Talks and tweets from the ADA

Every year at the American Diabetes Association (ADA) annual meeting, thousands of presentations are made. This year's 78th Scientific Session took place from 22 to 26 June in Orlando, Florida. I have attended (nearly) every year from 1978, and wrote several hundred articles summarizing various sessions over nearly two decades in the “Perspectives on the News” column in Diabetes Care. How, I wondered, could I give the readers of the Journal of Diabetes a sense of the fascinating breadth of information and understanding gleaned over the 5-day period? Here's an approach: a summary of my @zbloomgarden “tweets” of posters and of my notes from the meeting, recognizing that any such summary must be woefully incomplete. (Note, abstracts referred to below [numbers in parentheses] can be viewed at https://plan.core-apps.com/tristar_ada18/abstracts [accessed 3 August 2018]; many actual posters are available at https://ada.scientificposters.com/epsWelcome.cfm [accessed 3 August 2018]).

Barbara Corkey (Boston University, Boston, MA, USA) made the important point that although diabetes is the end result of multiple pathogenic abnormalities, it is incorrect to consider obesity, hypertension, insulin resistance, hyperinsulinemia, decreased insulin clearance, dyslipidemia, inflammation, non-alcoholic fatty liver disease, or any one of the myriad of interrelated factors as being “primary”; rather, one should think of all these factors as having the potential to “cause each other”. And, bringing together diabetes pathogenesis and cardiovascular disease (CVD), Lim et al. (Abstract 455) found that among >1000 people with diabetes, the levels of branched-chain amino acids (which have been shown to track with insulin resistance) predict subsequent heart failure.

In an interesting study (Abstract 296-LB), leptin levels were measured in 1064 obese people, and the leptin analog metreleptin was administered to those in the lowest leptin tertile. Among this lower third, those with the lowest baseline leptin had substantial weight loss, suggesting that in a (small) subset of people with obesity this may be a reasonable therapeutic approach. In a perhaps more practical study (Abstract 298-LB), a meal replacement approach was more effective than a food-based diet over 1 year, with 10.3% vs 5.5% weight loss and with diabetes resolution in approximately one-third versus one-fifth of subjects.

There may be a genetic basis to glucose–HbA1c mismatch, with some people being “high glycators” and others “low glycators”, a not uncommon issue in diabetes (Abstract 183-LB). Bernard Zinman (Mount Sinai Hospital, Toronto, Canada) addressed this in a symposium on diabetic kidney disease, first reviewing evidence from Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC)1, 2 and from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE)3, 4 that better glycemic control particularly tracks with improved renal outcome over the long-term in post-trial follow-up. HbA1c (affected by anemia and renal insufficiency), fructosamine (affected by hemoglobin, uric acid, and bilirubin), and glycated albumin (affected by hypoalbuminemia and proteinuria) are ultimately indirect approaches, suggesting that continuous glucose monitoring may be the optimal approach in determining overall glycemia as well as hypoglycemia frequency.

Complications

Edgar Peters (VU University Medical Center, Amsterdam, Netherlands) spoke at a symposium on the diabetic foot, asking whether 6 weeks is a sufficient duration of antibiotic treatment for osteomyelitis, and noting that an elevation in the sedimentation rate may persist for much longer periods, and may serve as a more useful biomarker than C-reactive protein (CRP) and procalcitonin in guiding the duration of antibiotic treatment, given the potential for adverse outcome associated with recurrence after antibiotic discontinuation.

Two fascinating debates at the ADA addressed aspects of diabetic nephropathy. Peter Rossing (Steno Diabetes Center, Gentofte, Denmark) argued for and Robert Nelson (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA) argued against the question of whether albuminuria in the absence of hypertension should be treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). Rossing pointed out that it is clear that such treatment is of benefit with blood pressure (BP) >140/90 mmHg, and noted that the time from microalbuminuria to end-stage renal disease (ESRD) may exceed 15–20 years, beyond the duration of existing clinical trials, leading to the question of what constitutes a normal BP, what situations should be considered high risk, for which 130/80 mmHg is the current ADA goal, and whether a normal BP may constitute masked hypertension under certain circumstances, further noting that BP lowering does not track well with the albuminuria-lowering effect of ACEi/ARB. Nelson suggested that relevant outcomes are renal failure, CVD, and cardiovascular (CV) mortality, but not microalbuminuria, pointing out that microalbuminuria may regress in association with lower BP, but also with lower levels of glycemia and lipids, and noting studies in which ACEi and ARB did not lead to improvement in albuminuria, and even in which ARB were associated with worse renal outcome, arguing that until biomarkers are found to show which patients with microalbuminuria benefit from treatment he would not use such agents. Dick de Zeeuw (University of Groningen, Groningen, The Netherlands) argued that albuminuria should be considered a therapeutic target, noting its association with endothelial dysfunction and its independent association with both CV and renal outcomes, and pointing to the relationship between albuminuria and endothelial glycocalyx, with evidence that sulodexide restores glycocalyx and reduces albuminuria. However, Merlin Thomas (The University of Melbourne, Melbourne, Vic., Australia) espoused the viewpoint that “the target is never albuminuria”, a surrogate that one would not expect to itself be a determinant of the benefit of a given treatment approach, making points that albuminuria is more of a symptom than a cause of renal disease, that the evidence shows benefits of ACEi/ARB rather than of specific albuminuria targets, and that there is at least the concern that maximally lowering albuminuria (e.g. with dual ACEi and ARB, or even with these plus a mineralocorticoid antagonist) may have a safety risk of increasing the likelihood of worsening renal function, particularly in people whose baseline renal function is severely compromised.

