Various and sundry recent publications

The outpouring of new and important information pertaining to diabetes and its treatment makes it both a challenge and a pleasure to endeavor to keep up. Some notes follow on an assortment of articles that attracted your editor’s attention.

1 INSULIN RESISTANCE AND OBESITY

An analysis from the nearly 80 000-person Nursesʼ Health Study 1993 to 2017 dataset found approximately 10% of the population studied having had had either irregular menstrual cycles or average cycle length >40 days at age 29 to 46 years. This was associated with ~40% greater premature (before age 70) mortality, with the risk particularly strong for cardiovascular (CV) mortality. The link to the insulin resistance syndrome and subsequent diabetes seems inescapable, with the clinical suggestion that menstrual history remains an important aspect of the medical history.¹ Using estimated glucose disappearance rate as a measure of insulin sensitivity calculated from its negative association with waist circumference, the presence of hypertension, and the glycosylated hemoglobin (HbA1c) level, the authors showed association of insulin resistance with total CV events, coronary artery events, and all-cause mortality in 774 persons with type 1 diabetes over 10-year follow-up.² Using data taken from 72 prospective cohort studies with >2.5 million participants, with up to 15 years follow-up, waist circumference was positively and hip circumference negatively associated with all-cause mortality. The subset of studies adjusting for body mass index (BMI) showed even stronger associations, suggesting that clinicians may err in relying on BMI, rather than using these readily obtained measurements in deriving information which may have more direct association with insulin resistance than does body weight.³ Comparing 11 diabetic persons with carefully supervised diet-induced weight loss vs 11 with similar weight loss following gastric bypass, glucose-lowering meds were reduced by three quarters, with similar 40% decrease in 24-hour integrated glucose and insulin levels, although gastric bypass led to rapid systemic appearance of ingested glucose with large early rise and subsequent fall in plasma glucose and insulin levels; the authors concluded that weight loss appears to underlie the effect of gastric bypass surgery.⁴

In an analysis of the relationship between resting heart rate (RHR) and the effect of dopamine agonist treatment on glycemia, 243 persons with RHR ≥ 70 receiving rapidly absorbed bromocriptine in the morning were compared with 129 receiving placebo, showing a significantly greater reduction in pulse with active treatment, which correlated with reduction in HbA1c, suggesting that elevated sympathetic nervous system tone, perhaps secondary to insulin resistance, is present in a subset of persons with type 2 diabetes and may be involved in the maintenance of hyperglycemia.⁵ In a meta-analysis of six randomized controlled trials of the dopamine agonist bromocriptine enrolling 3339 participants and of three trials of cabergoline 0.5 mg enrolling 117 participants, both led to similar 0.7% reduction in HbA1c⁶; this class of agents may deserve greater use.

2 GLUCOSE-LOWERING AGENTS

In a US Veterans dataset, comparing 18 544 persons treated with sodium-glucose–linked transporter 2 inhibitors (SGLT2i), 23 711 with glucagon-like peptide 1 receptor agonists (GLP-1RA), 39 399 with inhibitors of dipeptidyl peptidase 4 (DPP-4i), and 134 904 with sulfonylureas (SU), a composite outcome of estimated glomerular filtration rate (eGFR) decline >50%, end-stage chronic kidney disease (CKD), or all-cause mortality was least frequent with SGLT2i and GLP-1RA, intermediate with DPP-4i, and showed the greatest likelihood with SU. Compared with SU, among those with baseline eGFR<45, SGLT2i were associated with 40% lower likelihood of the composite and GLP-1RA with 26% lower likelihood. DPP-4i were associated with a nonsignificant 7% lower likelihood, not showing overlap with the reduction with SGLT2i and GLP-1RA. This suggestion of renal function preservation with the GLP-1RA as well as with SGLT2i is of interest and is concordant with existing evidence of association of GLP-1RA with reduction in albuminuria.⁷

