Pharmaceutical Care of Diabetic Mellitus

.
 Introduction
• Diabetes is a chronic condition caused by a
relative or an absolute lack of insulin.

• Its hallmark clinical characteristics are

symptomatic glucose intolerance resulting in
hyperglycemia and alterations in lipid and
protein metabolism.
 Introduction
• Insulin deficiency
– Quantitative: decreased in production by the β-cells of
the pancreas
– Qualitative: insulin resistance especially muscle, liver,
adipose, myocardial
• Improvements in insulin function
– Weight loss to decrease insulin resistance
– Can in turn improve β-cell function
 Microvascular Complications:

• Nephropathy

• Retinopathy

• Neuropathy

– Foot ulcers/lesions

– Numbness, pain

– Sexual dysfunction

– Gastroparesis

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 Macrovascular Complications

• Cardiovascular Diseases (CVD)

– Coronary Artery Disease (CAD)
– Myocardial Infarction (MI)
– Stroke or transient ischemic attack
(TIA)
• Peripheral Artery Disease (PAD)

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 Risk Factors
Obesity/overweight (BMI ≥ 25 kg/m2) History of CVD

Physical inactivity Prior diagnosis of pre-diabetes

First degree relative with DM HDL cholesterol < 35 mg/dL

Triglycerides > 250 mg/dL

High risk ethnicity/race:
• African American
• Latino Hypertension: BP ≥ 140/90 mmHg
• Native American or on treatment
• Asian Amerian
• Pacific Islander

Women with history of GDM or delivering a Conditions associated with insulin resistance:
baby weighing > 9 lbs • Severe obesity (BMI ≥ 40 kg/m2)
• Acanthosis Nigrans
Women with Polycystic Ovarian Syndrome
(PCOS)
Clinical Presentation of Diabetes Mellitus
Pre-Diabetes Diagnosis : Impaired glucose tolerance and
impaired fasting glucose

 Prediabetes is a term used to distinguish people who are at

increased risk of developing diabetes. People with
prediabetes have impaired fasting glucose (IFG) or impaired
glucose tolerance (IGT). Some people may have both IFG and
IGT.

 IFG is a condition in which the fasting blood sugar level is

elevated (100 to 125 mg/dL) after an overnight fast but is
not high enough to be classified as diabetes.

 IGT is a condition in which the blood sugar level is elevated

(140 to 199 mg/dL after a 2-hour oral glucose tolerance
test), but is not high enough to be classified as diabetes.
Pre-Diabetes Diagnosis : Impaired glucose tolerance and
impaired fasting glucose

• Progression to diabetes among those with prediabetes is not

inevitable. Studies suggest that weight loss and increased physical
activity among people with prediabetes prevent or delay diabetes
and may return blood glucose levels to normal.

• People with prediabetes are already at increased risk for other

adverse health outcomes such as heart disease and stroke.

– Risk for developing DM and CVD

• Estimates for developing diabetes over 5 years range from 9 - 50 %
– Evaluate and treat other risk factors:
• Obesity/overweight, dyslipidemia, and hypertension
 Diagnosis of Diabetes:
Measurements that may be used
• Fasting Plasma Glucose (FPG)
– Blood glucose measured after 8 hours fasting
• Oral Glucose Tolerance test (OGTT)
– Blood glucose measured 2 hours after 75 gram glucose load (use of anhydrous glucose
solution)
• Glycosylated hemoglobin or Hemoglobin A1c (A1C)
– Test without regard to meals, provides 3 month mean glucose
• Random plasma glucose (PG)
– For use in patients with symptoms of hyperglycemia/hyperglycemic crisis

American Diabetes Association (ADA) Professional Practice Committee. Standards of medical care in diabetes - 2013. Diabetes Care. 2013;36(1): S11-S66.
 Diagnosis of Diabetes:
Symptoms/Presentation

• Assessment for signs and symptoms of hyperglycemia

– Excess thirst, urination, and/or hunger
– Blurry vision or vision changes
• In severe hyperglycemia (BG > 240 mg/dL)
– Ketones may be present in urine
– Ketoacidosis can occur when the body breaks down fat and other molecules for
energy
• Can not use glucose for energy without insulin
 DIAGNOSIS
Gejala klasik DM + glukosa plasma sewaktu > 200 mg/dl (11.1 mmol/L)
Glukosa plasma sewaktu merupakan hasil pemeriksaan sesaat pada hari tanpa
memperhatikan waktu makan terakhir

Atau
Gejala klasik DM + kadar glukosa plasma puasa > 126 mg/dl (7.0 mmol/L)
Puasa diartikan pasien tak mendapat kalori tambahan sedikitnya 8 jam.