The excitement of the recognition that sodium–glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 receptor agonists (GLP1-RA), and thiazolidinediones are associated with CV benefit in diabetic people with existing CVD has led to new concepts of treatment. As Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA, USA) commented, it would be hard to imagine “going back” to introducing new diabetes treatment approaches without CV outcome trials (CVOTs). Such trials in people with existing CVD require approximately 15 000 person-years of exposure. There is now recognition of heart failure, as well as atrial fibrillation and sudden death, as important additional CV outcomes, and there is intriguing evidence of potential for nephroprotection with SGLT2 inhibitors, as well as perhaps with incretin-based treatments. Kaul also noted, “we really have yet to study the low-risk population”, but there is a major issue: because of their much lower event rates, CVOTs for all people with type 2 diabetes mellitus (T2DM), rather than just those with existing CVD, may need more than a fourfold increase in numbers of enrollees, and following tens of thousands of people with diabetes for a decade would be a massive undertaking. An interesting suggestion made by Steven Marso (University of Texas Southwestern Medical Center, Dallas, TX, USA) was to consider enrollment of patients with a positive coronary calcium score, a group at intermediary risk. Other markers for such studies may include microalbuminuria and elevation in CRP.

A fascinating subgroup analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) Trial of once weekly exenatide used propensity matching to assess CV outcomes among those of the 7396 placebo-treated participants who received an SGLT2 inhibitor compared with those not so treated, finding a 21% lower rate of major adverse cardiovascular events (MACE), 50% lower all-cause mortality, and significant improvement rather than reduction in estimated glomerular filtration rate (eGFR; Abstract 130-LB). An implication: if some 10% of those receiving placebo but fewer of those receiving exenatide received these agents (additional treatment presumably being given for those needing better glycemic control), then part of any CV benefit of exenatide q.w. may have been masked.

Glycemic treatment approaches

At a symposium on digital approaches to implementing knowledge from the National Diabetes Education Program, Ann Albright (Centers for Disease Control and Prevention, Atlanta, GA, USA), Linda Siminerio (University of Pittsburgh, Pittsburgh, PA, USA), John Piette (University of Michigan, Ann Arbor, MI, USA), and Athena Philis-Tsmikas (The Whittier Institute for Diabetes, La Jolla, CA, USA) reflected on various digital approaches, representing a continuum from mobile technology, texting, and emailing to a full “virtual lifestyle change program” based on “wearables”, apps, and coaches. Such approaches appear to have been effective in open-label uncontrolled studies of patients with diabetes in poor control, but there are issues with adherence and with real-world implementation, particularly in integration with electronic medical records and in making the intervention meaningful to the patient. Specific interventions seem possible, such as assuring that a population of people with diabetes has retinal screening or foot examination, but texting medication and blood glucose self-monitoring reminders had limited long-term efficacy. Judith Fradkin (Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA) pointed out the interest of the National Institute of Diabetes and Digestive and Kidney Diseases in digital translational research, noting that funding is available for appropriate products (see https://grants.nih.gov/grants/guide/pa-files/PAR-17-178.html, accessed 3 August 2018).

