Insulin and oral hypoglycemic drugs - 浙大现代教育技术To be used as add on therapy with SU, metformin, or TZD’s Increases the risk of Hypoglycemia when added to SU treatment

Insulin and oral

hypoglycemic drugs

Endogenous insulin is secreted from cells in the pancreas

Islet of LangerhansAlpha cell: 20%, glucagon

Beta cell: 75%, insulin

Delta cell: 5%, somatostatin

D1 cell: VIP

PP cell: pancreatic polypeptide

Glucose metabolism

and the regulation by

insulin and glucogan

Diabetes mellitus:

Insulin or its

responses

blood glucose

Acute or chronic

symptoms

A group of diseases characterized by high levels of

blood glucose resulting from defects in insulin

production, insulin action, or both

100 million people worldwide

85-90% cases are Type II

Diabetes Mellitus

CLASSIFICATION

TYPE 1 (IDDM,10%)

Deficiency of insulin secretion

Genetic predisposition and possible links to

viral infections and environmental factors

Possible autoimmune process with

destruction of beta pancreatic cells

Require insulin supplementation, prone to

develop DKA (酮症酸中毒）

CLASSIFICATION

TYPE 2 Resistance to action of insulin on target organs

Decrease in insulin production

Increased risk with obesity high fat, high caloric diets

Stronger genetic predisposition

Variety of initial presentations: HHNKS (高血糖高渗性非酮症综合征), nephropathy, retinopathy, neuropathies

Disease can be delayed or prevented with life style changes

Natural History of Type 2 Diabetes

0

50

100

150

200

250

-10 -5 0 5 10 15 20 25 30

Years of Diabetes

Glucose

(mg/dL)

Relative

Function

(%)

Insulin Resistance

Insulin Level“Beta-cell failure”

*IGT = impaired glucose tolerance

50

100

150

200

250

300

350

Fasting

Glucose

Post-meal

Glucose

Adapted from International Diabetes Center (IDC)

Minneapolis, Minnesota

Obesity IGT Diabetes Uncontrolled hyperglycemia

CLASSIFICATION

SECONDARY CAUSES

Exocrine pancreas disease: pancreatitis

Genetic syndromes: Downs, Turners

Infections: CMV, Congenital rubella

Drugs: Glucocorticoids, Dilantin, beta

agonists

Endocrinopathies: Cushing's, Acromegaly

Classification

Gestational

Presents only during pregnancy

135,000 cases annually

Increased risk of developing diabetes post

partum

Tight glycemic control required to prevent

macrosomia, fetal cardiac and CNS

abnormalities

CLINICAL FEATURES

Polyuria

Polydipsia

Polyphagia

Weight loss

TYPE 1 DM-- acute, severe

TYPE 2 DM-- chronic, less severe

正常人糖尿病尿崩症

Complications of diabetes mellitus

Acute complications Diabetic ketoacidosis

Hyperosmotic nonketotic coma

Chronic complications Cardiovascular diseases

Renal damage

Retinal damage

Nerve degeneration

Myopathy

Infection

Rhinocerebral

Mucormycosis

Therapy of Diabetes Mellitus

Diet

Exercise

Insulin and its enhancers

Oral hypoglycemic drugs


Structure of insulin


Insulin

1. Pharmacological effects(1) Carbohydrate metabolism: reducing blood glucose levels by

glycogenolysis , glycogen synthesis , gluconeogenesis (ketone

badies )

(2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids

(3) Protein metabolism: active transport of amino acids , incorporation of

amino acids into protein , protein catabolism

(4) HR , myocardial contractility, renal blood flow

Mechanism of insulin actions

Interacting with insulin receptor

Insulin promotes glucose utilization


Insulin



badies )








Insulin



badies )







Interaction

between insulin

and its receptorIRS: insulin receptor

substrate

tyr: tyrosine

P: phosphate

Insulin promotes the

translocation of glucose

transporters into the

membrane

2. Clinical uses(1) Insulin-dependent patients with diabetes

mellitus (type 1 diabetes mellitus)

(2) Insulin-independent patients: failure to other drugs

(3) Diabetic complications: diabetic ketoacidosis (酮症

酸中毒), hyperosmotic nonketotic coma（高渗性非酮症性昏

迷）

(4) Critical situations of diabetic patients: fever,

severe infection, pregnancy, trauma, operation

(5) Others: promotion of K+ uptake into the cells,

pshychiatric disorders


3. Preparations

Properties Preparations Onset Peak Duration

Fast-acting Regular insulin 0.5-1

h

2-3 h 6-8 h

Intermmediate-

actingNeutral protamine

hagedorn

2-4 h 6-10 h 12-18 h

Long-acting Protamine zinc insulin

suspension

3-6 h 6-10 h 24-36 h

Hirsch IB NEJM 352:174, 2005

Rapid Acting Insulin Analogues

Current agents include lispro, aspart, and glulisine.

