Lecture Diabetes mellitus - MD. Phạm Thu Ha

Diabetes mellitus

MD Phạm Thu Hà Dept. Endocrinology and Diabetes B¹ch mai Hospital

Objectifs

• Overview of diabetes • Discussion about guidelines of diabetes

management

• Implementation in Clinical practice

Number of pts diabetes estimated in 2000 & to 2030

(Diabetes Care 2004;27:1047-1053)

IDF Diabetes Atlas 2003

Prevalence of diabetes & prediabetes 35-64 yrs

GDM in 1990, 1995 and 2001

1990

1995

2001

No Data <4% 4%-6% 6%-8% 8%-10% >10%

Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and other obesity-related health risk factors, 2001. JAMA 2003 Jan 1;289(1).

US. Prevalence of diabetes 2010

• Diagnosed: 26

million people— 8.3% of population (90%+ have Type 2)b • Undiagnosed: 7 million people • 79 million people have pre-diabetes

CDC 2011

Diabetes Diagnosis Category FPG (mg/dL) 2h 75gOGTT A1C

<5.7

Normal <100 <140

Prediabetes 100-125 140-199 5.7-6.4 Diabetes >126** >200 >6.5 Or patients with classic hyperglycemic symptoms with plasma glucose >200 ** On 2 separate occasions

Diabetes Care 34:Supplement 1, 2011

OGTT

XN ĐH sau uống 75 g Glucose trong 250 – 300 ml nước ở các thời điểm 0p, 120p Chẩn đoán ĐTĐ khi ĐH 120p ≥ 2g/l (11mmol/l) Giảm DN Glucose 7,8 mmol/l ≤ ĐH 120p < 11mmol/l Bình thường ĐH 120p < 7,8mmol/l

Classification

Type 1  cell destruction, absolute deficit of insulin:children, 10%

adults- LADA( Latent Autoimmune Diabetes in Adults).)

( 90% adults)

Type 2  cell secretion dysfunction – insulin resistance Gestational :  cell secretion dysfunction –insulin rasistance/in

pregnancy

Others diabetes • Inheritanced  cell deficit

(MODY) • Exocrine pancreatic deseases • Endocrinopathy • Drugs & Chemical • Other rare types

Treatment

How to control BG ?

+

Self-monitoring BG patient

Dr : Control HbA1c

Goals achieved

Nutritional regime

• Important for both types

• Well balanced:protein, lipid , CH,Vitamins,minerals

• Avoid hyperglycemia postprandial ,hypoglycemia in

distance from meal.

• Energy enougth for activities

• Ideal body weight, raisonable weight loss if indicated

• Non potentional CV risk factors:Dysipidemia,

Hypertention, Heart faillure...

• Easy to follow, simple , not expensive

• Not changing too fast habit and total amount of food.

Nutritional regime

• Component ratio

• CARBOHYDRAT

+ Main energy source

+ 60 – 70 % total calories

• LIPID

+ 15 – 20% , less if CV risk

• PROTID

+ 10 -20% ( 0,8 – 1,2 g/kg)

+ When renal faillure : 0,6g/ kg

cân nặng

Nutrittional regime

• Microelements + Supplement of Vitamins • Others + More vegetebles, fibers,

less sweeet fruits

+ Alcohool 5 – 15 g/d • Distribution : 3 main

meals+ 2 snacks (for pts on insulin inj)

Exercise help to get to glycemic control goals and protect pts from cardiovascular deseases

Better glycemic control Ameliorate hemodynamic in the body Help Weight loss Better peripheral insulin sensitivity Healthy sensation

Physical activities

• Progressive setting, regularly 20- 30 min a day.

• Consult Dr opinion before practicing: caution if

severe CV complication, eye compl., nephropathy, neuropathy, foot damage…..