An interesting study showed that adding saxagliptin to dapagliflozin plus metformin substantially reduced genital tract fungal infection from approximately 5% to 3% of treated people, perhaps an approach for people with this side effect, although one that may simply be due to reduction in glycosuria because of lower glucose levels with the addition of the DPP-4 inhibitor (Abstract 1171). As a reminder that even minor degrees of renal insufficiency attenuate the glucose-lowering effect of SGLT2 inhibitors, a comparison of sitagliptin versus dapagliflozin showed HbA1c reductions of 0.51% versus 0.36% at baseline eGFR of 78 mL/min per 1.73 m² and HbA1c 7.8% (Abstract 1142). Sitagliptin also showed benefit when continued after initiation of insulin treatment, leading to a 1.88% reduction in HbA1c, whereas administration of insulin with placebo led to a 1.42% reduction (Abstract 112-LB). A network meta-analysis of drugs given in combination with metformin showed that DPP-4 inhibitors, thiazolidinediones, and GLP-1RA were associated with 27%, 22%, and 25% lower CVD mortality than sulfonylureas, whereas neither meglitinides nor α-glucosidase inhibitors were associated with better outcome (Abstract 1239). A propensity score matching comparison of 7561 people receiving DPP-4 inhibitors with the same number receiving a sulfonylurea showed a 34% reduction in the likelihood of dementia (Abstract 195-LB). A propensity score-matched comparison of dapagliflozin with a DPP-4 inhibitor in the CVD-REAL2 study showed the former to be associated with 26%, 13%, 14%, and 18% lower likelihood of death, heart failure, myocardial infarction, and stroke, respectively (Abstract 124-LB).

A 1-year study of 1550 people with type 1 diabetes mellitus (T1DM) receiving placebo or the SGLT1/2 inhibitor sotagliflozin at daily doses of 200 or 400 mg showed less severe hypoglycemia (7.4% vs 5.7% and 4.4%) and greater reduction in HbA1c (by 0.2% and 0.3%), but diabetic ketoacidosis (DKA) in 0.2% vs 2.9% and 3.8% (Abstract 5-LB). The use of SGLT2 inhibitors in T1DM was the topic of another symposium at the ADA, again showing greater DKA occurrence with dapagliflozin, with empagliflozin (apparently not with a very low 2.5-mg dose), and with the dual SGLT1/2 inhibitor sotagliflozin. A recent meta-analysis of 11 trials of 3523 T1DM people treated with an SGLT2 inhibitor versus placebo failed to show a significant reduction in severe or total hypoglycemia, but did show a 0.4% reduction in HbA1c and a 2.34-fold increase in DKA, occurring in 1.54% of those receiving the SGLT2 inhibitor compared with 0.46% of those receiving placebo.5 One must wonder whether this in itself offers a sufficiently great benefit:  risk ratio. A more compelling possibility was raised by David Cherney (University of Toronto, Toronto, Canada): might a cardiovascular/renal prevention trial with an SGLT inhibitor in T1DM, improve the “tremendous morbidity/mortality [and] unmet need” in these patients?

A 1-year study of 26 people with T1DM receiving liraglutide versus 20 receiving placebo showed a 0.5%–0.6% HbA1c reduction from a baseline of 7.8%, in association with weight loss and BP lowering, but without reduction in hypoglycemia (Abstract 3-LB). A comparison of insulin patch pumps with insulin pen treatment using mulitple daily injections showed no difference in glycemic response on continuous glucose monitoring (Abstract 73-LB). A comparison of a novel rapidly absorbed insulin aspart preparation with the currently used preparation in 1445 diabetic people showed a 16% reduction in nocturnal hypoglycemia, but no difference in daytime events (Abstract 96-LB). A new glucagon preparation administered by nasal spray was may soon be available (Abstract 138-LB), offering greater potential usefulness than the existing glucagon emergency kits.

