotensin converting enzyme(ACE)inhibitor and a thiazide-type diuretic reduced the rate of death but not the composite macrovascular out-come.However,this trial had no specified targets for the randomized comparison,and the mean SBP in the intensive group(135mm Hg)was not as low as the mean SBP in the ACCORD standard-therapy group.14However,a post hoc analysis of blood pres-sure control in6,400patients with diabetes andIntensive glucose control and cardiovascular risk Giorgino et al. Table2.Blood pressure and lipid levels and use of statin,antihypertensive medications,and aspirin in the ACCORD and ADV ANCE studies and the V ADT participants at study end(adapted from Refs.3–5)ACCORD(n=10,251)aADV ANCE(n=11,140)b V ADT(n=1,791)cStandard Intensive Standard Intensive Standard Intensive Blood pressure(mm Hg)Systolic128±16126±17137±18135±17125±15127±16 Diastolic68±1067±1074±1073±1069±1068±10 Cholesterol(mg/dL)LDL87±3387±33103±41102±3880±3180±33 HDL49±13(♂)49±13(♂)48±1448±1441±1240±1140±11(♀)40±10(♀)Total164±42163±42153±40150±40 Triglycerides(mg/dL)166±114160±125161±102151±94159±104151±173 On statin(%)888848468385 On antihypertensivemedications(%)858389887576 On aspirin(%)767655578586a Intensive(target HbA1c<6%)vs.standard(HbA1c7–7.9%).b Intensive(target HbA1c<6.5%)vs.standard(HbA1c>6.5%).c Intensive(target HbA1c4.8–6.0%)vs.standard(HbA1c8–9.0%).Abbreviations:HDL,high-density lipoprotein;LDL,low-density lipoprotein;♂,men;♀,women.coronary artery disease enrolled in the International Verapamil/Trandolapril Study(INVEST)demon-strated that tight control(<130mm Hg)was not associated with improved cardiovascular outcomes compared with usual care(130–140mm Hg).15In the V ADT,blood pressure,lipids,diet,and lifestyle were treated identically in both arms.By improving blood pressure control in an identical manner in both glucose arms,the V ADT excluded the effect of blood pressure differences on cardiovas-cular events between treatment arms and reduced the overall risk of macrovascular complications dur-ing the trial.5Participants in the V ADT(n=1,791) with hypertension(72.1%of total)received stepped treatment to maintain blood pressure below the tar-get of130/80mm Hg in standard and intensive glycemic treatment groups.Blood pressure levels of all subjects at baseline and on-study were analyzed to detect associations with cardiovascular risk.The primary outcome was the time from randomiza-tion to thefirst occurrence of MI,stroke,conges-tive heart failure,surgery for vascular disease,in-operable coronary disease,amputation for ischemic gangrene,or cardiovascular death.From data analy-sis,increased risk of cardiovascular events with SBP ≥140mm Hg emphasizes the need for treatment of systolic hypertension.Also,this study for the first time demonstrated that diastolic blood pressure (DBP)<70mm Hg in T2D patients was indepen-dently associated with elevated cardiovascular risk, even when SBP was on target.16Lipid profileIt has been widely demonstrated that intensive targeting of low-density lipoprotein(LDL)choles-terol contributes to CVD prevention in T2D.As a consequence,most guidelines suggest a target LDL-cholesterol level below100mg/dL as the primary goal in T2D individuals,with the option of achieving an LDL-cholesterol level below70mg/dL in those with overt CVD.Regarding the overall lipid-lowering approach in the ACCORD glucose control study,it should be observed that mean LDL cholesterol was below90mg/dL in both the intensive and standard glucose control arms,and that88%of subjects were on statin therapy.4Thus, the results from this study do not clarify whether lipid control and glycemic control,respectively,areGiorgino et al.Intensive glucose control and cardiovascularriskFigure3.All-cause mortality in intensive versus standard glycemia groups according to use of antihypertensive medications, statins,and aspirin in the ACCORD and ADV ANCE studies.∗P=0.0305for subjects on aspirin versus subjects not on aspirin. Adapted from Refs.3and18.related or synergistic,since the large majority of enrolled subjects were already receiving a lipid control regimen.Data from the Steno-2trial on combined control of glucose,lipids,and blood pressure levels demonstrated significant short-and long-term benefits from this multifactorial approach.11In the study,the effect seemed to be cumulative rather than synergistic.Recent results from the ACCORD-LIPID study indicate that intensive lipid control(i.e.,addition of afibrate to statin therapy)does not reduce car-diovascular events.17Specifically,the lipid-lowering arm of ACCORD failed to demonstrate any ben-efit of add-on therapy with fenofibrate to LDL-lowering treatment with HMG-CoA reductase in-hibitors(statins)on vascular outcomes in patients with diabetes.However,data from earlier studies and from a subgroup analysis of ACCORD indi-cate a probable benefit of adding treatment with fibric acid derivatives to individuals with persis-tently elevated triglyceride levels and low high-density lipoprotein(HDL)cholesterol despite statin therapy.17In the