LS：Lunch Symposium (1-15

LS1 NEW APPROACHES FOR CHRONIC KIDNEY DISEASE IN TYPE 2 DIABETES MANAGEMENT

RALPH DEFRONZO

Diabetic kidney disease is the leading cause of kidney failure worldwide; in the USA, it accounts for over 50% of individuals entering dialysis or transplant programmes. Unlike other complications of diabetes, the prevalence of diabetic kidney disease has failed to decline over the past 30 years. Hyperglycaemia is the primary aetiological factor responsible for the development of diabetic kidney disease. Once hyperglycaemia becomes established, multiple pathophysiological disturbances, including hypertension, altered tubuloglomerular feedback, renal hypoxia, lipotoxicity, podocyte injury, inflammation, mitochondrial dysfunction, impaired autophagy and increased activity of the sodium–hydrogen exchanger, contribute to progressive glomerular sclerosis and the decline in glomerular filtration rate. The quantitative contribution of each of these abnormalities to the progression of diabetic kidney disease, as well as their role in type 1 and type 2 diabetes mellitus, remains to be determined. Sodium–glucose co-transporter 2 (SGLT2) inhibitors have a beneficial impact on many of these pathophysiological abnormalities; however, as several pathophysiological disturbances contribute to the onset and progression of diabetic kidney disease, multiple agents used in combination will likely be required to slow the progression of disease effectively.

LS2 COMPREHENSIVE REVIEW ON RENAL SAFETY DATA FOR TRULICITY ON PATIENTS WITH TYPE 2 DIABETES

張宏猷

由於新型的血糖藥物發展快速，有越來越多血糖藥物可供選擇。其中，部分新型的血糖藥 物由於在 CVOT 取得了降低心血管事件風險結果，讓 ADA 的建議也從 2018 年開始，現在除 了控制血糖外，也將心血管事件預防的考量納入其中。當中有一部份提到，若病患有 ASCVD 風險，可考慮優先使用 GLP-1 RA。Trulicity 為台灣第一個一週一次的 GLP-1 RA 藥物，在 2018 年 REWIND 發表後，也同時拿到 ADA/EASD 在 primary 與 Secondary prevention 的認可， 隨後，台灣也於 2020 年拿到此適應症。在 REWIND 發表後的兩年間，Trulicity 陸陸續續發表 了許多其他次分析，其中也包含了對於腎功能的結果，此次演講將以腎病變當出發點，探究 Trulicity 是否能為糖尿病患合併腎病變的過程帶來幫忙。

LS3 SEE ASIA - SITAGLIPTIN AND ERTUGLIFLOZIN EFFICACY IN ASIAN T2DM PATIENTS

王治元教授

臺大醫院新陳代謝科

Current guidelines recommend that a single agent be added to treatment in patients with inadequate glycemic control with metformin monotherapy. Although some patients achieve glycemic control with dual therapy, many, especially those starting at higher HbA1c levels, may not. Further, patients who achieve glycemic control with dual therapy may experience progressive deterioration of glycemic control. In some cases, it may be appropriate to consider addition of a combination of two anti-hyperglycemic agents (AHAs) with complementary mechanisms of action, favorable safety profiles and without pharmacokinetic interaction, such as a sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase-4 (DPP-4) inhibitors.2 This may provide a more robust and sustained antihyperglycemic effect, resulting in more patients achieving and maintaining glycemic goals, and could become a useful alternative to the single stepwise antihyperglycemic approach. Ertugliflozin is an inhibitor of SGLT2, with high selectivity relative to SGLT1, Ertugliflozin as monotherapy or as add-on to metformin or metformin and sitagliptin improved glycemic control and reduced body weight, with a safety profile consistent with that of other SGLT2 inhibitors. Sitagliptin is a DPP-4 inhibitor indicated for treatment of type 2 diabetes. Sitagliptin as monotherapy, or as part of dual or triple therapy for patients with type 2 diabetes, provides clinically meaningful reductions in blood glucose. The primary objective was to determine whether coadministration of ertugliflozin with sitagliptin provides better glycemic benefit for patients with type 2 diabetes who were inadequately controlled with metformin. An updated data of VERTIS-CV adds additional understanding of Ertugliflozin on HF & Renal understanding.