The ADA meeting ended with a symposium in which the writing group presented the 2018 ADA-EASD consensus report on therapeutic approaches to hyperglycemia in T2D. Judith Fradkin noted the benefits of glycemic control in averting symptomatic hyperglycemia, with evidence of a reduction in microvascular complications by 50%–75% with HbA1c of 7% vs 9% in the DCCT and by 25% with HbA1c of 7% vs 7.9% in the UK Prospective Diabetes Study (UKPDS), but with greater benefit with reduction from higher levels of HbA1c. She pointed out that there is, however, uncertainty regarding macrovascular benefits of glycemic control in T2DM, and that these benefits appear to emerge slowly while adverse effects can be seen earlier, necessitating that risks and benefits be balanced, considering patient preferences. She noted that although HbA1c is the major tool used in assessment of glycemic control, with anemia or chronic kidney disease there may be discrepancies between HbA1c and glycemia, and that self-monitoring of blood glucose (SMBG) is useful for self-management with insulin treatment, although of more limited benefit outside insulin treatment with additional cost, while she considered the role of newer technologies not to have been established. Deborah Wexler (Massachusetts General Hospital, Boston, MA, USA) introduced the truly novel aspect of the consensus report, the recommendation that the presence of CVD is the major determinant of treatment recommendation: GLP-1RA are favored if atherosclerotic CVD predominates, in the order of liraglutide > semaglutide > exenatide q.w., or considering the SGLT2 inhibitor empagliflozin (interestingly, pioglitazone was not mentioned here despite the evidence of benefit in CVOTs); and SGLT2 inhibitors are recommended if heart failure predominates, and if the eGFR is adequate, with the recommendation to use GLP-1RA at lower eGFR levels, while avoiding thiazolidinediones. The potential renal benefits of SGLT2 inhibitors and liraglutide (based on its effect on albuminuria) were mentioned. Walter Kernan (Yale University, New Haven, CT, USA) further reviewed therapeutic options, mentioning among other points that long-acting insulin preparations may be associated with less hypoglycemia than neutral protamine Hagedorn (NPH) insulin, but that the former may not be better for all patients. Geltrude Mingrone (Catholic University, Rome, Italy) noted several disadvantages of SGLT2 inhibitors, in particular the increase in low-density lipoprotein cholesterol and the increase in amputation rates with canagliflozin and ertugliflozin, and opined that GLP-1RA “probably do not increase risk for pancreatitis…nor pancreatic cancer at least in the short term”. David D'Allessio (Duke University, Durham, NC, USA) gave the committee's recommendation “that metformin remain the initial drug…but there is the new data and new alternatives…[although] the safety, efficacy and costs continue to weigh”. He suggested considering initial combination treatment if a > 1% reduction in HbA1c is desired, reminded the audience that CV risk “be considered upfront” but “for the other 80%…need to minimize hypoglycemia…[and consider] issues of body weight”, with issues of cost leading to the use of metformin, then a sulfonylurea and/or a thiazolidinedione, in either order. Chantal Mathieu (University Hospital Gasthuisberg, Leuven, Belgium) opined that “the evidence now is strong enough” for combined use of GLP-1RA and insulin, whether as separate agents or in fixed-ratio premixed formulations, with consideration to adding an SGLT2 inhibitor, recognizing the risk of DKA with overly aggressive insulin down-titration and in the setting of surgery and other stress situations. John Buse (University of North Carolina, Chapel Hill, NC, USA) ended the session with some “knowledge gaps”, in developing approaches to personalization of treatment, in considering whether metformin's role as foundational treatment is just “a quirk of history”, in the use of SGLT2 inhibitors and GLP-1RA in primary prevention, and in whether they may have additive CVD benefit, in determining the appropriate use of SMBG and of continuous glucose monitoring, and a myriad of other fascinating questions.

每年在美国糖尿病协会(American Diabetes Association,ADA)的年会上都有数以千计的报告。今年第78届ADA科学大会于6月22日至26日在佛罗里达州奥兰多举行。自从1978年以来我(几乎)每年都会参会,  并且近二十年在Diabetes Care的《新闻透视》专栏中撰写了数百篇总结各种会议的文章。我在这5天的时间里收集到的海量信息和思考,  怎样才能够使得Journal of Diabetes的读者对此有所了解?在这里有一种方法:我的@zbloomgarden账号发送的“推文”的海报总结以及我的会议纪要,  但是我们一定要理解任何此类总结都不可能是完整的(注释:在https://plan.core-apps.com/tristar_ ada18/abstracts网站可以查看以下提及的摘要信息[括号中的数字] [accessed 3 August 2018];在https://ada.scientificposters.com/epsWelcome.cfm网站可以查看到许多原先展示的海报[accessed 3 August 2018])。

Barbara Corkey(Boston University, Boston, MA, USA)曾经提出了一个重要的观点,  即糖尿病虽然是多种异常致病因素的最终结果,  但是如果将肥胖、高血压、胰岛素抵抗、高胰岛素血症、胰岛素清除率下降、血脂异常、炎症、非酒精性脂肪性肝病或者众多相关因素中的任何一种当成是“主要致病因素”却是一种错误的观点;相反,  我们应该考虑到所有这些因素都有可能“彼此造成影响”。而且,Lim等(摘要455)在> 1000名的糖尿病患者中调查后发现,  糖尿病的发病机制与心血管疾病(CVD)相关,  支链氨基酸水平(既往已经证实它与胰岛素抵抗相关)可以预测随后发生的心力衰竭。