ACCORD and ADV ANCE studies and the V ADT,a large proportion of subjects,ranging from55%to85%,were also treated with aspirin (Table2).Thus,results from ADV ANCE,ACCORD, and V ADT suggest that a large proportion of par-ticipants in these trials,which were being treated intensively or less intensively for glucose targets, received extensive antihypertensive,lipid-lowering, and antiplatelet medications.Median levels of SBP, SDP,and LDL cholesterol in these cohorts were also indicative of a significant proportion of them be-ing adequately controlled for blood pressure and lipid targets(Table2).Therefore,the possibility ex-ists that active interventions for simultaneous con-trol of hypertension and hyperlipidemia and use of aspirin may have affected the impact of intensive glucose control on cardiovascular outcomes in the megatrials.Subgroups analyses,however,do not ap-parently support this conclusion(Fig.3).Whether patients were on antihypertensive or lipid-lowering medications was not associated with a different out-come of the intensive glucose control on mortality in ACCORD and ADV ANCE patients,even thoughIntensive glucose control and cardiovascular risk Giorgino et al.the different groups were largely unbalanced in size. Only aspirin use in the ACCORD study seemed to modulate the effects of intensive versus standard glucose control on mortality.18The“wrong patient”concept and the need for individualization of glucose targets The ADV ANCE and ACCORD studies and the V ADT provide conflicting evidence of mortality risk with intensive glycemic control.These trials showed an approximate15%reduction in nonfatal MI with no benefit or harm in all-cause or cardiovascular mortality.Potential explanations for the lack of im-pact of intensive glycemic control on CVD can be found in the patients’characteristics.Indeed,these studies were of shorter duration and enrolled gener-ally older patients than previous studies,including the DCCT and UKPDS in which the intensive con-trol had shown better outcomes.In addition,mean diabetes duration was longer and a greater portion of patients had established CV disease in the mega-trials(approximately32–40%)than in earlier trials (Table1).It is also possible that the follow-up of these studies was too short to detect a clinical ben-efit.Consistent with this hypothesis,in the UKPDS no macrovascular benefit was noted in the inten-sive control arm in thefirst10years of follow-up. Nevertheless,posttrial monitoring for an additional 10years(UKPDS80)revealed a15%risk reduction in MI and13%reduction in all-cause mortality in the intensive treatment group.19A possible explanation is that the wrong patients were investigated in the megatrials(Fig.2).Indeed, the population of the ACCORD study may not rep-resent the average patient with T2D in clinical prac-tice.Participants in this trial had T2D on average for10years at the time of enrollment,had higher HbA1c levels than most type2diabetic patients in the United States and most Western countries to-day(average of8.2%at baseline),and had known heart disease or at least two risk factors in addi-tion to diabetes,such as high blood pressure,high cholesterol levels,obesity,and smoking.4In the UKPDS,the benefits of intensive glycemic control on CVD were observed only after a long duration of intervention in newly diagnosed younger patients.2 In older patients with T2D with longer disease dura-tion,atherosclerotic disease may already have been established and thus intensive glucose control may have had little benefit.Conversely,patients with shorter disease duration,lower HbA1c,and/or lack of established CVD might have benefited signifi-cantly from more intensive glycemic control.20,21 Relevant to this concept,the V ADT showed that ad-vanced CVD,as demonstrated by computed tomog-raphy(CT)-detectable coronary artery calcium,was associated with negative outcomes.In a substudy co-hort of301T2D participants in V ADT,the ability of intensive glucose therapy compared with standard therapy to reduce cardiovascular events was exam-ined based on the extent of coronary atherosclerosis as measured by a CT-detectable coronary artery cal-cium score(CAC).The data showed that there was a progressive diminution of the benefit of intensive glucose control with increasing CAC.In patients with CAC≤100,1of52individuals experienced an event(HR for intensive therapy=0.08;range, 0.008–0.770;P=0.03),whereas11of62patients with a CAC>100had an event(HR=0.74;range, 0.46–1.20;P=0.21).Thus,this subgroup analy-sis indicates that intensive glycemic therapy may be most effective in those with less extensive coronary atherosclerosis.22Why does intensive treatment of hyperglycemia appear to be ineffective in reducing cardiovascular events in T2D with advanced atherosclerosis?Two potential mechanisms may be involved.First,once the atherosclerotic plaque has developed,modified lipoproteins,activated vascular cells,and altered im-mune cell signaling may generate a self-propagating process that maintains atherogenesis,even in the face of