Remain monomeric after injection, resulting in rapid absorption,

and relatively rapid onset and offset.

Onset of action is 5-15 minutes, with peak action at 60-90

minutes and duration of ~3-5 hours.

Advantages include:

increased convenience- can take just prior to meal.

better postprandial glycemic control.

Disadvantages include:

short duration of action- can be problematic in Type 1 diabetic

without basal insulinization, as with bedtime NPH.

more expensive than regular insulin (~double the cost).

Holleman and Hoekstra, NEJM, 337:176-83, 1997Hirsch, NEJM, 352:174-83, 2005

Actions of different insulin preparations

4. Adverse effects

(1) Hypersensitivity: treated with H1 receptor antagonist,

glucocorticoids

(2) Hypoglycemia: adrenaline secretion (sweating,

hunger, weakenss, tachycardia, blurred vision, headache,

etc.), treated with 50% glucose

(3) Lipoatrophy: localized in injection sites

(4) Insulin resistance: Acute: stress induced, need large dose of insulin

Chronic: need >200U/d and no complication


Insulin action enhancers

Thiazolidinediones (TDs) 噻唑烷酮类化合物

Rosiglitazone 罗格列酮

Pioglitazone 吡格列酮

Troglitazone 曲格列酮


Rosiglitazone

罗格列酮


Pioglitazone 吡格列酮

Insulin action enhancers

1. Pharmacological effects

Selective agonists for nuclear peroxisome

proliferator-activated receptor- (PPAR, 过氧化物酶增殖体激活受

体).

(1) Lowering insulin resistance

(2) Lipid metabolism regulation: TG, free fatty acid

(3) Antihypertensive effects

(4) Effect on vascular complications in type 2 patients


2. Clinical uses

Used for treatment of insulin-resistant

diabetic patients or type 2 patients

3. Adverse effects

Edema, headache, myalgia, GI reactions,

hepatic damage (troglitazone)


Oral hypoglycemic

drugs

Sulfonylureas（磺酰脲类）

Biguanides（双胍类）

-Glucosidase inhibitors（葡萄糖苷酶抑制药）

Others


Sulfonylureas（磺酰脲类）

Tolbutamide (D860) 甲磺丁脲

Chlorpropamide 氯磺丙脲

Glibenclamide 格列本脲 (优降糖)

Glipizide 格列吡嗪

Gliclazide 格列齐特 (达美康)

Sulfonylureas


(1)Hypoglycemic effect:blocking ATP-sensitive K+ channel: Ca2+ inflow ,

insulin release , stimulating insulin secretion

increasing insulin sensitivity (long-term use)

inhibit glucagon release

(2) Antidiuretic effect

(3) Effect on coagulation function

Action of sulfonylureas

Sulfonylureas


(1)Hypoglycemic effect:blocking K+ channel: Ca2+ inflow , insulin release ,

stimulating insulin secretion

increasing insulin sensitivity (long-term use)

inhibit glucagon release

(2) Antidiuretic effect

(3) Effect on coagulation function (Gliclazide)

2. Clinical uses

(1) Insulin-indenpedent diabetic patients (type 2):alone or combined with insulin

(2) Diabetes insipidus (尿崩症):Chlorpropamide (氯磺丙脲): antiuretic hormone (ADH)

Sulfonylureas

3. Adverse effects

(1) GI reactions

(2) CNS reactions

(3) Hypoglycemia: especially in elderly, hepatic or

renal insufficiencies

(4) Others: cholestatic jaundice, hepatic damage

(Chlorpropamide), leukopenia.

