Combination of

Oral Anti Diabetes Drugs

Laksmi Sasiarini
Malang Endocrinology Update X
2018
 Majority of Type 2 DM patients in Asia Pacific fail to
achieve glycemic control (HbA1c < 7.0%)

Australia Thailand Singapore India Indonesia

(St Vincent’s1) (Diab Registry2) (Diabcare3) (DEDICOM4) (Diabcare5)


30.0% 30.2% 33.0% 37.8% 32.1%
37.8
70.0% 69.8% 67.0% 62.2% 62.2 67.9%

Hong Kong China S. Korea Malaysia

(Diab Registry6) (Diabcare7) (KNHANES8) (DiabCare9)
HbA1c at or
39.7% 41.1% 43.5% 22.0% below target
HbA1c above target
60.3% 58.9% 56.5% 78.0%

DM, diabetes mellitus.

Bryant W, et al. MJA 2006;185:305–9. 2. Kosachunhanun N, et al. J Med Assoc Thai 2006;89:S66–S71. 3. Lee WRW, et al. Singapore
Med J 2001;42:501–7. 4. Nagpal J & Bhartia A. Diabetes Care 2006;29:2341–8. 5. Soewondo P, et al. Med J Indoes 2010;19(4):235–44.
6. Tong PCY, et al. Diab Res Clin Pract 2008;82:346–352. 7. Pan C, et al. Curr Med Res Opin 2009;25:39–45. 8. Choi YJ, et al. Diabetes

2
Care 2009;32:2016–20. 9. Mafauzy M, et al. Med J Malaysia 2011;66(2):175–81 .
 Greater challenge in low and middle countries1
In T2DM patient starting 2nd line treatment, less than
30% achieve LDLD-C and SBP target1

1. Gomes MB, et al. Presented at 53rd EASD, 11-15 Sep 2017, Lisbon, Portugal
 Very poor
glycaemic control

Indonesian HbA1c is the

highest compare with other
participant countries in
DISCOVER study, even after
initiating second line of
therapy
(mean+SD = 9.2+2%)1,
almost 70% patient > 8%).2

1. Wahono DS et al. 2nd ICE on IMERI, 7 November 2017, Jakarta, Indonesia

2. Ji L et al. 53rd EASD, 11–15 September 2017, Lisbon, Portugal.
There is often a delay in titrating monotherapy or in
initiating combination therapy, caused by “clinical
inertia” , which results in prolonged hyperglycemia
before treatment is stepped up, with the associated
risk of micro- and macrovascular complications.
• The 3 studies above indicate that it may take 1-3 years for
uncontrolled patients to receive additional therapy.
• Patient and physician factors may contribute to clinical inertia.
Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical inertia in people with type 2 diabetes. Diabetes Care. 2013;36:3411-3417.
Nichols GA, Koo YH, Shah SN. Delay of insulin addition to oral combination therapy despite inadequate glycemic control: delay of insulin therapy. J Gen Intern
Med. 2007;22:453-458.
Fu AZ, Qiu Y, Davies MJ, Radican L, Engel SS. Treatment intensification in patients with type 2 diabetes who failed metformin monotherapy. Diabetes Obes Metab.
2011;13:765-769.
 Aggresive
Management

Conservative
Management
 Disadvantage of up-titration of monotherapy is the
potential for dosages that reach, or exceed, the maximum
effective dose  lead to increased adverse effects.

 Use of combination therapy may permit use of a lower

(submaximal) dose of each agent to minimize dose-
related side effects.
The choice of which agent to add is based on drug
specific effects and patient factors :
• Safety
• Efficacy
• Hypoglycemia
• Weight change
• CV events
• Cost
• Renal effect
• Additional consideration
Schwartz SS et al. Diabetes Care 2016;39:179–186
Egregious Eleven Targeted Treatments for
Mediating Pathways of Hyperglycemia
Oral anti diabetes (OAD) yang ada di Indonesia

• Metformin
• Sulfonylureas (SUs) dan glinides
• α-glucosidase inhibitors (AGIs)
• Thiazolidinediones (TZDs)
• Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Sodium glucose co-transporter 2 (SGLT-2) inhibitors
Metformin
Mode of Action

