{}及臨床處置陳淑謐 藥師

東安藥局全聯會藥事照護小組委員

中華民國糖尿病衛教學會合格衛教師

2015年9月6日及9月13日

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Drug Induced Hyperglycemia

Drug Induced Hypoglycemia

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「Drug Induced Hyperglycemia」

‹#›4

Glycogenesis

� Insulin

Thesaurus

Drug Induced Diabetes• A number of medications have side effects which include

the raising of blood glucose levels. [多種藥物會引發高血糖]

• Drug induced diabetes is when use of a specific medication has lead to the development of diabetes.[指用藥後引發DM]

• Many therapeutic agents can predispose to or precipitate diabetes, especially when pre-existing risk factors are present, and these may cause glucose control to deteriorate if administered to those with existing diabetes.[尤其已有一些既存的 DM風險]

csm1

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csm1 predispose to or precipitate ：易患或促成chen shu mih, 2015/9/6

Drug Induced Diabetes

•They may act by increasing insulin resistance, by affecting the secretion of insulin, or both.[透過增

加阻抗或減少胰島素分泌或二者]

•For convenience, these agents may be subdivided into widely used medications that are weakly diabetogenic, and drugs used for special indications that are more strongly diabetogenic. [簡單分為弱致或強致DM藥物]

Drug Induced Diabetes• Examples of the former include antihypertensive

agents and statins[早期降壓及Statin藥物]

• Examples of the latter include steroids, antipsychotics and a range of immunosuppressive agents.[後期還包

括類固醇、抗精神病要及免疫抑制劑]

• There are also a number of known beta cell poisons including Streptozotocin.

Drugs Conferring a High Risk of Diabetes

Thiazides• Thiazide diuretics revolutionized the treatment of hypertension in the 1960s,

but were soon noted to increase the risk of diabetes.[不久就發現會增加血糖]• Subsequent experience showed that that this risk is greatly reduced by low-

dose therapy, whose benefits therefore outweigh its risks. [透過低劑量可克服]

• The thiazides have a weak inhibitory effect upon release of insulin from the beta cell.

• This effect is so marked in one member of the family, Diazoxide, that this is used to control excessive insulin secretion by unresectable insulinomas.[Diazoxide是最後造成高血糖的利尿劑，所以被用來當成胰島素瘤無法切除時，所致低血糖之處理藥物]

csm2

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csm2 不可切除的胰島素瘤chen shu mih, 2015/9/6

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Thiazide-Induced Hyperglycemia

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Thiazide Diuretic-Induced Hyperglycemia

•Reduce the total body potassium and subsequent decreased insulin secretion[機轉是全身鉀離子減少，而降低胰島素分泌]

•This effect is largely dose dependent[與高劑量正相關]

•Reversed by potassium replacement or drug discontinuation[透過補鉀或停藥可逆轉]

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Thiazide 仿單

Beta-blockers

• These impair insulin release, especially agents that are not selective for the β1-receptor subtype.[非選擇乙型阻斷劑]

• Several studies have linked chronic use of β-blockers with an increased risk for the development of diabetes.

• The Atherosclerosis Risk in Communities (ARIC) study found that the risk of diabetes in was increased by 28%in those taking a beta-blocker for hypertension over a 6-year period, as compared with other medications.

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機轉•Are likely explained through the diminution of insulin release [縮減胰島素釋出]

•Individual agents exhibit variable effects on insulin sensitivity[不同類BB，反應不盡相同]

•Carvedilol have favorable effects on insulin sensitivity and glucose tolerance (alpha-blocker: increased peripheral blood flow and the facilitation of glucose uptake by skeletal muscle.[Carvedilol因尚具alpha阻斷效果，增加周邊血流量

而有利骨骼肌回收葡萄糖，讓胰島素敏感性改善]

csm3

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csm3 favorable effects良好效果chen shu mih, 2015/9/6

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How about Thiazie + Beta-Blocker?

Thiazide Beta-Blocker

28% risk

• The risk conferred by non-selective beta blockers may be enhanced if these are combined with a thiazide diuretic.[6年研究：合併Thiazide+BB，增加28%DM 風險]

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PATIENTS ON STEROIDS

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Introduction

1/4 need to use over 6 months

Glucocorticoid-Induced Hyperglycemia

19500.9%: general population

2.5%: 70-79 years of age

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Frequency of Hyperglycemia in Patients Receiving High-Dose Steroids

Donihi A, et al. Endocr Pract. 2006;12:358-262. 19

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Glucocorticoid and Diabetes

The number of new publications on PubMed with search terms ‘glucocorticoids’ and ‘diabetes’ shown per five-year intervals. The numbers indicate publications in the specific five-year interval and do not indicate accumulated numbers. After 1975, the amount of research performed on the topic declined somewhat, but in recent years, the subject has received full attention

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Prednisolone

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Steroid •Steroid drugs can induce a form of iatrogenic Cushing's syndrome, and are probably the most widely used drugs which confer a high risk of diabetes.