在一项有趣的研究(摘要296-LB)中测量了1064名肥胖患者的瘦素水平,  并且对瘦素水平处于最低三分位数组的患者给予瘦素类似物美曲普汀治疗。在这个最低三分位数组中,  基线瘦素水平最低的患者体重下降非常明显,  这意味着在这个(小型)肥胖亚组人群中使用美曲普汀治疗可能是一种合理的治疗方法。在一项也许更为实际的研究(摘要298-LB)中,  经过1年以上的观察后发现膳食替代疗法与基于饮食控制的疗法相比更为有效,  两组受试者的体重分别下降了10.3%与5.5%,糖尿病缓解率大约分别为三分之一与五分之一。

患者的葡萄糖-HbA1c不相匹配可能有其遗传基础,  有些人容易“高糖基化”,  而有些人容易“低糖基化”,  这在糖尿病患者中并非罕见(摘要183-LB)。Bernard Zinman(Mount Sinai Hospital, Toronto, Canada)在糖尿病肾病专题研讨会上对此做了一个发言,  他首先回顾了来自于糖尿病控制与并发症试验(Diabetes Control and Complications Trial,DCCT)/糖尿病干预与并发症流行病学调查研究(Epidemiology of Diabetes Interventions Complications,EDIC)^1,2以及来自于控制糖尿病与血管疾病行动研究:百普乐与达美康缓释片对照评估试验(Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation,ADVANCE)^3,4的证据,  在这些试验之后的长期随访中发现,  更好的血糖控制尤其有利于改善肾脏结果。而控制HbA1c(受到了贫血与肾功能不全的影响)、果糖胺(受到了血红蛋白、尿酸以及胆红素的影响)以及糖化白蛋白(受到了低蛋白血症与蛋白尿的影响)最终都是间接的方法,  这意味着连续血糖监测可能是用来测定整体血糖控制情况以及低血糖频率的最佳方法。

并发症

Edgar Peters(VU University Medical Center, Amsterdam, Netherlands))在糖尿病足专题研讨会上发表了一个讲话,  关于在使用抗生素治疗骨髓炎时,  考虑到停用抗生素可能导致与复发相关的潜在不良后果,  提问6周的疗程是否充足,  并且指出了红细胞沉降率的升高可能会持续更长时间,  与C-反应蛋白以及降钙素原相比可能是更好的指导抗生素治疗时间的生物标志物。

在ADA上有两个吸引人的有关糖尿病肾病若干问题的辩论。在争论对没有高血压的蛋白尿患者是否应该使用血管紧张素转换酶抑制剂(ACEi)或血管紧张素II受体阻滞剂(ARB)治疗这个问题时,Peter Rossing(Steno Diabetes Center, Gentofte, Denmark)支持这个观点,  但是Robert Nelson(National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA)却反对这个观点。Rossing指出这种治疗方法明显有利于血压> 140/90 mmHg的患者,  并且还指出了从微量白蛋白尿进展到终末期肾病可能需要超过15-20年,  这个时间超过了目前临床试验所持续的时间,  而这又引出了另外的问题,  那就是什么构成正常的血压?目前ADA又将血压控制目标改成了130/80 mmHg, 那么哪种情况应该被认为是高危状态?而正常血压在某些情况下是否会形成隐蔽性高血压?他还进一步指出了ACEi/ARB降低蛋白尿的疗效并不总是与降压疗效相平行。Nelson认为临床相关结果应该是肾衰竭、CVD以及心血管(CV)死亡率,  而不是微量白蛋白尿,  指出微量白蛋白尿的缓解可能与较低的血压有关,  而且还与较低水平的血糖以及血脂有关,  并且值得注意的是在一些研究中ACEi与ARB并没有导致蛋白尿改善,  甚至在一些研究中使用ARB治疗还与肾脏恶化的结局相关,  他主张除非发现一些生物标志物能够提示哪些微白蛋白尿患者可受益于治疗,  否则他都不会使用这类药物。Dick de Zeeuw(University of Groningen, Groningen, The Netherlands)主张将蛋白尿视为治疗靶点,  他指出蛋白尿与内皮功能紊乱有关,  并且蛋白尿与CV以及肾脏结局之间都具有独立的相关性,  亦提出了蛋白尿与内皮糖萼之间的关系,  有证据表明使用舒洛地特治疗可以恢复糖萼并且减少蛋白尿。然而,Merlin Thomas(The University of Melbourne, Melbourne, Vic., Australia)赞成“靶点决不是蛋白尿”的观点,  作为一个代替物用于一种既定的方法治疗后不要期望它能成为是否获益的决定性因素”他指出了蛋白尿更多的是一种症状而不是肾脏疾病的原因,  有证据表明ACEi/ARB的治疗获益并不是特异性的来源于蛋白尿靶点,  并且至少值得我们关注的是最大程度地降低蛋白尿(例如联用ACEi与ARB治疗,  或者除了使用这些药物外甚至还要加用盐皮质激素拮抗剂)可能会有导致肾功能恶化的安全风险,  特别是在基线肾功能就严重受损的人群中。