Atau
Kadar glukosa plasma 2 jam pada TTGO > 200 mg/dl (11.1 mmol/L)
TTGO dilakukan dengan standar WHO menggunakan beban glukosa yang
setara dengan 75 g glukosa anhidrus yang dilarutkan ke dalam air.

Atau
A1C > 6.5%
 Diagnosis of Diabetes:
Values for Diabetes/Pre-Diabetes

Measurement Criteria for Diabetes Criteria for Pre-Diabetes

FPG ≥ 126 mg/dL 100 - 125 mg/dL

OGTT ≥ 200 mg/dL 140 - 199 mg/dL

A1C ≥ 6.5% 5.7 - 6.4%

Random PG ≥ 200 mg/dL N/A

American Diabetes Association (ADA) Professional Practice Committee. Standards of medical care in diabetes - 2013. Diabetes Care. 2013;36(1): S11-S66.
 Glycemic Control: Recommended goals

Measurement Normal IDF1 ADA/EASD2 AACE3 PERKENI

A1c* <6% <6.5% <7% <6.5% <7%

Fasting Gluc <100 <110 90-130 <110 < 100

PP (2h) Gluc <140 <155 <180 <140 < 140

* Realistic Target: Lowest A1c possible without unacceptable adverse effects

 IDF = International Diabetes Federation

 ADA = American Diabetes Association.
 AACE = American Association of Clinical Endocrinology
 PERKENI = Perkumpulan Endokrinologi Indonesia 2011
1. Global guideline for type 2 diabetes clinical guidelines taskforce (Brussels: IDF,2005)
2. Nathan DM et al. Diabetologia 2006;49:1711-21.
3. [Link]
Korelasi Hba1C dengan Gula Darah
 Treatment
• Diet,
• Drugs (insulin and oral hypoglycemic agents,
and other antihyperglycemic agents), and
• Exercise
 Pengaturan diet

– Diet yang dianjurkan: Karbohidrat : 60-70%, Protein : 10-15%,

Lemak : 20-25%
– Masukan kolesterol tetap diperlukan, namun jangan melebihi
300 mg per hari.
– Sumber lemak diupayakan yang berasal dari bahan nabati,
yang mengandung lebih banyak asam lemak tak jenuh
dibandingkan asam lemak jenuh.
– Sebagai sumber protein sebaiknya diperoleh dari ikan, ayam
(terutama daging dada), tahu dan tempe, karena tidak banyak
mengandung lemak.
– Masukan serat sangat penting bagi penderita diabetes,
diusahakan paling tidak 25 g per hari
 Olah raga

Dianjurkan olah raga teratur, 3-4 kali tiap minggu selama ± 0,5
jam yang sifatnya sesuai CRIPE (Continous, Rhythmical, Interval,
Progressive, Endurance training) (Anonim, 2001).
– Sedapat mungkin mencapai zona sasaran 75-85% denyut nadi
maksimal (220-umur), disesuaikan dengan kemampuan dan
kondisi penderita.
– Beberapa contoh olah raga yang disarankan, antara lain jalan
atau lari pagi, bersepeda, berenang, dan lain sebagainya.
– Olahraga aerobik ini paling tidak dilakukan selama total 30-40
menit per hari didahului dengan pemanasan 5-10 menit dan
diakhiri pendinginan antara 5-10 menit.
 Oral Medication Options
• Biguanides (metformin) • α-Glucosidase inhibitors
• Sulfonylureas – Acarbose, Miglitol,
• Dipeptidyl peptidase IV (DPP-IV) • Bile acid sequesterants
inhibitor
– Colesevelam
– Sitagliptin
• Dopamine-2 agonists
– Saxagliptin
– Bromocriptine
– Linagliptin
– Alogliptin
• Meglitinides (repaglinide)
• Thiazolidinediones (TZDs)
– Only Pioglitazone

28
 Korelasi Hba1C dengan Gula Darah

Ada pertimbangan khusus

untuk pasien dengan
kendali amat buruk
disertai katabolisme,
misalnya kadar glukosa
darah puasa diatas 250
mg/dl, kadar glukosa
darah acak diatas 300
mg/dl, A1C >10%, atau
gejala diabetes yang nyata
(poliuria, polidipsia, dan
berat badan menurun),
maka terapi insulin
dengan kombinasi pola
hidup merupakan terapi
pilihan
Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach, Position Statement by the ADA and the
EASD. Diabetes Care. 2012;35:1364-79.
The Australian National
Health and Medical
Research Council
(NHMRC) guideline for
blood
glucose control in type
2 diabetes
UMHS Management of Type 2 Diabetes Mellitus, May 2014
 Insulin

• normal insulin secretion : a relatively

constant background level of insulin
(basal) for the fasting and
postabsorptive period, and prandial
spikes of insulin after eating (bolus).