In a propensity score-matched analysis of 105 130 persons not having diagnosed cardiovascular disease (CVD) or CKD receiving SGLT2i and the same number treated with a DPP-4i, the former agents were associated with 29% lower likelihood of heart failure (HF), 56% lower likelihood of CKD, and 33% and 39% lower likelihood of all-cause and CV death; but no differences in stroke or myocardial infarction (MI).⁸ In another real-world comparative study, however, a propensity score-matched cohort of 209 867 new users of a SGLT2i vs the same number of users of a DPP-4i followed for a mean of 0.9 years had 5.1 vs 6.4 MI, 3.9 vs 7.7 CV deaths, and 2.6 vs 3.5 ischemic strokes, the composite of major adverse CV events occurring significantly less often at rates of 11.4 vs 16.5 per 1000 person-years; furthermore, there were 3.1 vs 7.7 HF events per 1000 person-years.⁹ Using the same dataset to match 208 757 new users of SGLT2i with the same number of users of a DPP-4i, ketoacidosis occurred at rates of 2.03 vs 0.75 per 1000 person-years, with overlapping 95% confidence ranges for dapagliflozin, empagliflozin, and canagliflozin; persons treated with insulin had lower risk, suggesting that, although infrequent, ketoacidosis might be particularly likely to occur in persons requiring insulin but not begun on this treatment.¹⁰

While there is impressive and growing evidence of CV outcome benefit of treatment with GLP-1RA, clinicians should as well use these agents because of the glycemic and weight loss benefits of the class. Among insulin-requiring patients (who are already self-injecting and hence may have less difficulty starting the drugs), meta-analysis of 14 trials of 3829 participants on active treatment vs 3235 receiving placebo found that GLP-1RA use led to 0.99% and 0.67% HbA1c reduction, fasting glucose reduction of 16 and 3 mg/dL, and weight loss of 2.7 and 1.3 kg, for long- and short-acting GLP-1RA, respectively. The long- vs short-acting GLP-1RA were also associated with fewer gastrointestinal side effects: nausea in 9.6% vs 19.9%, vomiting in 4.9% vs 7.7%, and diarrhea in 2.6% vs 5.3%, respectively.¹¹

3 COMPLICATIONS

Among 438 259 persons in the UK with measurement of HbA1c, absolute MI rates were more than twice as high in men than in women, but the relative increase was greater with diabetes among women. Both among men and among women, for every 1% higher HbA1c there was an 18% greater likelihood of MI, regardless of age (<60 or ≥60), BMI (<25 or ≥25), or social class.¹²

In an analysis of the effect of the GLP-1RA dulaglutide in the 9901-person, median 5.4-year follow-up REWIND trial, those in the lowest tertile of baseline cognitive function had a significantly lower risk of developing substantial cognitive impairment with active treatment; the authors suggest two potential mechanisms, reduction in subclinical or silent stroke, and action at central nervous system GLP-1 receptors, with direct effect on memory and learning.¹³

In an analysis of a 3-year follow-up of 6820 participants in the EMPA-REG trial, empagliflozin-treated persons with greater levels of albuminuria had higher risk of CV and renal events, and those with greater degrees of reduction in albuminuria during the period of intervention had lower hazard of major adverse CV events, of CV mortality, of HF hospitalization, and of renal outcomes.¹⁴ Another study suggesting the importance of albuminuria was an analysis of CV and mortality outcomes among 2820 participants in the Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents.Intervention Trial (TOSCA.IT), which suggested that among men with low prevalence of underlying CVD the composite of all-cause death, nonfatal MI, nonfatal stroke, and urgent coronary revascularization increased at cutoffs of albuminuria 22 mg/g creatinine, non–high-density lipoprotein (HDL) cholesterol 125 mg/dL, and HbA1c 7.7%.¹⁵ The finding that a level of albuminuria below 30 mg/g creatinine and of non-HDL cholesterol below 130 were useful risk discriminants reminds us that these are continuous variables, so that levels in the upper “normal” range should be considered noteworthy, and certainly the correct target for non-HDL cholesterol may well be below 130 mg/dL.