improved glucose control.Second,advanced glycosylation end-product formation,which may be involved in CVD,is not readily reversible and may require more than three tofive years of in-tensive glucose control to be reverted.Thus,the presence of multiple cardiovascular risk factors or established CVD may have reduced the benefits of intensive glycemic control in the high-risk cohort of ACCORD,ADV ANCE,and V ADT compared with the low-risk population of the UKPDS cohort,of whom only a minority had prior CVD.23The pres-ence of long-standing disease and prolonged prior poor glycemic control may be additional factors ac-celerating the progression of atherosclerotic lesions in T2D.The goal of individualizing HbA1c targets has gained more attraction after these recent clinical trials in older patients with established T2D failed to show a benefit from intensive glucose-loweringGiorgino et al.Intensive glucose control and cardiovascular riskTable3.Potential criteria for individualization of glucose targets in type2diabetes2–5,25,29HbA1c HbA1c Criterion<6.5–7.0%7.0–8.0% Age(years)<55>60 Diabetes duration(years)<10>10Life expectancy(years)>5<5 Possibility to performIGC for>5yearsYes No Usual HbA1c level(%)<8.0>8.0 CVD No Yes Prone to hypoglycemia No No Reduction of HbA1clevel upon IGCYes NoAbbreviations:CVD,cardiovascular disease;IGC,in-tensive glucose control.therapies on CVD outcomes.Recommendations suggest that the goals should be individualized,such that(1)certain populations(children,pregnant women,and elderly patients)require special con-siderations and(2)more stringent glycemic goals (i.e.,a normal HbA1c<6.0%)may further re-duce complications at the cost of increased risk of hypoglycemia.24For the latter,the recommen-dations also suggest that less intensive glycemic goals may be indicated in patients with severe or frequent hypoglycemia.With regard to the less intensive glycemic goals,perhaps consideration should be given to the high-risk patient with mul-tiple risk factors and CVD,as evaluated in the ACCORD study.4Thus,aiming for a HbA1c of 7.0–8.0%may be a reasonable goal in patients with very long duration of diabetes,history of se-vere hypoglycemia,advanced atherosclerosis,sig-nificant comorbidities,and advanced age/frailty (Table3),even though with what priority each one of these criteria should be considered is not clear at present(current recommendations from scientific societies also do not provide this spe-cific information).In younger patients without documented macrovascular disease or the above-mentioned conditions,the goal of attaining an HbA1c<6.5–7.0%may provide long-lasting bene-fits.In patients with limited life expectancy,more liberal HbA1c values may be pursued.In deter-mining the HbA1c target for CVD prevention,one should consider that at least three tofive years are usually required before possible differences in the incidence of nonfatal MI in T2D are observed.2 Thus,a clinical setting that allows tight glucose control to be implemented for this period of time should be available.Finally,an excess mortality was observed in the ACCORD study in those T2D in-dividuals who showed an unexpected increase in HbA1c levels upon institution of intensive glucose control.25Accordingly,patients exhibiting the pat-tern of worsening glycemic control when exposed to intensive treatment should be set at higher glucose targets(Table3).The above guidelines are apparently incorpo-rated into the updated version of the American Diabetes Association and the European Associa-tion for the Study of Diabetes recommendations on the management of hyperglycemia in nonpreg-nant adults with T2D.The new recommendations are less prescriptive and more patient centered.In-dividualized treatment is explicitly defined as the cornerstone of success.Treatment strategies should be tailored to individual patient needs,preferences, and tolerances and based on differences in age and disease course.Other factors affecting individual-ized treatment plans include specific symptoms,co-morbid conditions,weight,race/ethnicity,sex,and lifestyle.26Current“imperfect”glucose-lowering drugsThe inability of ACCORD,ADV ANCE,and V ADT to demonstrate significant reductions in CVD out-comes with intensive glycemic control also suggests that current pharmacological tools for treating hy-perglycemia in patients with more advanced T2D may have counterbalancing consequences for the cardiovascular system.The available agents used to treat diabetes have not been conclusively shown to reduce macrovascular disease and,in some in-stances,their chronic use may promote negative cardiovascular effects in diabetic subjects despite improvement of hyperglycemia.Importantly,these adverse cardiovascular side effects appear in several instances to be directly due to the mode of drug ac-tion.Selection of a treatment regimen for patients with T2D includes evaluation of the effects of med-ications on overall cardiovascular risk.27 Sulfonylureas have the benefit of acting rapidly to lower glucose levels but,unfortunately,on a。