LS4 NEW ERA OF CONVENIENT INSULIN REGIMENS: THE FIRST 2-IN-1 INSULIN CO-FORMULATION IDEGASP

王俊興

台灣第二型糖尿病患者接受胰島素治療時，多以基礎胰島素作為起始。然而國內研究顯 示，僅約一成患者在接受基礎胰島素 24 周後達到 HbA1c 的目標 (J Diabetes Investing 2016;

7:881-888)。而亞洲地區因人種以及飲食習慣以米食為主的關係，餐後血糖對高血糖的貢獻度 較西方人高，顯示餐後血糖的控制於亞洲族群更顯重要。因此，預混胰島素為目前常用來控制 餐後血糖的選項之一，預混型胰島素在一支筆針同時包含速效及中長效胰島素，可同時有效控 制及餐後血糖，並提供簡單方便的治療方式，減少病人須學習多種注射藥物的障礙。同時，目 前也將有新形態的可溶性雙胰島素問世，IDegAsp 為第一個能夠將兩種不同胰島素類似物混合 於同一筆針的可溶性雙胰島素，成分包含超長效胰島素 Insulin Degludec 及速效胰島素 Insuln Aspart，藥水呈透明澄清，病患使用前不須重新搖振均勻。此外，IDegAsp 可做為胰島素起始 以及強化的選擇，能減少低血糖發生風險，同時有效控制空腹及餐後血糖，並使用改良式注射 器幫助病患方便有效的控制血糖。

LS5

糖尿病之血脂異常治療

葉乃誠醫師

奇美 新陳代謝科

糖尿病腎病變 (Diabetic Kidney Disease, DKD) 是導致末期腎病變 (End Stage Renal Disease, ESRD) 最主要的原因，也是世界各國都非常重視的公衛議題，因它為個人和整體社會經濟都帶 來嚴重的負面影響。過去幾十年來在糖尿病腎病變的領域有許多觀念的變革與藥物的發展，因 此重新認識糖尿病腎病變乃為此演講的重點。 糖尿病合併腎病變的病人，心血管風險甚至逼近有發生過心肌梗塞的病人，所以如何藉由 三高控制將風險降低是重要的議題，降血糖藥物上除了 SGLT-2 血糖藥證明了對於心臟及腎臟 的好處外，血脂控制上在最新 ADA,ESC 的治療指引中，也將 LDL 的目標從 100 下修 70，針 對降血脂藥物的選擇也偏向更高強度的 statin，或加上 Ezetimibe 或 PCSK9i 來達到目標。

Atorvastatin 不需要根據腎功能調整劑量，且不會影響腎功能或造成蛋白尿等問題，對於糖 尿病合併有腎病變的病人是降脂達標的選擇之一。

LS5

糖尿病周邊神經病變之診斷與治療

董欣醫師

台中榮總神經內科

神經病變是糖尿病最常見的慢性併發症，亦為造成糖尿病患者殘障及產生多樣不適症狀的 主要原因之一。其盛行率可由初期診斷糖尿病時的 7.5% 至 25 年後的 50-60%。一般而言，糖 尿病病期超過十年以上，約有四分之一的第二型糖尿病患者出現糖尿病多發性神經病變。 糖尿病神經病變因為受影響的神經不同 , 在臨床上表現的很多樣性。大致上分為以侵犯「感 覺 - 運動 - 自律神經混合型」的對稱性多發性神經病變 ( 約占 70-75%) 及局部性神經病變 ( 約 佔 25-30 %)。 糖尿病神經病變之分類 一、多發性神經病變 二、自主神經病變 三、局部性神經病變或單一神經病變 糖尿病神經病變的治療目標在於：預防疾病形成 ( 良好的血糖控制 )、早期診斷、改善症 狀、避免次發性合併症及輔導病患自我照顧。重點在於良好的病患教育，幫助病患了解疾病可 能造成的症狀以及清楚認識良好控制血糖的重要性，將血糖控制在正常範圍內，有助於延緩或 預防周邊神經病變及其他併發症的發生（例如視網膜病變、腎臟病變等）。適當的足部護理及 物理與藥物治療等等。藥物治療治療的藥品包括抗憂鬱藥、抗癲癇藥 ( 如 Lyrica)、辣椒素軟膏、 Lidocaine 貼布、alpha-lipoic acid 和經皮神經電刺激。其中 Lyrica 是經由抑制興奮性神經傳遞物 質的釋放，從而降低神經疼痛的症狀。 起始劑量應從 150 mg / 天 (75 mg bid) 開始，最高建議劑量是 300 mg / 天，劑量越高止痛 效果越佳，疼痛改善了，睡眠品質也會提升 !