有关糖尿病及其治疗的重要新信息不断涌现, 这既是一种挑战, 也是一种努力跟上形势的乐趣。下面是一些吸引编辑注意的文章。

1|胰岛素抵抗与肥胖

对1993年至2017年近8万名护士的健康研究数据集的分析发现, 大约10%的研究人群在29~46岁之间有过不规则的月经周期或平均周期长度>40 d。这与过早(70岁之前)死亡率高出约40%有关, 心血管(CV)死亡率的风险尤其高。月经史与胰岛素抵抗综合征和随后的糖尿病的联系似乎是不可避免的, 临床提示月经史仍然是病史的一个重要方面。在对774例1型糖尿病患者超过10年的随访中, 以估计的血浆葡萄糖消失率作为胰岛素敏感性的衡量标准, 通过与腰围、高血压和糖化血红蛋白(HbA1c)的负相关水平来计算, 结果显示胰岛素抵抗与总心血管事件、冠状动脉事件和全因死亡率有关。使用来自72项前瞻性队列研究、参与者超过250万人的数据, 并进行了长达15年的随访, 发现腰围与全因死亡率呈正相关, 而臀围与全因死亡率呈负相关。对体重指数(BMI)进行校正的研究显示出更强的相关性, 这表明临床医生可能错误地依赖BMI, 而不是使用相对于体重来说更容易获得的指标, 来得出可能与胰岛素抵抗有更直接联系的信息。有研究比较了11例饮食诱导体重减轻的糖尿病患者和11例胃旁路手术后类似体重减轻的糖尿病患者, 降糖药物的剂量减少了四分之三, 24 h血糖和胰岛素的综合水平下降了40%, 尽管胃旁路手术导致摄入的葡萄糖迅速在全身出现, 血糖和胰岛素水平早期大幅上升, 随后又大幅下降；作者得出结论, 体重减轻似乎是胃旁路手术疗效的基础。

在分析静息心率(resting heart rate, RHR)和多巴胺激动剂治疗对血糖影响关系的研究中, 将243名RHR≥70的患者与129名服用安慰剂的患者进行比较, 结果显示, 积极治疗后试验组脉搏明显减慢, 这与HbA1c的降低有关, 表明交感神经系统张力升高可能继发于胰岛素抵抗, 并可能参与高血糖的维持。在一项meta分析中, 包括6项对3 339名参与者的多巴胺激动剂溴隐亭随机对照试验, 以及3项对117名参与者的0.5 mg的卡麦角林(cabergoline)试验, 结果相似, 均导致HbA1c降低0.7%；这类药物应该更多地使用。

2 | 降糖剂

在美国退伍军人数据集中, 比较了18 544名接受钠葡萄糖连共转运蛋白2抑制剂(SGLT2i)、23 711名接受胰高血糖素样肽1受体激动剂(GLP-1RA)、39 399名接受二肽基肽酶4抑制剂(DPP-4i)和134 904名接受磺脲类(SU)药物治疗的患者, 估计肾小球滤过率(eGFR)下降>50%、终末期慢性肾脏疾病(CKD)或全因死亡的复合结局在SGLT2i和GLP-1RA中最少出现, 位于中间是DPP-4i, SU则最多。在基线eGFR<45ml.min^-1.(1.73m2)^-1的患者中, 与SU相比, SGLT2i出现复合结局的可能性降低40%, GLP-1RA的可能性则降低26%。DPP-4i非显著降低7%, 这与SGLT2i和GLP-1RA的降低没有重叠。这提示GLP-1RA和SGLT2i对于保存肾功能的作用是有意义的, 并且同GLP-1RA与蛋白尿减少相关的现有证据是一致的。