有研究发现在明确合并CVD的糖尿病患者中使用钠-葡萄糖共转运体2(SGLT2)抑制剂、胰高血糖素样肽1受体激动剂(GLP1-RA)或噻唑烷二酮类药物治疗可以导致CV获益,  这令人兴奋并促使了治疗理念的更新。正如Sanjay Kaul(Cedars-Sinai Medical Center, Los Angeles, CA, USA)评论的那样,  很难想象“回到”在没有CV结果试验(CV outcome trials,CVOTs)的情况下引入新的糖尿病治疗方法的时代。在目前合并CVD的患者中进行这样的试验大约需要15000患者-年的样本量展示。目前人们已经认识到了心力衰竭以及心房颤动与猝死都是附带的重要CV结局,  并且目前还有一些吸引人的证据表明,SGLT2抑制剂和基于肠促胰岛素效应的治疗药物可能对肾脏具有保护作用。Kaul还指出,  “我们真的还没有来得及研究低风险人群”,  但是有一个主要的问题:如果在所有合并2型糖尿病(T2DM)的人群而不是仅仅在那些目前已经合并CVD的人群中进行CVOTs,因为前者的发生率低得多,  那么纳入试验的人数可能需要增加到4倍以上,  对数万名糖尿患者进行数十年的随访将是一项非常艰巨的任务。Steven Marso((University of Texas Southwestern Medical Center, Dallas, TX, USA)提出了一个令人感兴趣的建议,  那就是将冠状动脉钙化积分阳性的患者纳入试验,  这是一组处于中等风险的人群。这类研究的其他标志物可能还包括微量白蛋白尿以及CRP升高。

在一项引人注目的每周一次艾塞那肽降低心血管事件研究(Exenatide Study of Cardiovascular Event Lowering,EXSCEL)试验的亚组分析中,  采用倾向性匹配评估在7396名使用安慰剂治疗的参与者中,  比较接受SGLT2抑制剂与未接受SGLT2抑制剂治疗后的CV结局,  发现主要不良心血管事件的发生率降低了21%,全因死亡率降低了50%,并且估算的肾小球滤过率(eGFR;摘要130-LB)显著改善而不仅仅是下降。这意味着如果在接受安慰剂治疗的患者中大约有10%接受了额外治疗,  但是接受艾塞那肽治疗的患者却较少使用这些药物(对于那些需要更好的血糖控制的患者来说,  可能给予了额外的治疗),那么艾塞那肽每周一次(q.w.)治疗后的CV获益可能有部分被掩盖了。

降糖治疗方法

在国家(US)糖尿病教育计划(National Diabetes Education Program)知识的数字化方法专题研讨会上, Ann Albright(Centers for Disease Control and Prevention, Atlanta, GA, USA)、Linda Siminerio(University of Pittsburgh, Pittsburgh, PA, USA)、John Piette(University of Michigan, Ann Arbor, MI, USA)以及Athena Philis-Tsmikas(The Whittier Institute for Diabetes, La Jolla, CA, USA)回顾了多种形式的数字化方法,  体现出这代表了一个联贯的发展,,将原先的移动技术、短信、电子邮件转为基于“可穿戴系统”、应用程序以及辅导计划的一个完整的“虚拟生活方式改变计划”。这些方法在开放标签的无对照组研究中看起来似乎对那些控制不佳的糖尿病患者来说是有效的,  但是还存在依从性以及在真实世界中如何应用的问题,  特别是如何与电子医疗记录进行整合,  并且如何才能使得干预对患者有意义。特定的干预措施是可能实施的,  例如确保一个糖尿病人群进行视网膜病变筛查或者足部检查,  但是短信提醒用药以及提醒自我监测血糖的长期效果却很有限。Judith Fradkin(Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA)指出了糖尿病、消化疾病与肾脏疾病国家研究所对数字转换研究很感兴趣,  她还指出了合适的产品可以得到资助(见https://grants.nih.gov/grants/guide/pa-files/PAR-17-178.html, accessed 3 August 2018)。