dialysis 翻译基本解释●dialysis：透析●/daɪˈælɪsɪs/●n. 透析变化形式●n. 复数形式：dialyses具体用法●名词:o透析o同义词：hemodialysis, filtration, purification, separation, cleansingo反义词：contamination, pollution, impurity, mixture, combination o例句：●The patient underwent dialysis three times a week to removewaste products from his blood.（患者每周进行三次透析以去除血液中的废物。

）●Dialysis is a life-saving procedure for those with severe kidneyfailure.（透析是对严重肾衰竭患者的一种救命程序。

）●Many patients on dialysis need to follow a strict diet tomanage their condition.（许多透析患者需要遵循严格的饮食来管理他们的病情。

）●Advances in dialysis technology have improved the quality oflife for many patients.（透析技术的进步提高了许多患者的生活质量。

）●The hospital has a dedicated dialysis unit to cater to patientswith kidney issues.（医院有一个专门的透析部门来照顾肾脏问题的患者。

）●Dialysis can be performed at home or in a medical facility,depending on the patient's needs.（透析可以在家中或医疗设施中进行，具体取决于患者的需要。

临床药师参与1例心衰终末期合并利尿剂抵抗患者容量管理的体会杨　贤1，兰　希2，严思敏1，王文晓3，葛卫红1（1.南京大学医学院附属鼓楼医院药学部，江苏 南京 210008；2.南京大学医学院附属鼓楼医院心内科，江苏 南京 210008；3.青岛大学附属医院药学部，山东 青岛 266000）[摘要]　1例72岁男性患者，因“反复胸痛7年，胸闷气喘3年，加重1个月”入院，入院诊断为慢性心功能不全急性失代偿，陈旧性广泛前壁心肌梗死，冠状动脉支架植入后，急性肾功能不全。

