New insights into the older hypoglycemic agents in type 2 diabetes therapy

Type 2 diabetes (T2D) is one of the leading causes of morbidity and mortality, consuming a significant proportion of public health spending. Following lifestyle changes, the most common treatment for T2D is the addition of oral hypoglycemic agents with broader selection for patients over the time. This summary is based on a lecture given 6 June 2020 at the Eighth Asia Pacific Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy AP), reexamining the characteristics of the older hypoglycemic agents, including metformin, dipeptidyl peptidase (DPP)-4 inhibitors, sulfonylureas (SUs), thiazolidinediones (TZDs), acarbose, colesevelam, and bromocriptine.

1 METFORMIN

Metformin is the most widely prescribed first-line drug used in treating T2D worldwide. It lowers fasting plasma glucose and glycosylated hemoglobin (HbA1c) in a dose-response manner at dosages of 500 to 2000 mg daily. As with most earlier studies of diabetes treatment; however, initial studies of metformin enrolled persons with baseline HbA1c 10%,¹ leading to greater reported absolute reductions in HbA1c with metformin and SUs than seen with more recently developed agents.

In the UK Prospective Diabetes Study (UKPDS), HbA1c was initially reduced by 1% and increased progressively on all therapies during the next 5 years, in association with progressive loss of beta-cell function.² Metformin was seen as an insulin sparing drug because insulin levels went down with metformin therapy as opposed to the increase with SUs or insulin therapy. Moreover, metformin did not increase body weight to the same extent as that with SUs or insulin. Metformin has a number of advantages, including weight neutrality and lack of intrinsic association with hypoglycemia. It does have a number of disadvantages. About 25% to 30% patients treated with metformin experience gastrointestinal (GI) symptoms, such as diarrhea, nausea, vomiting, bloating, and flatulence, leading to ~4% rate of discontinuation. These adverse effects can be minimized with slow titration and/or dose reduction. Another side effect is vitamin B12 deficiency, which can worsen manifestations of diabetic neuropathy. Lactic acidosis (LA) is a rare but serious adverse effect. People with renal insufficiency could have an increase in lactate production after metformin treatment, which was clearly seen with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m². A recent report showed that there was a greater likelihood of LA hospitalizations among individuals with eGFR <60 mL/min/1.73 m² treated with metformin rather than SUs.³ In addition, there is no evidence of cardiovascular protective effects of metformin.

2 DPP-4 INHIBITORS

DPP-4 inhibitors have now been used for a quarter of a century and have proven cardiovascular safety, based on cardiovascular outcome trials with linagliptin, alogliptin, sitagliptin, and saxagliptin. However, there is some evidence of greater likelihood of congestive heart failure hospitalization with some of these agents.⁴ In addition to their effects on the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), DPP-4 inhibitors decrease the degradation of stromal cell-derived factor-1 (SDF-1). This peptide, although potentially improving cardiovascular function in early diabetes, may increase myocardial fibrosis when there is existing cardiovascular disease. DPP-4 inhibitors also may elevate sympathetic activity by increasing incretin levels, leading to adverse cardiovascular function.

An interesting study, Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY), compared metformin with the combination of metformin plus vildagliptin, another DPP-4 inhibitor, in persons with early T2D, finding that both initial treatment failure and secondary treatment failure were delayed significantly in the individuals receiving the combination treatment.⁵ Furthermore, among T2D patients requiring insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in greater reduction in HbA1c without an increase in hypoglycaemia.⁶

DPP-4 inhibitors, then, have a number of advantages, including weight neutrality, lack of intrinsic hypoglycemia, lack GI side effects, and efficacy over time with metformin. Their disadvantages lie in having lower initial efficacy, as well as in possibility of a heart failure risk.

3 SULFONYLUREAS

Prescribing of SUs, generally as add-on therapy when metformin alone does not achieve adequate glycemic control in patients with T2D, has been decreasing in recent years. A network meta-analysis of all-cause mortality comparing all the different SUs and looking at the comparison with metformin showed that gliclazide and glimepiride were associated with lower risk of all-cause and cardiovascular-related mortality compared with glyburide, whereas chlorpropamide and tolbutamide were associated with higher risk.⁷ All these agents, however, were associated with increased all-cause mortality when compared with metformin.

In the Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes (CAROLINA), the effect of treatment with the DPP-4 inhibitor linagliptin was compared with that of the SU glimepiride in patients with relatively early T2D.⁸ Greater weight gain was observed in the glimepiride group early in the study and maintained thereafter, with a weighted mean between-group difference of −1.54 kg. Moreover, there was a lower hypoglycemia risk in the linagliptin group than in the glimepiride group.