• the timing of insulin onset, peak, and

duration of effect must match meal
patterns and exercise schedules to
achieve near-normal blood glucose
values throughout the day.
Kendala dalam terapi Insulin

Ndak mau…

Sakit Mahal

GD tll rendah
Ketergantungan
 Kendala dalam terapi Insulin
1. “Sekali mulai terapi insulin, tidak bisa di stop lagi ”
(Persepsi yang salah, seperti “kecanduan” obat )
– Berikan insulin dengan “percobaan” jangka pendek :
“Cobalah suntik insulin selama 1 bulan saja, lalu kita
evaluasi lagi”
2. “ Suntik insulin sangat merepotkan”
( Pasien merasa tidak sanggup suntik sendiri)
– Demonstrasikan kepada pasien betapa simple nya
suntikan insulin
– Berikan insulin 1x /hari untuk mengurangi
ketidaknyamanan

Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.

Kendala dalam terapi Insulin
3. “Kegagalan terapi adalah kesalahan saya”
(suntikan insulin sebagai hukuman karena kegagalan pribadi)
Jelaskan bahwa insulin diperlukan karena perjalanan penyakit DM yg progresif,
bukan karena kegagalan pasien mengelola penyakitnya

4. “Famili saya disuntik insulin sebelum diamputasi kakinya”

(Insulin diberikan bila Diabetes sudah berat)
Jelaskan bahwa suatu saat insulin diperlukan karena perjalanan alamiah penyakit
DM yg progresif

5. “ Saya tidak berani suntik insulin sendiri, karena nyeri..! ”

(Anxietas terhadap suntik insulin)
Berikan contoh di depan pasien

Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.

 Penggunaan insulin pada diabetes
• DM tipe 1 / DM gestasional / DM tipe lain
• DM tipe 2 :
Obat oral gagal
Infeksi dan penyakit berat (PJK, stroke)
Hamil
Operasi besar
Gagal ginjal – gagal hati
Koma hiperglikemia

41
Pharmacokinetics of Various Insulins Administered
Subcutaneously or Inhaled
Theoretical insulin effect provided by various insulin regimens
A: Two daily injections of rapid-acting (insulin aspart, glulisine, or lispro) or
short-acting (regular) and intermediate-acting insulin (NPH). B: Morning
injection of rapid or short-acting insulin and an intermediate-acting insulin,
a presupper injection of rapid or short-acting insulin, and a bedtime
injection of intermediate-acting insulin. Suggested for patients with early
morning hypoglycemia followed by rebound hyperglycemia or for patients
with early morning hyperglycemia (rebound phenomenon). C: Preprandial
injections of rapid or short-acting insulin and long-acting (e.g., insulin
glargine or detemir) or intermediate-acting insulin (NPH) at bedtime. D:
Continuous subcutaneous insulin infusion. B, breakfast; HS, bedtime snack;
L, lunch; S, supper. Arrows, time of insulin injection (<15 minutes before
meals for rapid-acting insulin and ∼30 minutes before meals for short-
acting insulin).
 Initial Insulin dosage in T1DM

• 0.5 U/kg/day with negative to moderate

ketones
• 0.7 U/kg/day with large ketones
A total daily dose of insulin is estimated empirically (e.g., 0.5 unit/kg/day).
Provide 50% as long acting insulin and 50% as prandial insulin
 How to initiate insulin treatment in type 2

• Start with 0.2 units / kg (or)

• Body weight divided by 5 (or)

• Dose = FBS-50 (or)

10
• Average fasting blood sugar divided by 18
Bagaimana cara memulai insulin ??
 Insulin can be initiated at any time

• Traditionally, insulin has been reserved as the last line of

therapy…
• …However, considering the benefits of normal glycemic status,
insulin can be initiated earlier and as soon as possible

Inadequate Lifestyle + 1 OAD + 2 OAD + 3 OAD

INITIATE INSULIN
Strategy of insulin treatment
 Jika gula darah puasa • Gunakan insulin basal
meningkat

Jika gula darah sesudah • Gunakan insulin bolus

makan meningkat

Jika gula darah puasa dan • Gunakan insulin premix

sesudah makan meningkat • Atau tambahkan insulin
basal pada terapi OAD
• Atau mulai terapi basal
bolus

Perkeni, Petunjuk praktis terapi insulin pada pasien diabetes, 2011

RECOMENDATION

58
Kontribusi kadar glukosa puasa dan glukosa prandial terhadap HbA1c

Kontribusi kadar glukosa prandial

30%
40%
Kontribusi terhadap HbA1c

45%
50%
70%
70%

60%
“FIX THE FASTING
55% FIRST”
START
50% WITH BASAL INSULIN

30%
Kontribusi kadar glukosa puasa

< 7.3 7.4-8.4 8.5-9.2 9.3-10.2 >10,3

HbA1c
59
Monnier L et al. Diabetes Care 2003
 New position statement of the ADA and EASD on management of
hyperglycemia in type 2 diabetes