• A Canadian paediatric study found that 0.4% of childhood diabetes was ascribed to medication, and 55 of 56 children in this category were on steroids.

•Anabolic steroids (synthetic androgens mimicking testosterone or dihydrotestosterone) should not be confused with glucocorticoids. Although they have many unwanted effects, diabetes is not among them.

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csm4 1899年William Osler首先撰文描述慢性皮質醇過量可能造成的臨床表徵1，至1912年其同僚好友Harvey Cushing（庫欣）提出一位23歲女性出現肥胖、多 毛、及無月經的病例報告2

同化類固醇chen shu mih, 2015/9/6

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最近的新聞

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Incidence Rate

In hospital: > 50%

Neuropathy: 40%

Respiratory disease: 14.7%

Transplant: 2~52%

Definition: blood sugar >200mg/dL

Odds ratio: 1.36~2.31

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Why important?

Moreover, the control of transient hyperglycemia in similar situations during hospitalization has been associated with

First, the high prevalence and the problems of hyperglycemia itself, which are often severe, may

Second, corticosteroids increase the risk of infection due to persistent hyperglycemia, which has a deleterious effect on prognosis.

問題嚴重

引發感染 預後變差

有處理 有幫忙

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Supraphysiological Doses

Oral

Inhaled

IA

IVTopic IM

ALL

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Steroid-Induced Hyperglycemia Mechanism

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Steroid-Induced Hyperglycemia Mechanism

J Clin Invest. 2012;122(11):3854-3857. doi:10.1172/JCI66180.

骨骼肌：蛋白質分解及減少葡萄糖回收

肝：脂肪變性、糖質新生骨質替換

脂肪分解

csm5

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csm5 骨鈣素(骨質替換速率指標). 臨床用途：. Osteocalcin 是一種骨質生成速率(formation rate) 的指標chen shu mih, 2015/9/6

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•Glucocorticoids exert their impact on metabolism through

several different tissues in the body. [多個組織]

•In the presence of glucocorticoids there is an increase in

adiposity as well as an increase in lipolysis, leading to

elevated free fatty acids in the circulation and an increase in

insulin resistance. [脂肪分解 胰島素阻抗]

•Muscle undergoes proteolysis, releasing amino acids that

increase insulin resistance. [蛋白質分解 胰島素阻抗]

•Mechanisms leading to glucocorticoid-mediated insulin resistance

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•Glucocorticoids exert their impact on metabolism through

Postreceptor insulin signaling defects such as a decrease in

IRS-1 also contribute to insulin resistance.[接受器內胰島素

訊號變弱]

• In the liver, there is increased steatosis, causing insulin

resistance, which is compounded by increased

gluconeogenesis and hyperglycemia. [肝性脂肪變性]

•The bone is the site of osteocalcin [骨質更替]production,

driven by the IR. Osteocalcin normally participates in bone

turnover as well as suppresses increases in adiposity and

steatosis. These actions are inhibited by glucocorticoids.

•Mechanisms leading to glucocorticoid-mediated insulin resistance

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Steroid-Induced Hyperglycemia Pathophysiology

1. Counteract several effects of insulin:直接對抗胰島素作用

2. Gluconeogenesis:

•Increase endogenous glucose production directly by activating numerous

•Catabolism of muscle and adipose tissue (異化肌肉、脂肪）

3. 增加其他對抗胰島素激素：Glucagon, Epi.

4. 增加PPARa (增加內生性葡萄糖合成）

5. 透過迷走神經：至關重要的角色

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csm6 increase endogenous glucose production directly by activating numerous genes involved in the hepatic metabolism of carbohydrates, leading to an increment in gluconeogenesis,39–41 especially phosphoenolpyruvate carboxykinase and glucose-6-phosphatase,39,42–45 as well as indirectly by antagonizing the metabolic actions of insulin.46chen shu mih, 2015/9/5

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Blood sugar Increased

AC?

PC?

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Let’s Try to Think It~

• Corticosteroids reduce peripheral glucose uptake at the level of the muscle and adipose tissue.

• Skeletal muscle is primarily responsible for insulin-mediated capture of

postprandial glucose

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Blood sugar Increased: AC or PC or Both?

PC?

IV Oral

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Dose/Duration dependent?