在一项对105 130名未被诊断为心血管疾病(CVD)或接受SGLT-2i治疗的CKD人群进行的倾向性得分匹配分析中, 接受SGLT2i治疗的患者与接受DPP-4i治疗的相同人数的患者相比, 前者心力衰竭(HF)的可能性降低29%, CKD的可能性降低56%, 全因和心血管死亡的可能性分别降低33%和39%；但在中风或心肌梗死(MI)方面没有差异。然而, 在另一项真实世界的比较研究中, 对使用SGLT2i的209 867名新患者与使用DPP-4i的相同数量新患者的倾向得分匹配队列, 平均随访0.9年, 发现每1 000人年分别有5.1 vs 6.4的MI、3.9 vs 7.7的心血管死亡, 以及2.6 vs 3.5的缺血性中风, 主要不良心血管事件的复合发生率显著降低, 每1 000人年的发生率为11.4 vs 16.5；此外, 每1 000人年有3.1 vs 7.7的HF事件。使用相同的数据集将208 757名新的SGLT2i使用者与相同数量的DPP-4i使用者相匹配, 酮症酸中毒的发生率为每1 000人年2.03 vs 0.75, 其95%的置信度范围覆盖达格列净、恩格列净以及卡格列净, 而接受胰岛素治疗的患者出现酮症酸中毒的风险较低。这表明尽管不常见, 酮症酸中毒可能特别容易发生在需要胰岛素但没有开始使用这种治疗的患者身上。

有越来越多令人印象深刻的证据表明, GLP-1RA治疗能带来心血管结局受益, 临床医生也应该使用这些药物, 因为这类药物具有降血糖和降低体重的好处。在需要胰岛素的患者中(他们已经在自我注射, 因此启动药物的难度可能较小), 对3 829名积极治疗的参与者和3 235名接受安慰剂的14项试验的meta分析发现, 使用长效和短效GLP-1RA分别使HbA1c降低0.99%和0.67%, 空腹血糖分别降低16和3 mg/dl, 体重减轻2.7和1.3 kg。长效GLP-1RA与短效GLP-1RA相比, 胃肠道副作用较少:恶心分别为9.6%和19.9%, 呕吐分别为4.9%和7.7%, 腹泻分别为2.6%和5.3%。

3|并发症

在英国438 259名接受糖化血红蛋白(HbA1c)检测的患者中, 男性的绝对心肌梗死发生率是女性的两倍多, 但女性糖尿病患者的相对增幅更大。无论是男性还是女性, HbA1c每升高1%, 无论年龄(<60或≥60岁)、体重指数(<25或≥25 kg/m²)或社会阶层的不同, 心肌梗死的可能性都会增加18%。

在一项9 901人、中位数为5.4年的REWIND随访试验中, 对GLP-1RA度拉鲁肽的疗效进行了分析, 发现基线认知功能处于最低三分位数的患者, 在积极治疗后发生实质性认知损害的风险显著降低；作者提出了两种可能的机制, 一是减少亚临床或无症状卒中, 二是药物作用于对记忆和学习有直接影响的中枢神经系统GLP-1受体。

在对EMPA-REG试验6 820名参与者的3年随访分析中, 使用恩格列净治疗的蛋白尿水平较高的患者发生心血管事件和肾脏事件的风险较高, 而在干预期间蛋白尿减少程度较大的患者发生主要心血管事件、心血管死亡率、心衰住院和肾脏结果的风险较低。另一项表明蛋白尿重要性的研究是对有2 820名受试者参与的TOSCA.IT试验, 该试验评估了受试者的心血管事件和死亡率结局。结果表明在潜在心血管疾病患病率较低的男性中, 当蛋白尿为22 mg/g肌酐、非高密度脂蛋白胆固醇为125 mg/dl以及HbA1c达到7.7%时, 其全因死亡、非致命性心肌梗死、非致命性中风和急性冠心病的复合发病可能性增加。尿白蛋白水平低于30 mg/g肌酐和非高密度脂蛋白胆固醇水平低于130 mg/dl是有用的风险判别指标。这一发现提醒我们, 对于这些连续变量, 应当关注处于“正常”上限的水平。当然, 非高密度脂蛋白胆固醇的正确管理目标很可能是低于130 mg/dl。