Management of Type 2 Diabetes Mellitus - iaisurabaya.orgiaisurabaya.org/.../2018/05/Management-of-Type-2-Diabetes-Mellitus.pdf · Penatalaksanaan Diabetes Melitus Perkeni. Konsensus

Management of Type 2 Diabetes Mellitus

Name of Presenter:

SAID.GLI.18.04.0171(04/18)

What is Diabetes Mellitus ?

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

American Diabetes Association. Diabetes Care 2004 Jan; 27(suppl 1): s5-s10.

Number of people with diabetes worldwide and per region in 2017 and 2045 (20-79 years)

Amongst the 425 million people affected with diabetes in 2017, over 200 million come from Asia.

IDF-Diabetes Atlas 8-th eds-2017

IDF Diabetes Atlas, 8th Ed. 2017.

Top Ten Countries/Territories for Number of People with Diabetes (20-79 years)

Top Ten Countries for Number of IGT 2017 (20-79 years)

IDF Diabetes Atlas, 8th Ed. 2017.

Sumber : Riskesdas 2007

Sumber : Riskesdas 2013

Masalah DM di Indonesia Tahun 2007 - 2013

Prevalensi Diabetes Melitus Pada Penduduk Usia ≥ 15 Tahun Menurut Provinsi

di Indonesia Tahun 2013

(Sumber: Riskesdas, 2013)

3.7 3.6

3.4 3.3

3 3

2.8 2.7

2.3

2.5 2.5

2.3 2.3 2.2 2.2

2.1 2 2

1.9 1.9 1.8

1.6 1.6 1.6 1.5

1.3 1.3 1.2 1.2 1.2

1 1

0.8

2.1

0

0.5

1

1.5

2

2.5

3

3.5

4

Classification of Diabetes

Type 1 Diabetes

due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency

Type 2 Diabetes

due to progressive loss of β-cell insulin secretion frequently on the background of insulin resistance

Gestational diabetes mellitus Diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes prior to gestation

Specific types of diabetes due to

other causes

monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young), diseases of the exocrine pancreas

Diabetes Care 2018;41(Suppl. 1):S13–S27 | DOI: 10.2337/dc18-S002

Diabetes Symptoms

Weight loss – event eating

more (type 1), Tingling, pain,

or numbness in the hands/feet

(type 2)

Urinating often

Blurry vision

Cuts/bruises that are slow to heal

Feeling very

hungry

Extreme fatigue

Feeling very

thirsty

Diabetes Symptoms [Internet]. American Diabetes Association. [cited 2018Apr12]. Available

from: http://www.diabetes.org/diabetes-basics/symptoms/

peripheral glucose uptake

hepatic glucose production

pancreatic insulin secretion

pancreatic glucagon secretion

gut carbohydrate delivery & absorption

incretin effect

HYPERGLYCEMIA

?

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

Multiple, Complex Pathophysiological

Abnormalities in T2DM

_

_

+ renal glucose excretion

Ramlo-Halsted & Edelman. Clinical Diabetes,2000;18:80–85

Natural History of Type 2 Diabetes

*IGT=impaired glucose tolerance

Normal

Altered

Glucose

Metabolism IGT* Diagnosis

of T2D

Progression

of T2D

Insulin

concentration

Insulin Resistance

-Cell Dysfunction

Fasting glucose

Microvascular disease

Macrovascular disease

Post-meal glucose

Diabetes Care 2018;41(Suppl. 1):S13–S27 | DOI: 10.2337/dc18-S002

•Urbanization and modernization • less walking, less biking, and less daily physical activity.

•Dietary factors •Higher fat and lower carbohydrate intake •Unhealthy trans fats and saturated fats

•White rice consumption

•Higher glycemic index (GI) than whole grains

• Smoking •Associated with higher abdominal fat and a 45% increased risk of developing

diabetes

• Environmental pollutants •Also increase risk of insulin resistance and diabetes.

• Sleep-disordered breathing and sleep deprivation • Increases risk of diabetes and poor glycemic control

•Chronic infections •H. Pylori, Hepatitis B virus, etc.

Ronald CW, et al. Ann NY Acad Sci, 2013.