High doses

Stable levels of fasting insulin despite plasma glucose level increase

Acute inhibitory effect on β-cells

healthy subjects

血糖高 但空腹胰島素濃度一樣不變

短期高劑量類固醇直接傷害beta cell

Longer exposure

(2–5 days)

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Dose/Duration dependent?

High doses

Fasting hyperinsulinemia and increased insulin secretion during hyperglycemic clamp studies

Insulin resistance generated by corticosteroids 長期類固醇 因為胰島素阻抗

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Inhibit the production and secretion of insulin from

pancreatic β-cells, which depends on thedose and duration of exposure.

from herep 11

Dose/Duration dependent?

Postprandial ： develops in approximately 4 h

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Result1. Single morning dose: Prednisone/Methylprednisolone

(intermediate, lasting ∼12–16 h)

Hyperglycemia in the afternoon and night, especially after lunch, with little or no effect on fasting

2. Daily dose is divided: Throughout the day, but it will be predominantly postprandial

3. IA (intra-articular route): TriamcinoloneAfter 2 h (DM patient) Length of 2–3 days

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Screening, diagnosis, and control goals of corticosteroid-induced hyperglycemia

• The determination of fasting glucose clearly underestimatesglucocorticoid-induced hyperglycemia, especially in cases of intermediate-acting glucocorticoid treatment with single morning doses. (occurs predominantly in the evening) [僅評估飯

前血糖會低估類固醇所致之高血糖。傍晚最易血糖高]

• Morning, lunch postprandial glycemia or dinner preprandial glycemia should be moni- tored during the first 2–3 days of treatment [測早午餐後及晚餐前血糖]

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Steroid Therapy and Inpatient Glycemic Control

Steroids are counterregulatory hormones

Impair insulin action (induce insulin resistance)

Appear to diminish insulin secretion

Majority of patients receiving >2 days of glucocorticoid

therapy at a dose equivalent to ≥40 mg/day of prednisone

developed hyperglycemia

No glucose monitoring was performed in 24% of patients

receiving high-dose glucocorticoid therapy[不測血糖會低

估發生率]

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General Guidelines for Glucose Control and Glucocorticoid Therapy

•The majority of patients (but not all) receiving high-dose glucocorticoid therapy will experience elevations in blood glucose, which are often marked

•Suggested approach

Institute glucose monitoring for at least 48 h in all patients

Prescribe insulin therapy based on bedside BGmonitoring

For the duration of steroid therapy, adjust insulin therapyto avoid uncontrolled hyperglycemia and hypoglycemia

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Steroid Therapy and Glycemic ControlPatients With and Without Diabetes

•Patients without prior diabetes or hyperglycemia or those with diabetes controlled with oral agents

Begin BG monitoring with low-dose correction insulin scale administered prior to meals

•Patients previously treated with insulin

Increase total daily dose by 20% to 40% with start of high-dose steroid therapy [一開始就增加24＿40% TDD胰島素]

Increase correction insulin by 1 step (low to moderate dose)[之後依據餐前血糖數據微調增減餐前胰島素劑量]

Adjust insulin as needed to maintain glycemic controlAdjust insulin as needed to maintain glycemic control(with caution during steroid tapers)

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No evidence to confirm which hypoglycemic drugs and treatment regimens are more effective

[沒有哪個降血糖藥物證實對類固醇所致之高血糖特有效]• By high initial doses and a gradual reduction [短期類固醇用法式：一開始高劑量之後慢慢調降]

• Hypoglycemic drug: potent, immediate acting, and with an unlimited hypoglycemic action in order to control this rapid- onset hyperglycemia. [選用強效、立即作用將血糖藥物來處理]

• OAD: is limited [所以，不用口服類將血糖藥物]

• Insulin: in all other situations1. Efficacy and safety2. Immediate onset of action3. Unlimited hypoglycemic power4. Easily titrated.

Treatment ofTransient Glucocorticoid-Induced hyperglycemia

csm7

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csm7 ue to the limited hypoglycemic power, which does not allow for the correction of hyperglycemia in many situ- ations. Most available oral hypoglycemic drugs have a slow onset ofaction and/or a very limited or null titra- tion, giving them little capacity to adapt to major changes in requirements of hypoglycemic action. Fur- thermore, the action profile of oral hypoglycaemic drugs throughout the day does not usually coincide with the pattern of glucocorticoid-induced hyperglycemia.chen shu mih, 2015/9/5

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Intermediate-acting glucocorticoids1. Single, low and stable dose in the morning[早晨、單一、低劑量]