Sulfonylureas

4. Drug interactions

(1) Potentiation of hypoglycemic effects

replacement in plasma protein binding: salicylic acid, sulfates,

indomethacin, penicillin, warfarin, etc.

inhibition of hepatic microsomal enzymes: chloramphenicol,

warfarin

(2) Attenuation of hypoglycemic effects

induction of hepatic microsomal enzymes: phenytoin,

phenobarbital, etc.

interactions in pharmacodynamics: glucagon, thiazides, etc.

Sulfonylureas


Biguanides（双胍类）

Metformin 二甲双胍（甲福明）

Phenformin 苯乙双胍（苯乙福明）

Biguanides

1. Pharmacilogical effectsincreasing glucose uptake in fat tissues and

anaerobic glycolysis in skeletal muscles

decreasing glucose absorption in gut and

glucagon release

2. Clinical usesmild insulin-independent patients with obesity

3. Adverse effectssevere lactic acidosis (less for metformin),

malabsorption of vitamin B12 and folic acid


-Glucosidase inhibitors（葡萄糖苷酶抑制药）

Acarbose 阿卡波糖

Reducing intestinal absorption of starch (淀粉),

dextrin (糊精), and disaccharides (二糖) by

inhibiting the action of intestinal brush border

-glucosidase


Others

Repaglinide 瑞格列奈

Oral insulin secretagogue

Pharmacological effects Repaglinide lowers blood glucose by stimulating the

release of insulin from the pancreas.

It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion

Clinical uses Type2 DM, diabetic nephropathy, elder DM patient

Repaglinide (餐时血糖调节剂)

Incretin Mimetics

Mechanism of Action: Act as an incretin enhance insulin secretion in response

to an oral glucose load.

Suppress post-prandial glucagon secretion in a glucose-

dependent manner

Delay gastric emptying

Centrally suppress appetite

Preserve beta cell mass by reducing apoptosis and

increased neogenesis (animal models).

Keating, Drugs. 65(12):1681-92, 2005.

Riddle and Drucker. Diabetes Care 2006; 29:435-49.

Incretin Mimetics Exenatide (Byetta) is first

incretin mimetic on market.

Synthetic version of salivary protein found in the Gila monster53% overlap with human GLP-1.

Must be taken as a BID injection w/in 60 mins prior to meal

Major side effects: nausea, vomiting, diarrhea. Increases the risk of Acute pancreatitis.

Use not recommended in severe renal impairment.

Not recommended as monotherapy To be used as add on therapy with SU, metformin, or TZD’s

Increases the risk of Hypoglycemia when added to SU treatment.

Major advantage is weight loss (~5 kg) as well as maintained effect (?preserved beta cell function).

Efficacy: decreases A1C ~1.0%.

Keating, Drugs 2005 65(12):1681-92

Site of DPP-IV Inactivation

Exenatide

A SYL GQ AKE RVKAH G F VEA T TSD S SY LEGQAA K E F I AW LVKGR -NH2

GLP-1Human

Dipeptidylpeptidase IV (DPP-IV) Inhibitors

Mechanism of Action:

Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal

GLP-1 levels

Acts as an incretin enhances insulin secretion in response to an oral

glucose load.

Suppresses post-prandial glucagon secretion in a glucose-dependent

manner

Preserves beta cell mass by reducing apoptosis and increased

neogenesis (animal models).

Sitagliptin (Januvia) is first DPP-IV inhibitor on market.

Effective as monotherapy or when used in conjunction with

metformin or a thiazolidinedione.

Appears to maintain efficacy (?preserved beta cell fxn).

Efficacy: decreases A1C ~0.8%.

Riddle and Drucker. Diabetes Care 2006; 29:435-49.

Case 1

50y/o, Chinese Male,

CC: Hyperglycemia found ×2 m

PE: BMI 29 Kg/m2 WC: 102cm

Lab Findings: FBG 155mg/dl, 2hPG:

276mg/dl, HbA1c: 7.5%

Which DRUG or DRUGS will we order?

Treatment Strategies Beyond Lifestyle

In general, try to initiate pharmacotherapy with an

oral agent in newly diagnosed type 2 diabetics unless:

Fasting plasma glucose is >300 mg/dl with ketonemia or

ketonuria

Markedly symptomatic

In patients who need insulin initially, often can be

switched to oral agents after 6-8 weeks when glucose

toxicity resolves

Answer to Case 1 ( A newly diagnosed type

2 DM patient with obesity)

Lifestyle intervention

Metformin 500mg q.d.-t.i.d

“Failure” of a Single Oral Agent

Type 2 diabetes is a progressive disease, with ’d loss of beta cell function over time.