• Choose suitable discipline

exercise

• Important notes when practicing exercise

– Do not practicing if fasting Gl > 14mmol/l (

250mg%) + cetonuria(+). Or fasting Gl > 16,5 mmol/l (300mg%) and cetonuria (-)

– Fasting Gl < 5,5 mmol/l (100mg%)  Snack before

exercise.

– Blood sugar control before and after : choose

• Consumation rich in carbohydrate food before exercise

suitable sport , nutritional advice when practicing .

Medical treatment

Anti- hyperglycemic drugs

1. Insulin secretagogues

- Sulfonylurea - Glinides - Gliptins ( DPP-4 inhibitor ) DPP-4 inhibitors

- Metformin - Thiazolidinedione

Inhibitor of intestinal glucose absortion - Ức chế men alpha- glucosidase

-GLP-1 receptor agonists ( injectable)

2. Increasing Insulin sensitivity 3.

Main Pathophysiological Defects in T2DM

pancreatic insulin secretion

pancreatic glucagon secretion

incretin effect

?

HYPERGLYCEMIA

gut carbohydrate delivery & absorption

peripheral glucose uptake hepatic glucose production

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Products and dosing of sulfonylure

• Second generation

 Glyburide (Glibenclamide 1,25 - 2,5 - 5mg ) LiÒu 1,25 – 20 mg 1 - 2 times daily  Glipizide ( Glucotrol 5 - 10mg ) 5 – 40 mg 1 - 2 times daily  Gliclazide ( Diamicron 80mg, Diamicron MR 30mg) 80 – 320 mg uèng 2-3 times daily Diamicron MR (30 – 120mg) once daily  Glimepirid ( Amaryl 1 - 2 - 4mg ) 1 – 8mg liÒu once daily

INSULIN secretion stimulators NON- SULFONYLURE

• Mechanism

Stimulate  cell –insulin secretion, fast attach and dettach to

receptor  fast and short effect  glucose postprandial, risk of prolonged hypoglycemia

• Pharmacokinetic

+ Liver metabolited. Bill elimination, 10% renal elimination

+ Glucose dependent activities

• Dose & administration

Repaglinide, Nateglinide (Pradin, Novonorm 0,5mg )

0,5 – 16mg/ng before meal

Biguanide- Dose

• METFORMIN ( Glucophage 0,5 – 0,85 – 1,0 g )

• Low absortion by GIT

• Half life 1,5 – 4,5 h, effect duration 6 – 8h

• Mainly Renal elimination ( 80 – 100%)

• Dose 0,5 – 2,5g BID or TID

TZD- Indication , CI, Adverse effects

Indication

• Diabetes type 2 , Faillure with regime and exercise

Contraindication

• Pregnancy, lactation

• Less than 18 yrs old

• Heart faillure , hepatic faillure ( or GOT,GPT >2,5 N)

Adverse effecs

• Phù, thiếu máu Products • Pioglitazone ( Pioz 15 – 30 mg) 15 – 45 mg/ng. Once daily

Inhibitors of α - glucosidase

Mechanism : inhibite intestinal enzyme α glucosidase slowing absortion Products:

Acarbose (Glucobay )50/ 100mg 50 – 200mg 2 -3 times daily when eating Voglibose ( Basen ) 0,2 – 0,3 mg 0,2 – 0,3 mg 3 times daily when eating Miglitol ( Gliset ) 25/50/100mg 75 – 300mg 3 times daily when eating

GLP-1 mechanism

Food…

• Stimulate insulin secr.

• Inhib glucagon secr.

• Slowering stomach emptying

• Less food intake

GLP-1 secretion L-cells

Long term effets demonstrated in animals…

• Increase & maintain effects on beta-cell

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 Drucker DJ. Mol Endocrinol 2003; 17:161-171

DPP-4 Inh. Increase GLP-1 activated

Food

Int. secr. GLP-1

GLP-1 (7-36) Activated

DPP-4

Inh

DDP-4

GLP-1 (9-36) inactivated

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

Incretin mimetics- GLP 1 Exenatide

• Do not inactivated by DPP-IV • Injectable , circulating during 10h , • BID • Byetta Liraglutide: more prolonged action once a day

injection.