LS6 OPTIMIZE T2D TREATMENT STRATEGY TO MAXIMIZE PERSISTENCE OF OAD

PROF. ALICE CHENG

近年來，小於 40 歲的年輕糖尿病患者逐漸增加，且隨著平均餘命的增加，整體的糖尿病 治療年限大幅上升，而許多患者甚至確診 8 年即已使用到三線口服藥品加上胰島素注射才能 控制糖尿病，尤其亞洲族群糖尿病患者本身 beta-cell function 更是只有西方人的一半，該如何 選擇加藥的種類、用藥時機，才能最大化每一線藥品的治療年限、延緩患者施打胰島素的時 間，而針對 beta cell function，或許臨床上無法定期監測，但是否可以由試驗證據，應用至臨 床實踐中。

LS7 IMPORTANCE OF EARLY INSULINIZATION AND HOW TOUJEO HELPS

范綱志

Type 2 diabetes occurs when the body’s pancreas does not produce sufficient insulin and/or cells respond poorly to insulin and take in less glucose. Current guidelines recommend diet and lifestyle modification with or without oral diabetic agents (OADs) as the first step in treating Type 2 diabetes. However, to only rely on OADs for treatment will result in beta cells being overworked, gradually losing the cells’ ability to produce insulin to support the patient’s needs, thereby necessitating the initiation of insulin.

The invention of insulin injectables aims to supplement the body’s need for insulin and to slow the progression of the disease. Research has shown the benefits of early use of insulin to reduce HbA1c levels and to reduce the risk of comorbidities associated with increased HbA1c levels. In addition, with the advancement of once daily second-generation basal insulin, patients today can achieve glycemic control while reducing the risk of hypoglycemia. This helps to lower potential resistance to injectables and makes it safe for patients to embark on this treatment.

LS8 CURRENT CONCEPT OF LIPID LOWERING THERAPY

李貽恒

Statin reduces low-density lipoprotein cholesterol and improves clinical outcomes in high risk patients. In general, statin is a safe and well-tolerated medication. However, varieties of adverse effects are reported in some patients and may interfere long-term drug compliance. Statin-associated muscle events and liver function change account for most of these adverse effects. Patients are regarded as statin intolerance if they need to discontinue statin therapy due to these adverse effects. To date, there is no universal standard definition of statin intolerance. But a pragmatic definition of statin intolerance is essential and helpful for clinicians in daily practice. In this article, after expert consensus meetings and literature review, criteria were recommended to identify patients with statin intolerance in Taiwan. The purpose of this statement is to help health care professionals in Taiwan to diagnose and manage individuals who develop muscular and hepatic side effects after statin therapy.

LS9 VERIFY THE ROLE OF EARLY COMBINATION : FOCUS ON BETA CELL PRESERVATION

翁瑄甫

英國前瞻性糖尿病研究 UKPDS 和 ADOPT 研究表明，儘管經過治療，但由於β細胞功能 的逐步下降，血糖控制仍隨時間而惡化。這些數據突顯了第 2 型糖尿病（T2DM）的治療中保 存β細胞功能的重要性。 2020 年 Diabetes care Guideline 基於 VERIFY study 發表後建議在新診斷第二型糖尿病患可 建議病患積極使用 Metformin 合併 Vildagliptin， Metformin 治療失敗後才合併 Vildagliptin 可延 緩病患疾病進程，並降低第一次及第二次治療失敗風險，VERIFY Study 是一雙盲、隨機分配 的臨床試驗，主要針對新生糖尿病 A1C 介於 6.5% 至 7.5% 的病患，探討早期合併 metformin 及 Vildagliptin 與階梯式使用 Metformin 治療失敗後合併 vildagliptin 在治療上的差異。 以 incretin 為基礎的療法可改善 T2DM 患者的β細胞功能。許多的研究發現 Vildagliptin

治療使得β cell 與 T2DM duration 之間呈負相關。 與此，VERIFY study 中支持早期合併治療 Metformin 及 Vildagliptin 顯示早期合併治療得 以保存第二型糖尿病病患的β- 細胞功能，支持早期合併治療延遲第二型糖尿病自然疾病進程， 使得疾病進程得以改善。

LS10 EVOLUTION OF T2D CARE, MOVE FROM CONVENTIONAL TO COMPREHENSIVE THERAPY

蔡世澤

根據統計，多數第二型糖尿病人合併有心腎共病，而血糖與心腎互相影響並且息息相關。 2020 年底 ADA 發表 2021 新的治療指引，也指出針對心血管高風險族群除了血糖的控制之外， 提早做器官保護也一樣重要，而對於非屬於這些族群的糖尿病患者，應同時考量到藥物的療 效、減少患者對副作用的負擔及提升服藥順從性。因此，糖尿病治療必須思考長期治療策略， 讓病患在控制血糖的進程中，兼顧共病管理、降糖療效、以及順服性，以達到最大化的臨床 效益。