Inzucci SE, et al. Diabetologia. 2012

Suntikkan 10 iu Levemir sekali sebelum tidur. Atur dosisnya (+3 atau -3) setiap 3 hari
Fix the Fasting First sampai GDP mencapai target :
< 100 mg/dL (Perkeni 2011)

400
20

T2DM
300
GDP, mencapai target
15

Plasma glucose (mmol/l)

Plasma glucose (mg/dl)

Profile T2DM
200 Hyperglycaemia due to an increase in fasting glucose
10

100
5
Normal
Meal Meal Meal
0 0
06.00 10.00 14.00 18.00 22.00 02.00 06.00

Time of day (hours)

 Levemir® Dose Titration Guidelines:
3-0-3 Algorithm

Start with Levemir 10 U or 0,1-0,2 U per Kg BB

Dose Adjustment for Each Arm

increase dose
Mean 3-day FPG (mg/dL)

FPG>90 mg/dl (5.0 mm/L) 3U FPG>110 mg/dL (6.1 mmol/L)

FPG target range FPG target range

70-90 mg/dL 0 maintain
dose 80-110 mg/dL

decrease dose
FPG <70 mg/dL (3.8 mmol/L) FPG <80 mg/dL (4.4 mmol/L)
3U

Patients who experienced hypoglycemia reduced their daily dose by 3 units

Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-631.

increased by 2 units if glucose is relatively close to the fasting target (e.g. if fasting blood
glucose is 130–180 mg/dl), or 4 units if fasting blood glucose is > 180 mg/dl after 3 days of
monitoring. If hypoglycemia with blood glucose < 70 mg/dl occurs, basal insulin
should be decreased by 10% or 4 units, whichever yields the larger change.

American Diabetes Association

Korelasi Hba1C dengan Gula Darah
• A rule of thumb is that a patient should not be
advanced to more than 0.5 units/kg of body
weight for basal insulin without first
considering adding a rapid-acting insulin (e.g.,
0.1 units/kg) with meals
 After fasting glucose has been controlled, then what ??

Cek PPG, if high  goes to Basal – Bolus or switch to Premix

Insulin prandial yang diberikan dimulai dengan dosis 4 unit sehari dan dapat disesuaikan
(dinaikkan dosisnya sebanyak 2 unit) setiap 3 hari jika sasaran glukosa darah setelah makan
belum tercapai
REGIMEN BASAL-BOLUS
Kelebihan : ---- Insulin endogen

Levemir
1. Sangat ideal, dapat menghasilkan terapi yang menyerupai profil insulin
endogen ---- NovoRapid

2. Sangat mudah mengatur dosis insulin basal maupun bolusnya

Kelemahannya :
3. Pasien tidak menyukainya karena 4 x suntik
4. Pasien harus menggunakan 2 jenis insulin (berisiko pasien salah suntik)
dan biaya terapi lebih mahal

Makan Makan Makan Sebelum tidur

Pagi Siang Malam
Suntikkan 10 iu Levemir sekali sebelum tidur. Atur dosisnya (+3 atau -3) setiap 3
Basal – Bolus Concept dengan Levemir - NovoRapid
hari sd. GDP mencapai target GDP 80-110 mg/dL (Perkeni 2006)
Tambahkan Injeksi NovoRapid di setiap makan (2-6 iu) untuk mengendalikan
Gula darah 2 jam PP mencapai target < 140 mg/dL (Perkeni 2006)
400

20

300 T2DM
Plasma glucose (mg/dl)

Plasma glucose (mmol/l)

Profile
15 T2DM

200 Hyperglycaemia due to an increase in fasting glucose

10

100
5
Normal
Meal Meal Meal
0
0
06.00 10.00 14.00 18.00 22.00 02.00 06.00

Time of day (hours)

Regimen Premix

Kelebihan :
•
---- Insulin endogen
Sangat disukai pasien karena cukup menggunakan 1 jenis insulin dan 1 jenis pen (Data
NovoMix 1 x sehari (mulai 12 iu)
Diabcare 2008, pada 1829 pasien Indonesia menunjukkan premix paling banyak
NovoMix 2 x sehari (mulai 3 iu)
digunakan)
NovoMix 3 x sehari (mulai 3 iu)
Kelemahannya :
• Pengaturan dosis kurang fleksibel

Makan Makan Makan Sebelum tidur

Pagi Siang Malam
 Additional Concerns

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