2. Metformin and Pioglitazone: useful and the first choice

3. Insulin sensitizer effect, which avoids the risk of hypoglycemia, Metformin, its low cost

Steroid+ Immunosuppressants

1. Insulin resistance induced by glucocorticoids and inhibition in the biosynthesis and release of insulin induced by immunosuppressants

2.Insulin therapy

3. Initial schedule: single dose of NPH/NPL insulin before breakfast, keeping insulin sensitizers and removing OAD

Treatment ofProlonged Glucocorticoid-Induced Hyperglycemia

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Guideline to Management Steroid-Induced Hyperglycemia

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AC <200mg/dL

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AC >200mg/dL

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Initial Dose of Insulin

Antipsychotic agents• Antipsychotics may be used to treat schizophreniaand symptoms of psychosis which may occur in people with dementia.

• Side effects of antipsychotics include weight gain and hyperglycemia (high blood glucose levels). Blood sugar levels may return to normal if medication is stopped.

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Second-Generation Atypical Antipsychotics

Antipsychotic agents• However, if significant weight has been gained over the course

of the treatment. Insulin resistance and type 2 diabetes may be permanent. [過胖，有可能之前就有胰島素阻抗或T2DM]

• Diabetes is, for example, considered to be 2-3 times as common in people with schizophrenia as in the background population, probably because of lifestyle factors such as obesity and lack of exercise, although a family history of diabetes is common in those with schizophrenia.

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2003 FDA 就提出第二代抗精神病藥物必須標示高血糖、糖尿病風險

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Clozapine

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Olanzapine

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Significant weight gain?

However, cases of new-onset DM: absence of weight gain

Beta-cell inhibition via 5-ＨT1A Insulin secretion

Hyperglycemia

Glucagon test

SU treatment無效

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Atypical Antipsychotics-Induced Hyperglycemia

30% risk

5 YEARS STUDY

Immunosuppressive Agents

不用緊張下回分解

～回家休息吧～

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Protease Inhibitors• Protease inhibitors such as ritonavir form an important

element in highly active antiretroviral therapy (HAART) and strongly predispose to the development of diabetes by increasing insulin resistance and possibly by other direct effects upon the β-cell.

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Hyperglycemia and Protease Inhibitor (PI)-based ARV Therapy

●Potential for hyperglycemia●Screening for hyperglycemia:

●Standard glucose loading test at 24–28 weeks

●Consider earlier screening if on chronic PI-based therapy

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PI-Induced hyperglycemia

3~7% risk

Other Agents•Pentamidine, used by iv injection for the treatment of _Pneumocystis carinii _pneumonia, can cause transient hyperinsulinaemia associated with hypoglycaemia, followed by persistent beta cell failure requiring insulin treatment.

•Nicotinic acid, used as a lipid-lowering agent, can induce diabetes secondary to increased insulin resistance.

Is diabetes permanent?• Diabetes may not be permanent but this can depend on

other health factors.

• With some medications, blood glucose levels may return back to normal once the medication is stopped but, in some cases, the development of diabetes may be permanent.

Managing drug induced diabetes• If you need to continue taking the medication that has brought on

diabetes, it may make your diabetes more difficult to control than would otherwise be the case.

• If you are able to stop the course of medication, you may find your blood glucose levels become slightly easier to manage.

• Following a healthy diet and meeting the recommended exercise guidelines will help to improve your chances of managing your blood glucose levels.

References• http://www.diabetes.co.uk/drug-induced-diabetes.html• http://www.diapedia.org/other-types-of-diabetes-

mellitus/drug-induced-diabetes• www.intechopen.com

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「Drug Induced Hypoglycemia」

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Hypoglycemia-Induced Seizure

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Major Drugs induced Hypoglycemia

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Ethanol impairs gluconeogenesis-- metabolism

of ethanol lactate uptake by gluconeogenesis

Treatment—

a. Intravenous dextroseb. Adequate food intake during alcohol

ingestion

Ethanol hypoglycemia

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Asparaginase-induced Hypoglycemia

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Asparaginase

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Disopyramide

• Disopyramide, group I antiarrhythmic drug

• Commonest side effects result from anticholinergic activity.

• It stimulates insulin secretion and may lead to hyperinsulinemic hypoglycemia.

• It is excreted by the kidneys, therefore older patients and patients with chronickidney disease using this drug are at risk of hypoglycemic episodes (Cacoub et al., 1989).

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csm8

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csm8 http://www.ncbi.nlm.nih.gov/pubmed/22000561chen shu mih, 2015/9/4

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Salicylate-induced Hypoglycemia

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Salicylate

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Whipple’s triad

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Thank You!