The primary effects of metformin are to decrease hepatic

glucose production and increase insulin-mediated peripheral
glucose uptake

Muscle Liver Intestine Adipose tissue

 Glucose uptake  Gluconeogenesis  Anaerobic glucose  Glucose uptake
metabolism
 Glucose oxidation  Glycogenolysis  Glucose oxidation

 Glycogenesis  Oxidation of FA

 Oxidation of FA

FA: Fatty Acids

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

SUs and Glinides
Mode of Action

Pancreatic β-cell
• Sulfonylureas (SUs) and glinides
increase endogenous insulin ATP-sensitive
potassium channel
secretion by binding to Glucose Glycolysis ATP
pancreatic β-cells and triggering uptake respiration SUs /
a cascade of intracellular glinides
events1–3 Glucokinase

• The mode of action of SUs and

glinides is similar, but stimulation
of insulin secretion is more rapid
and short-acting with glinides
• SU receptors are also found on
other cells, including the cardiac
myocytes
Insulin release Ca2+
Voltage-gated
ATP = orange calcium channel
Ca2+ = light green
SU: sulfonylurea; GLUT: glucose transporter.

1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:1–11. 2. Schuit FC, et al. Diabetes 2001;50:1–11. 3. Krentz
AJ, Bailey CJ. Drugs 2005;65:385–411.
 Slide 15

Alpha glucosidase inhibitors

Mode of Action

• Slow digestion of sucrose

and starch and therefore
delay absorption
• Slow post-meal rise in blood
glucose
• Side effects : flatulence,
abdominal discomfort ,
diarrhoea
• As mono-therapy will not
cause hypoglycaemia

1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:1–11. 2. Schuit FC, et al. Diabetes 2001;50:1–11. 3. Krentz
AJ, Bailey CJ. Drugs 2005;65:385–411.
Thiazolidinediones (TZDs)
Mode of Action

Thiazolidinediones (TZDs) increase the sensitivity of muscle

and adipose cells to insulin and suppressing hepatic glucose
production

Adipose tissue Muscle Liver

 Glucose uptake  Glucose uptake  Gluconeogenesis

 Fatty acid uptake  Glycolysis  Glycogenolysis
 Lipogenesis  Glucose oxidation  Lipogenesis
 Pre-adipocyte  Glycogenesis*  Glucose uptake*
differentiation
*Inconsistent findings

TZD: Thiazolidinediones

Krentz AJ, Bailey CJ. Drugs 2005;65:385–411.

DPP-4 inhibitors
Mode of Action

Increases and prolongs GLP-1

β-cells
and GIP effects on β-cells
DPP-4
Food intake inhibitor
Glucose-dependent insulin secretion

Net effect:
Stomach DPP-4 Pancreas
blood glucose

GI tract Incretins
(GLP-1, GIP) Increases and prolongs
α-cells
GLP-1 effect on α-cells

Glucose-dependent glucagon secretion

Intestine

* GIP does not inhibit glucagon secretion by α-cells

DPP-4: dipetidyl peptidase-4; GI: gastrointestinal; GIP:glucose-dependent insulinotropic polypeptide; GLP-1: glucagon-like
peptide

Drucker DJ et al. Nature 2006;368:1696–705. Idris I, et al. Diabetes Obes Metab 2007;9:153–65. Barnett A. Int J Clin Pract
2006;60:1454–70. Gallwitz B, et al. Diabetes Obes Metab 2010;12:1–11.
SGLT-2 INHIBITOR
Mode of Action

The SGLT2 is expressed in the proximal tubule and mediates

reabsorption of approximately 90 percent of the filtered
glucose load.
SGLT2 inhibitors promote the renal excretion of glucose.
 Which the alternative therapy?
HbA1C Advantages Disadvantages
Metformin 1-2 No hypoglycemia,no weight gain, Gastrointestinal (GI) symptoms
Broad benefit Contraindicated in renal insuffisiency
SU 1.5 Rapidly effective, inexpensive Weight gain and hypoglycaemia