Diabetes Care. 2007;30:1608-1610 Regul Pept. 2004;117:77-88. Am J Health Syst Pharm. 2005;62:173-181.

Inhibitors Dipeptidyl peptidase-IV (DPP-IV)

• New drugs

• Mechanism: DPP-IV inhibitors increase

endogenous GLP-1 and lowering postprandial glycemia

• Effect :

– Reduction HbA1C : 0.5-1%

• Adv effects:

- Vasc. Edem.

Inhibitors DPP-IV

• Other cautions:

– Safe , neutre for body weight – Less hypoglycemia – Correction dosing if renal faillure.

• Indication : type 2 alone or combination with MET, SU,

TZD

• Products : sitagliptin ( Januvia), Vildagliptin(

Galvus),Saxagliptin (Onglyza)

• Costly

Reduction of HbA1c

Products

Mechanism

↓HbA1c

 Glucose absortion(GIT)

~0.7%

INH -Glucosidase Acarbose, Miglitol

~1.5%

Biguanides (Metformin)

 Glucoseneogenese  Insulin sensitivity (liver>muscles)

 Insulin sensitivity(muscles> liver)

~1.4%

Agonists PPAR (Pioglitazone, Rosiglitazone)

~2.0%

 Insulin secrstion( ß cell) Glimepiride:  (?) Insulin sensitivity

Sulphonylurea (Glimepiride, Gliclazide..)

 Insulin secretion

~1.3%

Phenylalanine (Nateglinide, Repaglinide)

Adapted from Inzucchi, JAMA 287:360-372, 2002

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

. ANTI-HYPERGLYCEMIC THERAPY

•Therapeutic options: Insulin

Rapid (Lispro, Aspart, Glulisine)

l e v e

Short (Regular)

l

n

i l

Intermediate (NPH)

u s n

I

Long (Detemir)

Long (Glargine)

Hours

0 2 4 6 8 10 12 14 16 18 20 22 24

Hours after injection

i n s u l i n

Time of action Peak onset

Duration

Rapid Aspart ( Novolog) Lispro (Humalog) Glulisine(Apidra)

1 – 3 h 1 – 2 h 1h

3 – 5h 3 – 4h 3 -4 h

10 – 20 min 10 – 15 min 10 – 20 min

Regular “ R”

0,5 – 1h

2 – 4 h

6 - 8h

Intermediate NPH “ N ” Lente “ L ”

1,5 – 3h 2 – 4 h

4 – 10h 7 – 12 h

12 – 22h 16 - 22 h

Long acting Ultralente “ UL’’ Glargin ( Lantus) Levemir

4 – 8 h 1 – 2 h 1 -2 h

Thay đổi No No

18 – 30 h 24h 18-24h

Premixt insulin

• INSULIN MIXTARD NPH/Regular

70/30, 50/50

NPH/Lispro Mixt 75/25

NPH/Aspart Mixt 70/30

Time to onset after 25 – 30 min if regular or faster if rapid

Max duration of action depent on each components

Indication of insulin

• Diabetes type 1 • Diabetes type 2 faillure on regime & exercise, oral

agents, alergic to oral therapy

• Emergency hyperglycemia • Pancreatectomy • Associate pathology:

– Infection, trauma, surgery, renal or hepatic faillure. – Corticotherapy – Other types diabetes

Insulin need increased in many cases

American Diabetes Association. Medical Management of

Non-Insulin-Dependent (Type II) Diabetes. 3rd ed. 1994:44-48.