Various Environmental Factors of Diabetes Development in Asian Population

Diagnosis and Goal of Treatment in Type 2 Diabetes

Kadar Tes Laboratorium Darah untuk Diagnosis Diabetes dan Prediabetes

Konsensus Perkeni 2015

Sasaran Pengendalian DM

Parameter Target

IMT (kg/m2) 18.5 - < 23

Tekanan darah sistolik (mmHg) <140

Tekanan darah diastolic (mmHg) <90

Glukosa darah preprandial kapiler (mg/dl) 80-130

Glukosa darah 1-2 jam PP kapiler (mg/dl) <180

HbA1c (%) < 7 (atau individual)

Kolesterol LDL (mg/dl) <100 (<70 bila risiko KV sangat tinggi)

Kolesterol HDL (mg/dl) Laki-laki: >40; Perempuan: >50

Trigliserida (mg/dl) <150

Konsensus Perkeni 2015

Keterangan: KV = Kardiovaskular, PP = Post prandial

Depicted are patient and disease factors used to determine optimal A1C targets (ADA, 2018)

ADA. Diabetes Care 2018;41(Suppl. 1):S55–S64 | DOI: 10.2337/dc18-S006

18

Adapted from: 1. International Diabetes Federation. Time to Act: Type 2 diabetes, the metabolic syndrome and cardiovascular disease in Europe. 2006. 2. International Diabetes Federation. Time to Act. 2001. 3. Seaguist ER. Diabetes 2010;59:4–6.

Major microvascular and macrovascular complications of diabetes

Sexual dysfunction

Peripheral sensory dysfunction

Coronary heart disease

Skin infection

Atherosclerosis

Gastro-intestinal and bladder dysfunction

Diabetic foot

Diabetic retinopathy

Diabetic nephropathy

Diabetic neuropathy

Cerebrovascular disease

Peripheral vascular disease

Coronary disease

Cognitive impairment3

Cardiac autonomic neuropathy

Microvascular1,2 Macrovascular1,2

UKPDS 35: Impact of increasing A1c on Cardiovascular Disease in T2DM

Fatal and non-fatal MI 14% rise in rise per 1% in A1c

Fatal and non-fatal stroke 12% rise in rise per 1% in A1c

Amputasi/death from PVD 43% rise in rise per 1% in A1c

Heart failure 16% rise in rise per 1% in A1c

Haza

rd R

atio

Haza

rd R

atio

A1c (%) A1c (%)

Stratton et al. UKPDS 35. BMJ 2000;321:405-412

Diabetic

retinopathy

Diabetic

nephropathy

Diabetic

neuropathy

Limb

amputation

• Coronary heart disease

• Ischaemic stroke

• Congestive heart failure

Aim of treatment: to prevent the complications of diabetes

Non-vascular complications: Cancer Infections Degenerative diseases Depression Cognitive disorders …

Adapted from Grobbee DE. Metabolism 2003; 52: 24–28.

* The most common cause of death in patients with diabetes

Guidelines of the Management of Type 2 Diabetes

Langkah-langkah penatalaksanaan

DM

1. edukasi

2. Terapi gizi

medik

3. Latihan

Jasmani

4. Intervensi

Farmakologis

Penatalaksanaan Diabetes Melitus

Perkeni. Konsensus Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 di Indonesia, 2015

Algorithm of type 2 diabetes management in Indonesia

Healthy Life Style Modification

HbA1C <7.5% HbA1C ≥7.5%

HbA1C >9.0%

Monotherapy* with one of

below

- Metformin

- GLP1 R-agonist

- DPP4-I

- AGI

- SGLT2-I *

- Thiazolidindione

- Sulfonylurea

- Glinide

Metf

orm

in o

r o

ther

firs

t line d

rug

2 s

eco

nd lin

e d

rugs

- GLP1 R-agonist

- DPP4-I

- Thiazolidindione

- SGLT2-I *

- Basal Insulin

- SU / Glinide

- Cholesevelam**

- Bromocriptin QR**

- AGI

- GLP1 R-agonist

- DPP4-I

- Thiazolidindione

- SGLT2-I *

- Basal insulin

- SU / Glinide

- Cholesevelam**

- Bromocriptin QR**

- AGIIf HbA1C is not

achieved in 3 months,

added second drug

(combination 2 drugs)