There are also some worrisome studies suggesting the possible mortality risk of SUs. A large epidemiological database in the United Kingdom looking at individuals receiving metformin plus SUs vs metformin plus DPP-4 inhibitors showed a marked decrease in mortality and increase in major atherosclerotic cardiovascular events.⁹ In a similar study comparing metformin plus TZDs vs metformin plus SUs, a 60% increase in mortality was reported among those receiving SUs, with a significant increase in atherosclerosis, cardiovascular disease, and hospitalization rates.¹⁰

The advantage associated with SUs is their initial glucose lowering effect is greater than that of other agents, such as the DPP-4 inhibitors, TZDs, and even metformin. Its disadvantages include hypoglycemia, weight gain, and the possible risk of cardiovascular mortality.

4 THIAZOLIDINEDIONES

TZDs, also known as glitazones, are hypoglycemic agents that act as insulin sensitizers in a variety of tissues. Among many potential benefits, there is evidence with these agents of anti-atherosclerotic effects.

Observational data from two cohorts with 8000 individuals showed that pioglitazone had a potent effect in reducing stroke events in patients with T2D.¹¹ The Insulin Resistance Intervention after Stroke (IRIS) trial was designed to test whether pioglitazone would reduce the rates of stroke and myocardial infarction after ischemic stroke or transient ischemic attack (TIA) in patients without diabetes having insulin resistance.¹² The results showed that the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo, although with greater risk of weight gain, edema, and fracture, commonly recognized class side effects. The TZDs, may, then be of benefit in individuals at risk of cardiovascular endpoints.

TZDs also have potential renal benefits. In a large retrospective study comparing individuals receiving rosiglitazone, metformin and SUs, initiation of SUs was associated with 20% greater risk of the composite outcome of an eGFR event or end-stage renal disease (ESRD).¹³ Other studies have shown that TZDs (both rosiglitazone and pioglitazone) significantly decrease urinary albumin and protein excretion in patients with diabetes.¹⁴

TZDs have advantages in cardiovascular benefit and potential renal benefits, but they have disadvantages such as weight gain, fluid retention, and risk of heart failure in susceptible patients.

5 ACARBOSE

Acarbose, an α-glucosidase inhibitor, has pronounced effect on lowering postprandial glycemia and HbA1c among patients with T2D receiving diet alone, metformin, SUs, or insulin.¹⁵ Acarbose improved long-term glycemic control in patients with non-insulin-dependent diabetes mellitus regardless of concomitant antidiabetic medication.

There is controversy as to whether there is cardiovascular benefit of acarbose in prediabetes. The STOP-Noninsulin-Dependent Diabetes Mellitus (NIDDM) trial suggested acarbose was associated with a significant reduction in the risk of cardiovascular disease and hypertension.¹⁶ However, the Acarbose Cardiovascular Evaluation (ACE) trial showed that acarbose at a daily dosage of 50 mg TID in impaired glucose tolerance patients with coronary heart disease already receiving comprehensive antihypertensive, lipid-lowering, and antiplatelet coagulation therapies did not reduce the risk of major adverse cardiovascular events, although it reduced the development of diabetes.¹⁷

The advantages of acarbose include no intrinsic hyperglycemia or weight gain. Its side effects include GI symptoms, such as flatulence and diarrhea, as well as hypoglycemia when used with SUs or insulin.

6 OTHER AGENTS: COLESEVELAM AND BROMOCRIPTINE

Colesevelam, one of the bile acid sequestrants, is an effective agent in lowering low-density lipoprotein (LDL) cholesterol levels. A meta-analysis showed that colesevelam treatment improves glycemic control, with 0.55% reduction in HbA1c and 1 mmol/L reduction in fasting glucose.¹⁸ A recent 24-week, open-label randomized trial comparing the efficacy and safety of colesevelam and ezetimibe as second-line LDL lowering options in T2D suggested modest HbA1c reduction.¹⁹ However, patient discontinuation because of cost issues and GI side effects reduced the efficacy of the agent.

Bromocriptine, a sympatholytic dopamine D2 receptor agonist used in treatment of hyperprolactinemia and of Parkinson's disease, may offer a therapy with the potential to maintain glycemic control and reduce cardiovascular disease risk. It appears to have a central effect in reducing insulin resistance. In a large study of T2D patients in good glycemic control (HbA1c ≤ 7.0%), the likelihood of an increase in HbA1c to over 7% was 28.5% with placebo and 21.1% with bromocryptine.²⁰ Moreover, bromocriptine-QR was associated with improvement in cardiovascular outcome. Its adverse events include GI side effects and faintness.

DISCLOSURE

None.