• Gestational diabetes

Injection site

From My Insulin Plan, International Diabetes Center, 2001

Diabetes Guideline Management

• AACE updates periodically (2011) • http://www.aace.com/pub/guidelines/ • AACE Medical Guidelines for Clinical

Practice for the Management of Diabetes Mellitus

Screening For Diabetes

• A1C or FPG or 75 g oral GTT • Testing should be considered in all adults who are overweight (BMI >25 kg/m2)

And • Have the following additional risk

factors…….

Risk Factors for Screening

Diabetes Care 34:Supplement 1, 2011

• Physical inactivity • First-degree relative with diabetes • High-risk race/ethnicity (e.g., African • American, Latino, Native American, Asian American, Pacific Islander) • Women who delivered a baby weighing 9 lb or were diagnosed with GDM

Risk Factors for Screening (cont’d)

• Hypertension (140/90 mmHg or on therapy for

hypertension)

• HDL <35 mg/dl and/or a triglycerides >250mg/dl • Women with polycystic ovarian syndrome (PCOS) • A1C >5.7%, IGT, or IFG on previous testing • Other clinical conditions associated with insulin resistance

(e.g., severe obesity, acanthosis nigricans)

Diabetes Care 34:Supplement 1, 2011

• History of CVD

Risk Factors for Screening

• In the absence of the previous criteria, testing begins

at age 45

• Normal results, repeat at least at 3-year intervals • Consider more frequent testing depending results and

risk status

• At-risk BMI may be lower in some ethnic groups

Diabetes Care 34:Supplement 1, 2011

(i.e., Native American)

Glycemic goals AACE

ADA

Test

IDF (Western Pacific region)

HbA1c (%)

<=6,5

< 6,5

Fasting (mmol/l)

5,0-7,2

<= 6,0

<=6,1

<7,8

<10 6,0-8,3

ADA Diabetes care 2006; 27:15-35

Type 2 diabetes practical target and treatment 3rdEdn; Hong kong Asian-Pacific type 2 diabetes policy group, 2005

Postprandial 2h (mmol/l) Bed time

Concept of combination therapy

Regime, execise

monotherapy

Combination OAD

Titration

10 AODs+ basal insulin

AOD+ multiple Insulin

)

9 %

( c 1 A b 8 H

ACTION POINT:

7 HbA1c = 7%

HbA1c = 6.5%

6

*OAD = oral antidiabetic

5 n¨m

10 n¨m

Duration of diabetes

A1C ~ “Average Glucose”

7.0 7.8 8.6 9.4 10.1 10.9 11.8 12.6 13.4

126 140 154 169 183 197 212 226 240

eAG A1C % mg/dL mmol/L 6 6.5 7 7.5 8 8.5 9 9.5 10 Formula: 28.7 x A1C - 46.7 - eAG

American Diabetes Association

Oral Medications: ADA/EASD Tier approach

STEP 1 STEP2 STEP3

Tier 1: Well Validated Therapies

Lifestyle + Metformin +Basal Insulin

At Diagnosis: Lifestyle + Metformin

Lifestyle +Metformin + Intensive Insulin

Lifestyle + Metformin + Sulfonylureas

Tier 2: Less Well Validated Therapies

Lifestyle + Metformin + Pioglitazone

Lifestlye + Metformin+ Pioglitazone+ Sulfonylurea

Lifestyle + Metformin + GLP- 1 agonist

Lifestyle + Metformin + Basal Insulin

Nathan DM, Buse JB, Cavidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B; ADA/EASD. Medical management of hyperglycemia in type 2 diabetes: a consensum algorithm of the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009. 32 (1); 193-203.

www.idf.org

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM: A Patient-Centered Approach

ANTIHYPERGLYCEMIC THERAPY • Implementation Strategies

- Initial drug therapy - Advancing to dual combination therapy - Advancing to triple combination therapy - Transitions to and titrations of insulin

OTHER CONSIDERATIONS

Age Weight Sex/racial/ethnic/genetic differences Comorbidities (Coronary artery disease, Heart failure,

Chronic kidney disease, Liver dysfunction, Hypoglycemia)