Combination 3 drugs

Notes:

* Registered drugs, it selection and usage is considered

based on benefit, adverse, and availability

** Cholesevelam is not yet available in Indonesia, and

Bromocriptin QR is generally used in pituitary tumor

Combination 3 drugs

Combination 2 drugs

Insulin ± other drugs

Clinical features (-) Clinical features (+)

Starts or intensification insulin

therapy

In 3 months,

HbA1C > 7%

+ Monotherapy in 3

months, HbA1C > 7%

Combination 2 drugs* with

different mechanism

If HbA1C is not

achieved in 3 months,

added third drug

(combination 3 drugs)

If HbA1C is not

achieved in 3 months,

started or intensified

insulin therapy

Metf

orm

in o

r oth

er

firs

t line d

rug

Indonesian Endocrine Society (Perkeni) Consensus 2015

Sulfonylurea – Focus on Glimepiride

• For decades, sulfonylureas (SUs) have been important drugs in the antidiabetic therapeutic.

• They have been used as monotherapy as well as

combination therapy. • Modern SUs, such as glimepiride are associated with

better safety profiles.

Kalra S, et al. Indian J Endocr Metab 2018;22:132-57

Sulfonilurea – mekanisme kerja

Sulfonilurea menstimulasi sekresi insulin oleh sel β pankreas

Sulfonilurea berikatan pada reseptor sel beta

Sel beta

Dinding sel

Peningkatan kadar kalsium intraseluler memicu lepasnya insulin

Insulin disekresi dalam darah

Kanal kalsium

Kanal kalium menutup

Kanal kalium

Hal ini menyebabkan kanal kalsium sel beta membuka, meningkatkan aliran kalsium ke dalam sel

Sulfonilurea

Reseptor SUR/KIR 6.2

Glimepiride : Unique Dual Mode of Action

26

Action on insulin

secretion

Action on insulin

resistance

Glimepiride + +

Conventional Sulfonylureas + -

Glinides + -

Biguanides - +

Glitazones - +

-Glucosidase Inhibitors - +

Henry. Endocrinol Metab Clin. 1997;26:553-573; Gitlin, et al. Ann Intern Med. 1998;129:36-38 Neuschwander-Tetri, et al. Ann Intern Med. 1998;129:38-41; Goldberg, et al. Diabetes Care 21:1897-1903

Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139 Fonseca, et al. J Clin Endocrinol Metab. 1998;83:3169-3176; Bell & Hadden. Endocrinol Metab Clin. 1997;26:523-537

De Fronzo, et al. N Engl J Med. 1995;333:541-549; Bailey & Turner. N Engl J Med. 1996;334:574-579

Changes in A1c Observe with Oral Antihyperglycemic Therapy in subject with DM2

Kabadi UM et al. Manage Care 2004

Sonnenberg G.E. et al.: Short term comparision of once- versus twice-daily administration of glimepiride in patients with non-insulin-dependent diabetes mellitus. Ann Pharmacother. 1997;31:671-6

Glimepiride can control 24 hour blood glucose with once or twice daily administrations.

Placebo

3 mg glimepiride twice-a day (BID)

6 mg glimepiride once-a-day (QD)

350

300

250

200

150

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

08.00 breakfast 12.00 Lunch

18.00 Dinner

Glimepiride – once or twice dosing

Blood glucose mg/dl

29

Korytkowski M et al. Diabetes Care 2002; 25(9):1607-11.

Insulin Secretion of Glimepiride

Glimepiride : Treat fasting AND postprandial hyperglycemia

First Phase Second Phase Insulin secretion

Before treatment After treatment

Incr

em

en

tal p

lasm

a in

sulin

(p

mo

l/L)

0

50

100

p=0.04

p=0.02

First and second phase insulin secretion

before and after treatment with Glimepiride

Euglycemic and hyperglycemic clamp studies in 11 obese patients with T2DM with good glycemic control before and after 4 months treatment with ®glimepiride to assess effect of glimepiride® on insulin secretion

Müller G et al. Diabetes Res Clin Pract 1995;28 (suppl):S115-S137

Comparison of Extrapancreatic Action of Glimepiride and Other Sulfonylureas

Mean plasma insulin increase (µU/ml) PI

Mean blood glucose decrease (%) BG

Glimepiride®

5 0 10 15 20

Su

lfo

nylu

rea

Glibenclamide

Gliclazide

Glipizide

PI/BG ratio

0.03 (n=16)