一项有趣的研究表明,  在达格列净联合二甲双胍治疗的基础上再加用沙格列汀,  可使治疗患者的生殖道真菌感染率大幅度下降约从5%显著降低到3%,也许对出现这种副作用的患者来说这是一种治疗方法,  尽管这可能仅仅是因为加入DPP-4抑制剂治疗后降低了血糖水平,  从而导致尿糖减少(摘要1171)。一项西格列汀与达格列净的对照研究结果提示,  即使是轻微的肾功能不全也会降低SGLT2抑制剂的降糖疗效,  在基线eGFR为78 mL/分钟/每1.73m²并且HbA1c为7.8%的患者中,  两组患者的HbA1c降幅分别为0.51%与0.36%(摘要1142)。有研究发现,  启用胰岛素治疗的患者加用西格列汀后还可进一步获益,  可使HbA1c下降1.88%,然而胰岛素加上安慰剂治疗后导致的HbA1c下降却只有1.42%(摘要112-LB)。一项对与二甲双胍联用的治疗药物进行的网络meta分析结果显示,  使用DPP-4抑制剂、噻唑烷二酮类药物和GLP-1RA与使用磺脲类药物相比,  相关的CVD死亡率分别减少27%、22%与25%,然而却没有发现氯茴苯酸类药物与α-葡萄糖苷酶抑制剂与更好的结局相关(摘要1239)。对7561名接受DPP-4抑制剂治疗的患者与同样数量的接受磺脲类药物治疗的患者进行倾向性评分匹配比较后显示,  前组患者出现痴呆的可能性降低了34%(第195-LB篇摘要)。在CVD-REAL2研究中,  对使用达格列净治疗的患者与使用DPP-4抑制剂治疗的患者进行倾向性评分匹配比较后显示,  前组出现死亡以及发生心力衰竭、心肌梗死与中风的可能性分别低了26%、13%、14%与18%(第124-LB篇摘要)。

在一项为期1年的纳入了1550名1型糖尿病(T1DM)患者的研究中,  患者随机分为接受安慰剂治疗组或每日使用200 mg或400 mg SGLT1/2抑制剂索格列净治疗组,  结果发现与安慰剂组相比两个治疗组很少出现严重低血糖(发生率分别为7.4%、5.7%与4.4%),并且HbA1c明显下降(与安慰剂组相比分别下降了0.2%与0.3%),但是与安慰剂组相比两个治疗组的糖尿病酮症酸中毒(diabetic ketoacidosis,DKA)的发生率却有所增加(分别为0.2%、2.9%与3.8%)(第5-LB篇摘要)。在ADA上另一个专题研讨会的主题是T1DM患者使用SGLT2抑制剂治疗,  结果再次表明使用达格列净、恩格列净(显然不是采用非常低的2.5mg剂量)或SGLT1/2双抑制剂索格列净治疗后DKA的发生率显著增加。在最近一项纳入了11个试验(使用一种SGLT2抑制剂治疗并且有安慰剂对照组)共包含3523名T1DM患者的meta分析中,  与接受安慰剂治疗的患者相比,  没有发现接受SGLT2抑制剂治疗的患者严重低血糖或者总的低血糖发生率有显著下降,  但是却发现HbA1c下降了0.4%,DKA发生率增加了2.34倍,  治疗组与安慰剂组的DKA发生率分别为1.54%与0.46%⁵。人们不禁想知道的是,  这种治疗本身带来的受益-风险比是否足够大。David Cherney(University of Toronto, Toronto, Canada)提出了一种更加有说服力的可能性:在T1DM患者中使用SGLT抑制剂治疗保护心血管/肾脏的试验对于这些患者“极大的发病率/死亡率[以及]未满足的需求”是否有改善作用?

在一项为期1年并纳入了26名接受利拉鲁肽治疗与20名接受安慰剂对照治疗的T1DM患者的研究中,  发现HbA1c从基线的7.8%下降了0.5%-0.6%,同时还伴有体重减少与血压下降,  但是低血糖的发生率却没有下降(第3-LB篇摘要)。在一项比较胰岛素贴片泵治疗与胰岛素笔每日多次注射治疗的对照研究中,  动态血糖监测结果提示两组患者的血糖应答反应没有差异(第73-LB篇摘要)。在一项纳入了1445名糖尿病患者的对照研究中,  发现使用新型快速吸收的门冬胰岛素制剂治疗与目前使用的制剂相比前者的夜间低血糖发生率降低了16%,但是日间低血糖事件却没有差异(第96-LB篇摘要)。一种新的胰高血糖素鼻喷雾剂型可能在不久后上市(第138-LB篇摘要),它的潜在效用比现有的胰高血糖素急救包更高。