临床药师评估后，认为患者存在容量超负荷并且合并利尿剂抵抗，建议将托拉塞米注射液由静脉滴注改为静脉持续输注。

同时联合小剂量多巴胺改善肾血流。

后患者存在低钠血症，药师建议加用托伐普坦片（15 mg ，qd ）纠正电解质紊乱。

出院前患者心衰症状好转，体质量较入院时有明显下降，血钠、血钾均恢复至正常范围。

[关键词]　临床药师；心力衰竭；容量管理；利尿剂抵抗；电解质；药学监护[中图分类号]　R969.4 [文献标识码]　A [文章编号]　1672 – 8157(2021)01 – 0017 – 04Experience of clinical pharmacists participating in the capacity management of a heart failure patient with diuretic resistanceYANG Xian 1, LAN Xi 2, YAN Si-min 1, WANG Wen-xiao 3, GE Wei-hong 1(1. Department of Pharmacy, Nanjing Drum TowerHospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; 2. Department of Cardiology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; 3. Department of Pharmacy, the Affiliated Hospital of Qingdao University, Qingdao 266000, China )[ABSTRACT]　One 72-year-old male patient was hospitalized because of repeated chest pain for 7 years, chest tightness andasthma for 3 years and aggravation for 1 month. The patient was diagnosed as acute decompensation for chronic heart failure, old extensive anterior myocardial infarction, post coronary stent implantation and acute renal insufficiency. After evaluation by the clinical pharmacist, the patient was considered to have capacity overload and diuretic resistance. Pharmacist suggested to use torasemide injection by continuously intravenous infusion instead of intravenous drip. At the same time, small doses of dopamine was also suggested to be used combined with torasemide to improve renal blood flow. And then tolvaptan tablets (15 mg, qd) were also advised to be given to him for correcting electrolyte turbulence. The patient's symptoms of heart failure improved, the body weight decreased significantly compared with that of admission, and the level of blood sodium and blood potassium all returned to the normal range before discharge.[KEY WORDS]　Clinical pharmacist; Heart failure; Capacity management; Diuretic resistance; Electrolyte; Pharmaceutical care·临床药师园地·[通信作者]　葛卫红，女，主任药师，研究方向：临床药学。

血清残余胆固醇水平对冠心病的影响及临床意义陈翠1，2，杨莉婷3，唐陶1，2，徐浩2，刘茂41.川北医学院附属医院遗传与产前诊断中心，四川南充637000；2.川北医学院检验医学院，四川南充637000；3.南充市中心医院检验科，四川南充637000；4.川北医学院附属医院心血管内科，四川南充637000【摘要】目的探讨血清残余胆固醇(RC)水平对冠心病的影响及其临床意义。

方法回顾性分析2019年6月至2020年6月因胸闷胸痛于川北医学院附属医院心内科住院行冠脉造影检查的230例患者的临床资料，根据冠脉造影结果分为冠心病组190例和非冠心病组40例(CON 组)，根据临床诊断标准又将冠心病患者分为稳定性心绞痛组(SAP 组)70例和急性冠脉综合征组(ACS 组)120例。

比较三组患者的一般资料和RC 水平，采用Spearman 秩相关分析RC 水平与Gensini 评分的相关性，采用多因素Logistic 回归分析影响冠心病发生的风险因素，绘制受试者工作特征曲线(ROC)分析RC 对冠心病发生的预测价值。

结果ACS 组、SAP 组和CON 组患者的性别、年龄、吸烟史、高血压史、LP(a)比较差异均无统计学意义(P >0.05)，但ACS 组和SAP 组患者的总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、载脂蛋白A (ApoA)、载脂蛋白B (ApoB)水平明显高于CON 组，而高密度脂蛋白胆固醇(HDL-C)水平明显低于CON 组，且ACS 组患者的TC 、LDL-C 、ApoB 水平明显高于SAP 组，差异均有统计学意义(P <0.05)；ACS 组和SAP 组患者的RC 水平分别为(0.98±0.37)mmol/L 、(0.86±0.23)mmol/L ，明显高于CON 组的(0.68±0.16)mmol/L ，且ACS 组的RC 水平明显高于SAP 组，差异均具有统计学意义(P <0.05)；经Spearman 秩相关分析结果显示，RC 水平与Gensini 评分呈正相关(P <0.05)；经多因素Logistic 回归分析结果显示，年龄、吸烟、RC 、LDL-C 、ApoA 为冠心病的独立危险因素(P <0.05)；经ROC 分析结果显示，血清RC 预测冠心病发生的曲线下面积(AUC)为0.755，灵敏性和特异性分别为53.20%和87.50%。