2型糖尿病(T2D)是很多疾病的发病和死亡的主要原因之一, 占公共卫生支出的很大比例。随着生活方式的改变, T2D最常见的治疗方法是加用口服降糖药, 而随着时间的推移, 患者也有了更广泛的选择。本综述基于2020年6月6日在第八届亚太地区糖尿病、肥胖与高血压争议与共识会议(Controversies to Consensus in Diabetes, Obesity and Hypertension, CODHy AP)上的一个演讲, 重新分析了较老的降糖药特征, 包括二甲双胍、二肽基肽酶(DPP)-4抑制剂、磺脲类(SU)、噻唑烷二酮(TZDs)、阿卡波糖、盐酸考来维仑和溴隐亭。

1.二甲双胍

二甲双胍是全世界治疗T2D最广泛使用的一线处方药物。它能够降低空腹血糖和糖化血红蛋白(HbA1c), 剂量为500~2 000 mg/d, 呈量效关系。然而与大多数早期糖尿病治疗研究一样, 最初的二甲双胍研究招募了基线HbA1c为10%的患者, 导致报告的服用二甲双胍和SUs的HbA1c绝对值比使用新近开发的药物有更大的降幅。

在英国前瞻性糖尿病研究(UK Prospective Diabetes Study, UKPDS)中, HbA1c最初降低了1%, 在接下来的5年里, 所有疗法的HbA1c都逐渐升高, 这与β细胞功能的逐渐丧失有关。二甲双胍被视为一种节省胰岛素的药物, 因为二甲双胍治疗可以降低胰岛素水平, 而不像SUs或胰岛素那样会提高胰岛素水平。此外, 二甲双胍增加体重的程度不同于SUs或胰岛素。二甲双胍有许多优点, 包括不影响体重且和低血糖没有内在联系。它也有一些缺点。大约25%到30%使用二甲双胍治疗的患者出现胃肠道症状, 如腹泻、恶心、呕吐、腹胀和胀气, 导致约4%的停药率。这些不良影响可以通过缓慢加量或减少剂量来最小化。另一个副作用是维生素B12缺乏, 这会加重糖尿病神经病变的表现。乳酸酸中毒(Lactic acidosis, LA)是一种罕见但严重的不良反应。肾功能不全患者在二甲双胍治疗后乳酸生成增加, 可出现估计肾小球滤过率(EGFR)<30 mL/min/1.73 m²。最近的一份报告显示, EGFR<60 mL/min/1.73 m²的患者服用二甲双胍后, 因LA住院的可能性更大, 而不是服用SUs的患者。此外, 没有证据表明二甲双胍具有心血管保护作用。

2.DPP-4抑制剂

DPP-4抑制剂已经使用了四分之一个世纪, 并且基于利格列汀、阿格列汀、西格列汀和沙格列汀的心血管转归试验证明了其心血管安全性。然而, 有证据表明, 使用这些药物治疗后, 因充血性心力衰竭而住院的可能性更大。除对胰高血糖素样肽-1(glucagon-like peptide-1, GLP-1)和葡萄糖依赖性胰岛素样多肽(glucose-dependent insulinotropic polypeptide, GIP)的影响外, DPP-4抑制剂还可降低基质细胞衍生因子-1(stromal cell-derived factor-1, SDF-1)的降解。这种肽虽然有可能改善早期糖尿病患者的心血管功能, 但存在心血管疾病时可能会增加心肌纤维化。DPP-4抑制剂也可能通过增加肠促胰岛素水平来提高交感神经活性, 从而导致心血管功能不良。

一项维格列汀联合二甲双胍早期治疗2型糖尿病的研究, 比较了二甲双胍和二甲双胍加另一种DPP-4抑制剂维格列汀在早期T2D患者中的疗效, 发现在接受联合治疗的患者中, 初次治疗失败和继发治疗失败的时间都显著延迟。此外, 在需要甘精胰岛素治疗的T2D患者中, 与停止治疗相比, 继续服用西格列汀可导致糖化血红蛋白(HbA1c)更大地降低, 而不会增加低血糖。

因此, DPP-4抑制剂有许多优点, 包括不影响体重、无低血糖和胃肠道副作用, 以及联用二甲双胍的长期疗效。缺点在于初始疗效较弱, 以及存在心力衰竭风险。

3.磺脲类药物

磺脲类药物通常在二甲双胍不能完全控制T2D患者的血糖时作为补充治疗, 近年来其使用一直在减少。全因死亡率的网络meta分析比较了所有不同的SUs, 并比较了与二甲双胍的效果。结果显示, 与格列本脲相比, 格列齐特和格列美脲的全因死亡和心血管相关死亡率较低, 而氯丙酰胺和甲苯丁酰胺的风险较高。然而, 与二甲双胍相比, 所有这些药物都与全因死亡率的增加有关。