LS11 ADVANCED IN INJECTABLE THERAPY: ADDRESSING THE NEED FOR INTENSIFICATION AND HOW WE MAKE IT SIMPLER

LEIGH PERREAULT

The global burden of type 2 diabetes is increasing worldwide, although the the benefits of early, aggressive glycemic control are clearly established, treatment remains suboptimal. Many patients fail to achieve long-term glycemic control, approximately 50% of patients with type 2 diabetes mellitus (T2DM) do not achieve glycemic targets and require treatment intensification.

Many studies have shown that delayed treatment intervention of diabetes is associated with increased risk of complications. Now a day, several studies demonstrate that early intensification is associated with a larger reduction in A1c across all baseline A1c categories, and may decrease the risks of CV events in T2D patients.

Patients with A1c>9% usually required injectable therapy for intensification. Traditional intensified strategies with prandial insulin can cause hypoglycemic episodes, weight gain and burden of multiple daily injections. Adding glucagon-like peptide-1 receptor agonists, such as the short-acting lixisenatide, are able to control postprandial excursions, without weight gain, and with a low risk of hypoglycemic events. iGlarLixi (Soliqua®) is a titratable, co-administration of BI/GLP-1RA in a single once-daily injection. This so-called fixed-ratio combination (FRC) agent can exploits the complementary mechanisms of action, with greater reduction in HbA1c, improving convenience of mitigating GI symptoms due to gradual dose increment.

In this talk, Dr. Perreault will lead the audience to explore the journey of iGlarLixi clinical program and let us know why iGlarLixi can make T2D treatment simpler from her clinical experience.

Overall, the efficacy, safety, and convenient once-daily administration schedule of iGlarLixi make it a valuable treatment option for patients with T2DM requiring treatment intensification.

LS12 ADVANCING DIABETES CARE WITH GLP-1 RECEPTOR AGONISTS

杜思德醫師

Glucagon-like peptide 1 is a hormone of the incretin system, responsible for a variety of glucose regulating effects, including the secretion of glucose-dependent insulin and inhibition of glucagon release. This effect can be impaired for type 2 diabetes patients (T2D). Using GLP-1 receptor agonist (GLP-1RA) to solve this defect is an effective therapy for T2D, and has accumulated more than ten years of clinical experience. This presentation reviews the evidence of subcutaneous GLP-1RA and its role in the treatment of T2D. Clinical trials and real world evidence of subcutaneous GLP-1RA have

shown that these drugs have a good glycated hemoglobin (HbA1c) lowering effect , an inherently low potential for hypoglycemia, and reduce body weight. Cardiovascular outcome trials have established cardiovascular safety and have shown that human-based GLP-1RA can reduce the risk of major adverse cardiovascular events (MACE) in patients with established or higher CV risks.

LS13 PREVENTING HYPOGLYCEMIA BY USING TECHNOLOGY IN DIABETES SELF-MANAGEMENT

林慶齡

The international standard ISO (International Organization for Standardization) 15197 defines various requirements for SMBG systems, concerning safety and reliability, analytical performance (e.g. system accuracy), information supplied by the manufacturer and performance in the hand of layusers. The currently applicable version of the standard is ISO 15197:2013, its predecessor was ISO 15197:2003.

Regarding system accuracy, ISO 15197:2013 describes the following minimum criteria: Criterion A: At least 95% of a system’s measurement results shall fall within ±15 mg/dl of the comparison measurement results at blood glucose (BG) concentrations <100 mg/dl and within ±15% at BG concentrations ≥100 mg/dl. Criterion B: At least 99% of individual measurement results shall fall within Consensus Error Grid zones A and B. Criterion A is also applicable for user performance evaluation.

A number of accuracy evaluation studies performed in recent years have reported that not all available SMBG systems show sufficient measurement quality to comply with ISO 15197 requirements. However, there are qualitative differences even among SMBG systems that comply with ISO 15197 requirements. Simulation studies show that higher accuracy leads to clinical benefit. User performance evaluation studies showed that SMBG systems showing high accuracy when used by trained professionals do not necessarily also showed high accuracy in the hands of lay-users. This underlines the importance of patient education and training, not only to avoid meter-independent factors like contamination of hands, but also to highlight meter-specific details. A reliable and accurate SMBG system is an important aspect in optimizing insulin-dependent patients’ therapies.