0.16 (n=16)

0.07 (n=14)

0.11 (n=13)

Sulfonylureas

tested in fasted

male beagle dogs

to determine

ratios of mean

plasma insulin

release/ blood

glucose decrease

Mean increase in plasma insulin (PI) and mean % decrease

in blood glucose (BG) over 6 hours after single dose

Glimepiride has better extrapancreatic activity among sulfonylureas

Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73

Hypoglycemia vs Glibenclamide

*Defined as requiring IV glucose or glucagon

Significantly lower incidence of severe hypoglycemic events with Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)

0.86

5.6

Glibenclamide Glimepiride

# Ep

iso

des

/100

0 p

erso

n-y

ears

0

2

4

6

Prospective, population-based, 4-year study to compare frequency of severe hypoglycemia in patients with T2DM treated with Glimepiride (estimated n=1768) versus glibenclamide (estimated n=1721)

32

Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19

Mean intra-individual weight change relative to baseline

-1.9 kg

(p<0.0001*)

-2.9 kg

(p<0.05*) -3.0 kg

(p<0.005*)

Months of treatment

Safety: Weight

Mean

weig

ht

ch

an

ge (

kg

)

*vs. baseline

4 12

- 1

- 2

- 3

18 0

Open, uncontrolled,

observational study.

1770 T2DM patients

were enrolled and 284

were followed-up for

1.5 years. Patients

received 0.5 to > 4 mg

glimepiride once daily.

Treatment with Glimepiride has a stable weight neutral or even weight reducing effect in most patients with Type 2 diabetes

Kejadian Hipoglikemia dan HbA1c sebelum, selama, dan setelah Ramadan

GLIRA Study Group Diabetes Care 2005; 28: 421

9.2

9

8

7

6

5

Pre-Ramadan During

Ramadan

7.7

Hb

A1

c (

%)

Post Ramadan

Period

7.1 7.3

7.7

8.4

Hypoglycemic

events : 25 (in 13

patients)

Hypoglycemic

events : 15 (in

11 patients)

Hypoglycemic

events : 8 (in 8

patients)

Newly diagnosed (n=100)

Already Treated (n=232)

Glimepiride tidak meningkatkan kejadian Hipoglikemia

Use of Glimepiride during Ramadan

Glimepiride bekerja selama

24 jam mengontrol gula

darah harian, cukup dikonsumsi

1x sehari

Panduan Penatalaksanaan DM Tipe 2 Pada Individu Dewasa di Bulan Ramadan, PERKENI 2015

Renal Impairment Dose Adjustment for insulin Compounds and oral medicines for Diabetes in CKD

National Kidney Foundation. Am J Kidney Dis. 2012; 60(5): 850-886

Cost

• SUs are associated with a significantly lower cost per QALYs and result in the longest time to insulin dependent1

• The cost comparison indicates that SUs would be the preferred as an add-on to metformin2

• Lower cost without compromising the glycemic efficacy and tolerability will make SUs the prime choice2

Lowers Costs

1Zhang Y, et al. Diabetes Care. 2014 May 1;37(5):1338-45 2Abrahamson MJ. Diabetes Care. 2015 Jan 1;38(1):166-9.

SUs incurs lower cost per QALY

81.75 54.85

232.84 325.97

245.7

0100200300400

Co

st p

er m

on

th(U

SD) Expected medication cost per QALY)

• Use of SU was associated with significantly lower cost per quality-adjusted

lifeyears (QALY) and resulted in the longest time to insulin dependent

Zhang Y, et al. Diabetes Care. 2014 May 1;37(5):1338-45

Take Home Message…….

• Diabetes can be managed by healthy lifestyle in combination with medical treatment

• Choosing the medication for patients should refer to doctor’s recommendation

• Early detection and treatment of diabetes can decrease the risk of developing the complications of diabetes

• Based on PERKENI guideline Glimepiride as an oral antidiabetic, can be initiated as monotherapy or combination with oral antidiabetics/ insulin/GLP-1 agonist in treating patients with newly diagnosed T2DM