在T2D患者中使用利格列汀vs格列美脲的心血管结果研究中, 将DPP-4抑制剂利格列汀与SU格列美脲治疗相对早期的T2D患者的疗效进行了比较。格列美脲组在研究初期体重增加更大, 随后继续保持, 其组间体重的加权平均差为-1.54 kg。此外, 与格列美脲组相比, 利格列汀组的低血糖风险更低。

也有一些令人担忧的研究表明SU可能存在死亡风险。英国的一个大型流行病学数据库对接受二甲双胍加SUs与二甲双胍加DPP-4抑制剂治疗的个体进行了比较, 结果显示SU组死亡率显著降低, 动脉粥样硬化性心血管事件明显增加。另一个相似的研究比较了二甲双胍加TZDs和二甲双胍加SUs, 结果显示接受SUs治疗的患者死亡率增加了60%, 动脉粥样硬化, 心血管疾病和住院率显着增加。

SU的优势在于其最初的降糖作用大于其他药物, 例如DPP-4抑制剂、TZD甚至二甲双胍。它的缺点包括低血糖、体重增加和心血管死亡的可能风险。

4.噻唑烷二酮

TZD, 也称为格列酮类, 是降血糖药, 可在多种组织中充当胰岛素增敏剂。在诸多潜在的好处中, 有证据表明这类药物具有抗动脉粥样硬化作用。

来自两个有8 000名患者的队列研究表明, 吡格列酮对减少T2D患者的中风事件有效。中风后胰岛素抵抗干预(Insulin Resistance Intervention after Stroke, IRIS)试验旨在测试吡格列酮在没有胰岛素抵抗的糖尿病患者中是否会降低缺血性卒中或短暂性脑缺血发作(TIA)后的卒中率和心肌梗死率。结果表明, 吡格列酮治疗组的卒中或心肌梗死风险低于安慰剂组, 尽管体重增加, 水肿和骨折风险增加是公认的副作用。但TZD可能还是对有心血管风险的个体有益。

TZD还具有潜在的肾脏益处。在一项大型回顾性研究中, 比较接受罗格列酮, 二甲双胍和SUs治疗的个体, 结果发现SUs发生eGFR事件或终末期肾脏疾病(end-stage renal disease, ESRD)的复合风险增加20%。其他研究表明, TZDs(罗格列酮和吡格列酮)均可显著降低糖尿病患者的尿白蛋白和蛋白质排泄量。

TZD在心血管益处和潜在的肾脏益处方面具有优势, 但在易感患者中却具有诸如体重增加、体液潴留和心力衰竭等缺点。

5.阿卡波糖

阿卡波糖(一种α-葡萄糖苷酶抑制剂)对单独接受饮食控制、二甲双胍、SUs或胰岛素治疗的T2D患者降低餐后血糖和HbA1c都有显著效果。阿卡波糖可改善非胰岛素依赖型糖尿病患者的长期血糖控制用药。

关于糖尿病前期中阿卡波糖是否具有心血管益处存在争议。 停止-非胰岛素依赖型糖尿病(STOP-NIDDM)试验表明, 阿卡波糖可显著降低心血管疾病和高血压的风险。然而, 阿卡波糖心血管评估(Acarbose Cardiovascular Evaluation, ACE)试验显示, 阿卡波糖每日剂量为50 mg TID, 在已经接受全面降压、调脂和抗血小板凝血疗法的冠心病合并葡萄糖耐量异常患者中, 尽管减少了糖尿病的发生, 但并未降低重大不良心血管事件的风险。

阿卡波糖的优势在于不存在内在的高血糖症和体重增加风险。当与SUs或胰岛素联用时, 它的副作用包括胃肠道症状, 例如肠胃气胀、腹泻以及低血糖。

6.其他制剂:盐酸考来维仑和溴隐亭

盐酸考来维仑是一种胆汁酸螯合剂, 是降低低密度脂蛋白(LDL)胆固醇的有效药物。一项meta分析显示, 盐酸考来维仑治疗可改善血糖控制, HbA1c降低0.55%, 空腹血糖降低1 mmol /L。最近一项为期24周的开放标签随机试验, 比较了盐酸考来维仑和伊泽替米作为二线降脂选项的疗效和安全性, 显示其可以适度降低HbA1c。然而, 由于费用问题和胃肠道副作用而导致患者停药降低了该药的效果。

溴隐亭是一种用于治疗高泌乳素血症和帕金森氏病的多巴胺D2受体激动剂, 可能提供一种维持血糖控制和降低心血管疾病风险的疗法。它似乎对降低胰岛素抵抗具有重要作用。在一项对血糖控制良好(HbA1c≤7.0%)的T2D患者大型研究中, 安慰剂组HbA1c升高至7%以上的可能性为28.5%, 溴隐亭的可能性为21.1%。此外, 溴隐亭可以改善患者的血糖相关心血管结局。它的不良事件包括胃肠道副作用和眩晕。