血液透析滤过质量控制临床实践指南英文回答：Blood dialysis is a common medical procedure used to remove waste products and excess fluid from the blood when the kidneys are unable to perform this function adequately. Quality control in blood dialysis is essential to ensure the safety and effectiveness of the procedure. Clinical practice guidelines provide recommendations on how to monitor and control the quality of blood dialysisfiltration.One important aspect of quality control in blood dialysis is the monitoring of the dialysis machine and equipment. Regular maintenance and calibration of the machine are crucial to ensure accurate and reliable filtration. This includes checking the pressure, temperature, and flow rate of the dialysate, as well as the functioning of the dialyzer. Any abnormalities or malfunctions should be promptly addressed to preventcomplications during the procedure.Another aspect of quality control is the monitoring of the dialysis prescription. The prescription includes parameters such as the duration and frequency of dialysis, the dialysate composition, and the blood flow rate. It is important to ensure that the prescription is tailored to the individual patient's needs and that it is followed accurately during each dialysis session. Regular review of the prescription by the healthcare team is essential to make any necessary adjustments based on the patient's condition and response to treatment.Monitoring the adequacy of dialysis is also a key component of quality control. This involves assessing the removal of waste products and excess fluid from the blood. The most commonly used parameter to evaluate dialysis adequacy is the Kt/V, which measures the clearance of urea during a dialysis session. Regular measurement of Kt/V helps to ensure that the dialysis is effectively removing waste products from the blood. Other parameters, such as the reduction ratio of urea and the ultrafiltration rate,can also be used to assess dialysis adequacy.In addition to these technical aspects, quality control in blood dialysis also includes the monitoring of patient outcomes. This involves assessing the patient's overall well-being, including their symptoms, laboratory values, and overall quality of life. Regular follow-up appointments and communication with the healthcare team are important to address any issues or concerns that may arise during or after dialysis.Overall, quality control in blood dialysis is essential to ensure the safety and effectiveness of the procedure. It involves monitoring the dialysis machine and equipment, following the dialysis prescription accurately, assessing dialysis adequacy, and monitoring patient outcomes. By implementing these quality control measures, healthcare providers can provide optimal care to patients undergoing blood dialysis.中文回答：血液透析是一种常见的医疗程序，用于在肾脏无法充分执行此功能时，从血液中去除废物和多余的液体。

E-mail:zgqkyx@·2017··证据·标准·指南·【编者按】　营养干预是糖尿病综合管理的核心和基石。

而在我国临床营养师广泛缺位的背景下，营养干预的重任更多落在糖尿病专科医生和全科医生身上。

全科医生在糖尿病患者的连续性综合管理中的特殊地位，使其成为我国糖尿病营养干预的主力军。

这也对我国全科医生的糖尿病营养知识和技能提出了较高的要求。

2018年3月英国糖尿病协会（Diabetes UK）更新的糖尿病营养指南在为其本国全科医生提供工作指南的同时，对我国全科医生也具有借鉴意义。

本文结合国内指南和临床实践特点对该版本英国指南主要内容进行介绍，以期为我国全科医生的糖尿病临床营养实践提供参考。

程改平　四川大学华西医院临床营养科主管技师，医学硕士。

四川省预防医学会妇幼分会委员。

长期从事临床营养工作和营养教学，包括营养状况评估、临床营养治疗、营养教育等；擅长内分泌代谢疾病临床营养治疗、体质量管理等。

参编医学教材《医疗膳食学》《公共营养学》《疾病与营养》等；作为主研人员参与多项省部级科研课题、核心期刊发表营养相关论文多篇。

2018年《英国基于证据的预防管理糖尿病营养指南》解读程改平1，李舍予2，胡雯1*【摘要】　2018年3月，英国糖尿病协会发布《英国基于证据的预防管理糖尿病营养指南》。

该指南建立在2011年指南基础上，主要基于食物而非营养素提出建议，内容包括教育和治疗实施模式、2型糖尿病预防、心血管疾病风险管理、糖尿病并发症管理和其他问题（包括合并症、营养支持、妊娠期和哺乳期、进食障碍、微量营养素、食物补充剂、功能性食品、商业性糖尿病食品，以及营养性和非营养性甜味剂）等内容。