Need to progress to multi-drug therapy or add insulin in order to maintain a similar level of glycemic control.

If glycemic goals are not met with agent in one class, we must add second agent with different mechanism of action or add insulin

2Nathan et al. Diabetes Care. 29:1963-1972, 2006.

• ADA consensus algorithm recommends addition of a SU, thiazolidinedione, or insulin if metformin therapy is not effective in getting patients to goal A1C.2

1Kahn et al. N Engl J Med, 355:2427, 2006

Algorithm for the management of T2DM

From: China Guideline for Type 2 Diabetes (CDS,2007)

Add insulin

Add one or several agents below: Sulfonylurea

or Meglitinide (one of the two), Glitazones ,

Alpha-Glucosidase Inhibitor

Diet,exercise,

weight loss

+

Metformin

3 month later HbA1c﹥6.5%

3 month later HbA1c > 6.5%

Overweight or

obese patients

(BMI >=24Kg/m2)

Algorithm for the management of T2DM (Cont’)

Non-obese Patients

(BMI﹤24kg/m2)

Diet, exercise, weight loss +

One or several agents below: Metformin,

Sulfonylurea or Meglitinide (one of the two),

Thiazolidinedione, Alpha-Glucosidase Inhibitor

Add insulin

3 month later HbA1c > 6.5%

From: China Guideline for Type 2 Diabetes (CDS,2007)

Use of Oral Agents to Optimize Glycemic

Control: Conclusions

Choice of oral agents needs to be matched with patient

characteristics (thin vs. obese) as well as concurrent

medical issues (renal, hepatic, cardiopulmonary status).

Diabetes is a progressive disease, and will require an

increasing number of agents and/ or addition of insulin as

the duration of diabetes increases.

Each oral agent can only improve A1C a maximum of 2%,

so if poor control persists on multiple agents, insulin is

needed.

Use Of Insulin In Type 2 Diabetes

Indications When glycemic control deteriorates despite

combination oral agents.

Surgery in patients with type 2 DM (transient)

Pregnancy

Method: Start with bedtime intermediate (NPH) or long

acting (glargine, detemir) insulin in addition to oral agents.

If doesn’t work, switch to basal-bolus therapy as used in conventional type 1 DM treatment

• Can continue metformin.

• Stop insulin secretagogues.

4:00

25

50

75

16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

Pla

sm

a In

su

lin

µU

/ml)

Basal/Bolus Insulin Absorption Pattern w/

Standard Insulin Preparations

8:0012:008:00

Time

REG REGREG

NPH

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargine

Basal-Bolus Treatment with

Rapid and Long Acting AnaloguesP

lasm

a In

su

lin Lispro Lispro Lispro

or or or

Aspart Aspart Aspart

or oror

Glulisine Glulisine Glulisine

Insulin Pump and Glucose Monitoring

Insulin Pump – “Open Loop”

Patient sets basal infusion

rate and w/ superimposed

boluses

Continuous Glucose Monitor

“Closed Loop” insulin pump system is ultimate goal…

infusion rate adjusted based on input from continuous

glucose monitor.

Case 2

64y/o, Chinese Male.

CC:polydipsia,polyuria,polyphagia × 12y

lower limb edema × 3 m

Metformin 500mg bid + Glipizide 80mg tid

PE: BMI 22kg/m2, WC 78cm, decreased sensation and medium pitting edema in both lower limbs

Lab Findings:

UA: PRO 3+,GLU 2+ ;

FBG 188mg/dl, 2hPG 266 mg/dl

HbA1c 8.3%;

Case2 (Cont’)

Liver function tests: nl transaminase, Alb 28g/l

SCr:1.5mg/dl, CCr: 52ml/min

Which DRUG or DRUGS should we Prescribe?

Answer to case 2 (long diabetes history with diabetic

Nephropathy and Chronic renal insufficiency )

Should start with insulin treatment

Regimen:

1. Regular insulin or rapid acting insulin analogs tid pre-

meal + NPH or long acting insulin analog at bedtime

2. Insulin Pump

Documents

Insulin and oral hypoglycemic drugs - 浙大现代教育技术To be used as add on therapy with SU, metformin, or TZD’s Increases the risk of Hypoglycemia when added to SU treatment