ADA会议在一个专题研讨会中闭幕,  在会上写作小组针对T2DM患者的高血糖治疗方法提交了2018年ADA-EASD的共识报告。Judith Fradkin指出了血糖控制在缓解高血糖症状方面的益处,  来自DCCT的证据表明将HbA1c控制到7%与9%相比微血管并发症减少了50%-75%,而来自英国前瞻性糖尿病研究(UK Prospective Diabetes Study,UKPDS)的证据表明将HbA1c控制到7%与7.9%相比微血管并发症减少了25%,但是HbA1c从更高水平下降后的获益会更大。然而,  她还指出T2DM患者血糖控制后的大血管获益目前还不明确,  并且这些获益似乎会较晚出现,  而降糖带来的不良作用却会较早出现,  所以降糖必须平衡风险与获益,  还要考虑到患者的喜好。她指出虽然HbA1c是评估血糖控制情况的主要工具,  但是如果合并贫血或者慢性肾脏疾病,  那么HbA1c与血糖之间就可能存在不一致的现象,  此时使用胰岛素治疗的患者在自我管理糖尿病时进行自我监测血糖就很有用,  虽然除了胰岛素治疗以外增加的额外费用所产生的获益很有限,  但是她还考虑到了使用新技术后的获益目前还没有得到明确。Deborah Wexler(Massachusetts General Hospital, Boston, MA, USA)介绍了共识报告的真正创新之处,  患者是否合并CVD是推荐进行何种治疗的主要决定因素:如果是以动脉粥样硬化CVD为主,  那么使用GLP-1RA治疗是有益的,  优选顺序为利拉鲁肽>索马鲁肽>艾塞那肽q.w.,或者可以考虑使用SGLT2抑制剂恩格列净(有趣的是,  尽管在CVOTs中有证据表明使用吡格列酮治疗可以获益但是在这里却没有被提及);如果是以心力衰竭为主,  那么就推荐使用SGLT2抑制剂治疗;如果eGFR水平能够满足用药,  那么推荐在较低eGFR水平的患者中使用GLP-1RA,与此同时要避免使用噻唑烷二酮类治疗。还提到了SGLT2抑制剂与利拉鲁肽(基于它对蛋白尿的影响)具有潜在的肾脏益处。Walter Kernan((Yale University, New Haven, CT, USA)进一步回顾了各种治疗方法,  他提到了长效胰岛素制剂与中性鱼精蛋白锌(NPH)胰岛素相比可能导致的低血糖更少,  但是前者可能并不是对所有的患者都更好。Geltrude Mingrone(Catholic University, Rome, Italy)指出了SGLT2抑制剂的几个缺点,  特别是使用坎格列净与埃格列净治疗后患者的低密度脂蛋白胆固醇水平以及截肢率都有所增加,  并且他认为GLP-1RA“可能并不会增加胰腺炎的风险…并且至少在短期内也不会增加胰腺癌的风险”。David D'Allessio(Duke University, Durham, NC, USA)给出了委员会的建议“二甲双胍仍是初始治疗药物…但是目前已有新的数据与新的选择…[虽然]我们需要继续衡量安全性、有效性以及成本”。他建议如果希望HbA1c的降幅> 1%,那么一开始就要考虑联合治疗,  要提醒读者的是“首先要考虑”CV风险,  但是“对于其他80%患者来说…需要尽量减少低血糖…[并且还要考虑到]体重的问题”,  考虑到成本问题首选二甲双胍治疗,  然后从磺脲类药物和/或噻唑烷二酮类药物中任选一个。Chantal Mathieu(University Hospital Gasthuisberg, Leuven, Belgium)认为联合使用GLP-1RA与胰岛素治疗的“证据目前已经足够强了”,  无论是单独的制剂还是固定比例的预混制剂,  都可以考虑加用一种SGLT2抑制剂治疗,  要认识到DKA的风险与过度激进地下调胰岛素剂量有关,  并且还与手术环境以及其他应激情况有关。John Buse(University of North Carolina, Chapel Hill, NC, USA)在结束会议时提出了一些知识的空白点,  包括在研究个性化治疗方案的过程中,  在考虑到将二甲双胍当做基础治疗药物是否只是“历史的巧合”时,  在CVD一级预防中使用SGLT2抑制剂与GLP-1 RA,及它们是否具有额外的CVD获益时,  在如何确定适当使用SMBG以及动态血糖监测,  还有无数其他有趣问题时。