• • • •

Diabetes Care, Diabetologia. 19 April 2012 [

T2DM Antihyperglycemic Therapy: General Recommendations

Diabetes Care, Diabetologia. 19 April 2012

T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012

[Epub ahead of print]

T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012

[Epub ahead of print]

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Sequential Insulin Strategies in T2DM

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS •Age •Weight •Sex / racial / ethnic / genetic differences •Comorbidities

- Coronary artery disease - Heart Failure - Chronic kidney disease - Liver dysfunction - Hypoglycemia

Diabetes Care, Diabetologia. 19 April 2012

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS •Age: Older adults

- Reduced life expectancy - Higher CVD burden - Reduced GFR - At risk for adverse events from polypharmacy - More likely to be compromised from hypoglycemia

Less ambitious targets HbA1c <7.5–8.0% if tighter targets not easily achieved Focus on drug safety

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS •Weight

 Emerging concerns regarding association with increased mortality  Proper drug selection in the hypoglycemia prone

- Hypoglycemia

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid Hypoglycemia

Adapted Recommendations: When Goal is to Minimize Costs

Guidelines for Glycemic, BP, & Lipid Control

American Diabetes Assoc. Goals

< 7.0% (individualization)

70-130 mg/dL (3.9-7.2 mmol/l)

< 180 mg/dL

HbA1C Preprandial glucose Postprandial glucose

Blood pressure < 130/80 mmHg

LDL: < 100 mg/dL (2.59 mmol/l)

< 70 mg/dL (1.81 mmol/l) (with overt CVD)

Lipids

HDL: > 40 mg/dL (1.04 mmol/l)

> 50 mg/dL (1.30 mmol/l)

TG: < 150 mg/dL (1.69 mmol/l)

HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.

ADA. Diabetes Care. 2012;35:S11-63

Blood Pressure

• Done at every visit • Target is <130/<80 • ACE inhibitors typically first line

American Diabetes Association. Diabetes Care. 2011;34(suppl 1)

Lipids (Cholesterol)

• Fasting lipid panel at least annually • Goals: Total cholesterol <200 Triglycerides <150 HDL >40 men, >50 women LDL <100 (<70, CVD or high risk)

American Diabetes Association. Diabetes Care. 2011;34(suppl 1)

Nephropathy (Kidney Disease) Screening

• Annual urine testing for

micro- or macro- albuminuria

• Annual creatinine and GFR • Start at diagnosis for type 2 • Start 5 years after diagnosis type 1

Diabetes Care. 2011;34(suppl 1)

Retinopathy Screening

• Type 1 annual starting after age 10 or after

5 years post diagnosis

• Type 2 annual starting shortly after

diagnosis

• Consider less frequent if one or more normal exams (not usually done)

Diabetes Care. 2011;34(suppl 1)

Neuropathy Screening

• Screen at diagnosis and annual thereafter • Filament testing • Vibratory testing • Reflexes

American Diabetes Association. Diabetes Care. 2011;34(suppl 1)

Elements of the DM protocol

• Blood pressure screening and treatment if >130/80 • Daily aspirin use, if not contraindicated • Annual dilated eye examination • Annual monofilament foot examination • Chronic care flow sheet to track elements of the protocol • Annual (or more frequently as indicated) laboratory measurement of:

– Hemoglobin A1C (goal <7) – Lipid Profile/LDL (LDL goal < 100) – Urine for microalbumin or 24 hour urine protein

• Vaccinations

• Influenza • Pneumovax

SUMMARY: Use the Guidelines to Improve Patient Care

• Primary care providers and their office staff are at

the forefront of the diabetes epidemic

• Help patients understand and control their “ABCs”

– A − A1C – B − Blood pressure – C − Cholesterol

• Always remember the basics

– Eye exam, foot exam, urine test – Review nutrition, exercise, and smoking

Diabetes Can Cause Problems in Many Parts of the Body: What Problems Can You Look For?