本文对部分内容并结合我国全科医生实际情况及我国的糖尿病医学营养指南进行解读。

【关键词】　糖尿病；营养疗法；指南【中图分类号】　R 587.1　【文献标识码】　A　DOI：10.12114/j.issn.1007-9572.2018.00.011程改平，李舍予，胡雯．2018年《英国基于证据的预防管理糖尿病营养指南》解读［J］．中国全科医学，2018，21（17）：2017-2021．［］CHENG G P，LI S Y，HU W．The interpretation of 2018 Diabetes UK evidence-based nutrition guideline for the prevention and management of diabetes［J］．Chinese General Practice，2018，21（17）：2017-2021．The Interpretation of 2018 Diabetes UK Evidence-based Nutrition Guideline for the Prevention and Management of Diabetes　CHENG Gai-ping1，LI She-yu2，HU Wen1*1.Department of Clinical Nutrition，West China Hospital，Sichuan University，Chengdu 610041，China2.Department of Endocrinology and Metabolism，West China Hospital，Sichuan University，Chengdu 610041，China*Corresponding author：HU Wen，Senior technologist；E-mail：Wendy_nutrition@【Abstract】　Diabetes UK updated the Evidence-based Nutrition Guidelines for the Prevention and Management of Diabetes on March 2018，by its previous version of 2011.The current version provided comprehensive recommendations based onthe daily dishes instead of nutrients，including diabetes education and prevention，management of cardiovascular disease risks，management of diabetic complications and associated issues （orbidities，nutrition support，nutrition during pregnancyand lactation，eating disorders，micronutrients，food supplements，functional foods，commercial food for diabetes and nutritive and non-nutritive sweeteners）.We are interpreting the selected recommendations from the guideline for Chinese general practitioners along with the latest Chinese nutrition guidelines of diabetes.【Key words】　Diabetes mellitus；Nutrition therapy；Guidebooks1.610041四川省成都市，四川大学华西医院临床营养科2.610041四川省成都市，四川大学华西医院内分泌代谢科*通信作者：胡雯，主任技师；E-mail：Wendy_nutrition@·2018· E-mail:zgqkyx@糖尿病患者数量在全球范围内快速增长，我国已成为糖尿病大国。

· 述评·肾移植术后血管并发症的诊疗策略张江伟　丁小明【摘要】　随着肾移植供受者评估标准、器官获取保存方案、手术技术等不断进步，肾移植术后血管并发症的发生率有所下降，但仍是肾移植较为严重的手术并发症之一，可导致移植物丢失及受者死亡，严重影响肾移植效果。

因此，本文就肾移植术后常见血管并发症，包括血管狭窄、动脉夹层、假性动脉瘤、血管破裂、血栓等的发生概况、临床表现、诊断和治疗策略进行综述，并结合西安交通大学第一附属医院肾移植术后血管并发症发生和诊治情况，总结肾移植术后常见血管并发症的诊疗策略，以期为肾移植术后血管并发症的临床诊断和治疗提供参考，降低血管并发症的发生率，提高肾移植疗效和受者生存率。