LS14 RELENTLESS PROTECTION OF PROLIA (DENOSUMAB) IN ENDOCRINOLOGY

廖國盟

• 骨質疏鬆症（osteoporosis）是一種因骨量減少或骨密度降低而使骨骼微細結構發生破壞的慢 性疾病，惡化的結果將導致骨骼脆弱，並使骨折的危險性明顯增高。 • 對於具有高骨鬆性骨折風險或已發生骨鬆性骨折的患者而言，僅提供非藥物治療是不足的， 應要積極使用抗骨鬆藥物治療。 • Prolia（保骼麗），注射針劑，屬細胞核 kB 受體活化因子抑制劑（RANKL Inhibitor），每 6 個月皮下注射一次，使用方便，對蝕骨細胞的抑制效果比雙磷酸鹽類的藥物更強。 • 積極治療骨質疏鬆症，預防突如其來的脆弱性骨折。

LS15 PRECISION MEDICINE IN THYROID CANCER- UPDATED NTRK FUSION - TKI USE IN RAI-REFRACTORY DTC AND ATC

諶鴻遠

NTRK gene fusion 的 RR-DTC 和 ATC • NCCN guidelines 中建議，對於晚期、進行性 (progressive) 的甲狀腺癌，或有危及生命的疾病 時，可以讓病患接受基因檢測，以確認是否有 NTRK、RET 等基因融合 (gene fusion)，並了 解其腫瘤突變負荷量 (tumor mutational burden, TMB)。對於 NTRK gene fusion 呈陽性的病患， 可以給予 Larotrectinib 或 entrectinib；如果有 RET fusion，可給予 selpercatinib；如果 TMB≥

10 mut/Mb，可給予免疫治療藥物；而沒有做基因檢測的狀況下，對於進行性及 / 或有症狀 的疾病，則可考慮使用 lenvatinib 或 sorafenib2。對於 ATC 的病患，則建議在一開始就盡快做 基因檢測 2 。 • Larotrectinib 治療：合併第一期的試驗和第二期的 NAVIGATE 研究來看，共有 28 位帶有

NTRK 基因融合的局部晚期或轉移性甲狀腺癌病患，其中 ATC、濾泡型甲狀腺癌 (follicular thyroid cancer, FTC) 和甲狀腺乳突癌 (papillary thyroid cancer, PTC) 病患分別佔 25%、7% 和 68%4。結果顯示，ATC 病患接受 Larotrectinib 治療反應有些兩極，總體反應率 (overall response rate, ORR) 為 29%。而 Larotrectinib 對於中樞神經系統 (central nervous system) 轉移 的病患治療也有效 ( 圖三 )；在整體病患中，治療持續時間 (duration of treatment) 最長可達 45.4 個月以上，反應持續時間 (duration of response) 在第 12 個月還有 95%，而第 12 個月的 無惡化存活期 (progression-free survival, PFS) 和整體存活期 (overall survival, OS) 比率分別為 81% 和 92%4。安全性表現的部分，則是幾乎沒有第 3 和第 4 級的不良反應 4 。 • 對於晚期甲狀腺癌，Larotrectinib 可以加強 (enhance) 放射碘吸收的能力：發表在 N Engl J

Med 中的一項案例報告中提到，一位 64 歲的女性患有 PTC 達 34 年，且有肺部轉移。陸續 接受碘 -131、lenvatinib 治療後仍復發，且有一些較嚴重的不良反應。予以基因檢測後顯示 為 NTRK3 gene fusion，因此給予 larotrectinib 100 mg BID，治療後病患的狀況即控制下來。 此外，在接受 larotrectinib 治療前，病患的影像檢查顯示除了胃和腸子之外，沒有放射碘吸 收的情形，然而，在 larotrectinib 治療後則發現，肺部變成有放射碘吸收的情況 5 。

Reference

1. Zaballos MA, et al. J Endocrinol. 2017; 235(2): R43-R61.

2. NCCN guidelines: Thyroid cancer. 2020 version 2.

3. Suzuki K, et al. Cancers (Basel). 2019; 11(9): 1290. 4. Cabanillas ME, et al. Poster presented at ESMO Virtual Congress 2020, September 19–21, 2020.

Abstract 1916P.

5. Groussin L, et al. N Engl J Med. 2020; 383(17): 1686-1687.