TZD 0.5–1.4 No hypoglycaemia, some benefits Fluid retention, heart failure, weight
on lipids and inflammation gain, expensive
Insulin 1.5–3+ Most effective, no maximum dose, Hypoglycaemia, weight gain, need for
improved lipid profile Self monitor blood glucose
AGI 0.5–0.8 No hypoglycaemia, weight neutral GI side-effects, expensive
GLP-1 0.5–1.0 No hypoglycaemia, weight loss GI side-effects, expensive, injected
analogue
DPP-4 0.5–0.8 Weight neutral Long-term safety not established,
inhibitor expensive
Meglitinide 1.0–1.5 Fewer hypoglycemia than TID dosing, expensive
sulfonylurea
SGLT-2 0.8–1.0 No hypoglycemia, weight loss, Risk of dehydration, UTI
inhibitor

Nathan, et al. Diabetes Care 2009;32: 193-203

Egregious Eleven Targeted Treatments for
Mediating Pathways of Hyperglycemia
• Reinforce advice on diet, lifestyle and adherence to drug treatment.
• Agree an individualised HbA1c target
• Base choice of drug treatment on: effectiveness, safety, tolerability, the person’s individual clinical
circumstances, preferences and needs, available licensed indications or
• combinations, and cost (if 2 drugs in the same class are appropriate, choose the option with the
lowest acquisition cost)
• Do not routinely offer self-monitoring of blood glucose levels unless the person is on insulin, on oral
medication that may increase their risk of hypoglycaemia while driving or operating machinery, is
pregnant or planning to become pregnant or if there is evidence of hypoglycaemic episodes
Practice Guideline for the
Treatment for Diabetes in
Japan 2013
Clinical Practice Guideline 2015
32
 Very poor
glycaemic control

Indonesian HbA1c is the

highest compare with other
participant countries in
DISCOVER study, even after
initiating second line of
therapy
(mean+SD = 9.2+2%)1,
almost 70% patient > 8%).2

1. Wahono DS et al. 2nd ICE on IMERI, 7 November 2017, Jakarta, Indonesia

2. Ji L et al. 53rd EASD, 11–15 September 2017, Lisbon, Portugal.
Nonadherence to treatment is affected by factors such as
 out-of-pocket costs,
 tolerability/side effects, and
 the complexity of daily treatment regimens
Another factor that may influence the ability of patients to
achieve and maintain their HbA1c treatment targets are
time limitations for PCPs.
Patients with diabetes attended for up to four visits to their
PCP per year, with an average of 10 min per visit…

 HEALTH-SYSTEM-WIDE APPROACHES
• pharmacist-led diabetes medication-therapy
management programs
• diabetes self-management education classes
Diskusi kasus
Ny. A, 45 tahun baru terdiagnosis DM tipe 2.

Data apa yang dibutuhkan untuk menentukan pilihan terapi

DM yang sesuai untuk pasien ?
 Diabetes history
 Medical and drug history
 Lifestyle
 Realistic goals
IMT : 24,6 kg/m2
HbA1c : 8,7%
GD puasa : 206 mg/dL
GD 2 jam setelah makan : 312 mg/dL

Pilihan terapi untuk kendali glukosa darah ?

Monoterapi atau terapi kombinasi ?
Ny. Sari, 58 tahun seorang ibu rumah tangga terdiagnosis DM tipe 2
sejak 5 tahun yang lalu.

Saat ini melakukan kunjungan ke poliklinik dengan riwayat

mengkonsumsi obat glibenclamid 5 mg dua kali sehari setelah makan
(kadang diminum tiga kali sehari tergantung kadar glukosa darah),
metformin 500 mg sekali sehari diminum setelah makan malam.

Dari anamnesis diketahui pasien tidak rutin memeriksakan diri ke

dokter, namun obat DM selalu diminum.

Pasien pernah mendapatkan edukasi terkait pengaturan gaya hidup,

namun sejauh ini sulit mengendalikan dietnya. Rutin melakukan jalan
pagi 2-3x/minggu selama 30-45 menit. Pasien beberapa kali mengeluh
keringat dingin dan terasa lapar terutama menjelang dini hari dan
membaik setelah minum teh manis.
Hasil pemeriksaan fisik :
Tekanan darah 112/73 mmHg, nadi 76x/menit,
TB 158 cm, BB 64 kg.
Hasil pemeriksaan penunjang : HbA1c 8,4%, GDP 198
mg/dL, GD 2 jam setelah makan pagi 264 mg/dL
Thank You