【关键词】　肾移植；血管并发症；血管狭窄；动脉夹层；假性动脉瘤；血栓；供者来源性感染；数字减影血管造影（DSA ）；经皮腔内血管成形术【中图分类号】　R617, R543　【文献标志码】 A 【文章编号】 1674-7445（2024）01-0001-09Diagnosis and treatment strategies for vascular complications after kidney transplantation Zhang Jiangwei, Ding Xiaoming.Department of Kidney Transplantation , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an 710061, China Corresponding author: Ding Xiaoming, Email: ***************.cn【Abstract 】 With persistent progress in donor-recipient evaluation criteria, organ procurement and preservation regimens and surgical techniques, the incidence of vascular complication after kidney transplantation has been declined,whereas it is still one of the most severe surgical complications of kidney transplantation, which may lead to graft loss and recipient death, and seriously affect the efficacy of kidney transplantation. Therefore, the occurrence, clinical manifestations, diagnosis and treatment strategies of common vascular complications after kidney transplantation,including vascular stenosis, arterial dissection, pseudoaneurysm, vascular rupture and thrombosis were reviewed in this article. In combination with the incidence, diagnosis and treatment of vascular complications after kidney transplantation in the First Affiliated Hospital of Xi'an Jiaotong University, diagnosis and treatment strategies for common vascular complications after kidney transplantation were summarized, aiming to provide reference for clinical diagnosis and treatment of vascular complications after kidney transplantation, lower the incidence of vascular complications, and improve clinical efficacy of kidney transplantation and survival rate of recipients.【Key words 】 Kidney transplantation; Vascular complication; Vascular stenosis; Arterial dissection;Pseudoaneurysm; Thrombosis; Donor-derived infection; Digital subtraction angiography(DSA); Percutaneous transluminal angioplastyDOI: 10.3969/j.issn.1674-7445.2023168基金项目：国家自然科学基金（81970670）作者单位： 710061　西安，西安交通大学第一附属医院肾移植科作者简介：张江伟（ORCID 0000-0002-7979-0142），博士，住院医师，研究方向为肾移植，Email ：******************.cn 通信作者：丁小明（ORCID 0000-0002-9082-9191），Email ：***************.cn第 15 卷　第 1 期器官移植Vol. 15　No.1　2024 年 1 月Organ Transplantation Jan. 2024　 作者简介：丁小明，二级主任医师，教授，博士研究生导师，西安交通大学第一附属医院肾移植科主任。

动脉硬化闭塞症诊断及疗效标准(2015年修订稿)动脉硬化性闭塞症（Arteriosclerosis obliterans，ASO）多发于40岁以上人群。

男、女均可发病，以男性多见，病变为全身性疾病，主要累及大、中动脉，尤其是腹主动脉以下诸分支分叉起始部位，如腹主动脉分叉、髂总动脉及股总动脉等分叉处多见。

受累动脉管壁变厚、变硬，并伴有粥样斑块及胆固醇沉积，致使管腔狭窄、血栓形成或闭塞，引起肢体远端供血不足，重者可发生溃疡及坏死。

1.诊断标准(1)发病年龄一般在40岁以上；(2)有慢性肢体动脉缺血表现：怕冷、发凉、麻木、间歇性跛行、疼痛，皮肤苍白、紫黯、营养障碍、溃疡或坏疽，肢体动脉搏动减弱或消失；(3)常伴有高血压病、冠心病、高脂血症等疾病；(4)彩色超声多普勒、CTA 、MRA、DSA、光电容积血流、ABI、经皮氧分压等检查有肢体动脉内膜斑块形成、狭窄或闭塞者；(5)排除血栓闭塞性脉管炎、糖尿病性周围血管病变、大动脉炎、雷诺氏病等疾病。

2．临床分期标准(1)一期(局部缺血期): 以间歇性跛行为主要表现,伴有慢性肢体缺血症状：发凉、怕冷、疼痛、麻木，皮肤苍白、患肢足背、胫后动脉搏动减弱，相关检查提示为动脉狭窄。

ABI小于0.9。

(2)二期（营养障碍期）：以静息痛为主要表现，缺血症状加重：患肢肌肉明显萎缩、皮肤干燥、苍白、潮红或紫黯、汗毛脱落，患肢足背、胫后动脉搏动消失，ABI小于0.7。

(3)三期（坏死期）: 以坏疽为主要表现，缺血症状进一步加重：肢端溃疡或坏疽。

多伴有剧烈疼痛、合并感染可出现发热等全身症状，患肢足背、胫后动脉搏动消失，ABI 小于0.4。

根据坏死范围, 分为3 级:Ⅰ级:坏死(坏疽)局限于足趾或手指。

Ⅱ级:坏死(坏疽)扩延至足背及足底, 超过趾跖或指掌关节。

Ⅲ级:坏死(坏疽)扩散至踝关节及小腿、手部及腕关节者。

3．症状量化评分标准(1)皮肤温度感:①正常，0分；②偶尔觉凉，2分；③持续性发凉或比正常穿得多时缓解，4分；④冰凉, 局部保暖后仍有寒凉感，6分。