Diabetes Mellitus

Capita Selecta
2016
 EPIDEMIOLOGY
Diabetes Mellitus
Diabetes: A global emergency
Diabetes around the world
Diabetes around the world
 Prevalence of Type
1 Diabetes

IDF Diabetes Atlas, 4rd ed.2009

IDF Diabetes Atlas, 5th ed.2011

 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

8
Care 2009;32:2016–20. 9. Mafauzy M, et al. Med J Malaysia 2011;66(2):175–81 .
 Failure to maintain glycemic control can lead to
several complication consequences
the most frequent cause
Stroke
of new cases of blindness 2-4 x risk for stroke
among adults aged and coronary heart
disease
20 to 74.
Diabetic
Retinopathy

Cardiovascular
disease

Diabetic
Myocardiac infarct
Nephropathy Most common cause
of death in diabetics
Accounts for ~40% of all new
cases of Diabetic
end-stage renal disease
(ESRD).
Neuropathy
Most common cause of
lower limb amputation

National Diabetes Information Clearinghouse. Diabetes Statistics–Complications of Diabetes.

http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#comp.
PATHOPHYSIOLOGY
Diabetes Mellitus
Normal
PREDIABETES DIABETES

Puasa : <100 mg/dl IFG : 100-125 mg/dl ≥ 126 mg/dl

2 hours post OGTT : IGT : 140-199 mg/dl ≥ 200 mg/dl

<140 mg/dl

FPG : Fasting plasma glucose (Gula darah puasa)

2-h PG : 2-hour plasma glucose (Gula darah 2 jam setelah makan)
IFG : Impaired fasting glucose (Gula darah puasa terganggu)
IGT : Impaired glucose tolerance (Toleransi glukosa terganggu)
Insulin
production
and
action
CLASSIFICATION

Type 1 Due to b-cell destruction, usually leading to absolute

insulin deficiency
Type 2 Due to a progressive insulin secretory defect on the
background of insulin resistance
Other • Genetic defects in b-cell function
specific • Genetic defects in insulin action
types of • Diseases of the exocrine pancreas (such as cystic
diabetes fibrosis), and
• Drug-or chemical-induced (such as in the treatment of
HIV/ AIDS or after organ transplantation)
Gestasional diabetes mellitus (GDM)
(diabetes diagnosed during pregnancy that is not clearly overt diabetes)
Natural history of type 1 diabetes
 Slide 16

Main pathophysiological defects in type 2 DM

Brain
Intestines Pancreas
pancreatic
incretin insulin
effect secretion
pancreatic
glucagon ? Kidney
secretion
gut
carbohydrate Glucose
reabsorpsion
delivery and
absorption Hyperglycemia
Muscle
Liver

peripheral
glucose
uptake
hepatic Adipose
glucose
production
Adapted from:Inzucchi SE, Sherwin RS. Diabetes Mellitus. In: Goldman L, Ausiello D, eds. Cecil Textbook of Medicine. 23rd
Edn. Philadelphia, Pa: Saunders Elsevier; 2007.
Pathogenesis of T2DM :
• Insulin secretory dysfunction
• Insulin resistance (muscle, fat, liver)
• Increased endogenous glucose production
• Deranged adipocyte biology
• Decreased incretin effect
 PATHOGENESIS OF TYPE 2 DIABETES

Genetics Environment
Excess energy intake
Sedentary life
INSULIN RESISTANCE

Obesity
↑ FFA
↑ Glucose

Impaired glucose tolerance

ß cell failure ß cell failure

TYPE 2 DIABETES
Cheng AYY, Fantus G. CMAJ 2005; 18:213-226
IR and -cell dysfunction are fundamental to
Type 2 Diabetes
Obesity IFG Diabetes Uncontrolled
hyperglycaemia
350 – Postprandial
300 – glucose
250 –
Glucose 200 –
Fasting
(mg/dl) glucose
150 –
100 –
50 –
250 –
200 – IR
Relative
150 –
function
(%) 100 –
Clinical Insulin secretion
50 – diagnosis
0–
-10 -5 0 5 10 15 20 25 30
Years of diabetes

Adapted from Burger HG et al. 2001. Diabetes Mellitus, Carbohydrate Metabolism, and Lipid Disorders. In Endocrinology.
4th ed. Edited by LJ DeGroot and JL Jameson. Philadelphia: W.B. Saunders Co., 2001.
Originally published in Type 2 Diabetes BASICS. International Diabetes Center, Minneapolis, 2000.
 Stages of type 2 Diabetes in relationship to
100 -cell function

75
Beta cell function (%)

50

IGT Postprandial
Hyperglycemia Type 2
Type 2
25 Diabetes
Diabetes
Phase 1 Type 2
Phase 3
Diabetes
Phase 2
0
- 12 - 10 -6 -2 0 2 6 10 14
Years from diagnosis
hypoX-jsk-7-99
Diagnosis DM
Non-modifiable risk factors Modifiable risk factors
for type 2 diabetes for type 2 diabetes
Hyperglycemia

 Fasting (basal = post absorbtive)

hyperglycemia
 Prandial hyperglycemia
Insulin serum
U/ml
Prandial secretion

Breakfast Dinner

Lunch

40 Snack

Basal

hour
0

Insulin secretion (Rosenzweigh,1994)

Physiologic Plasma Glucose and Insulin Secretion: 24-hour profile

Meals

Prandial insulin

Basal insulin

Prandial glucose

Basal glucose
 Mechanism of Hyperglycemia

Insulin resistance
β-Cell defect + (liver, muscle, fat tissue)

Fasting - hyperglycemia ± PP - hyperglycemia

Manifestation of Hyperglycemia
Management
of diabetes mellitus
Pharmacological
treatment of
type 2 diabetes

28
Oral anti diabetes (OAD) yang ada di Indonesia

• Metformin
• Sulfonylureas (SUs) dan glinides
• α-glucosidase inhibitors (AGIs)
• Thiazolidinediones (TZDs)
• Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)
• GLP-1 agonist
• SGLT-2 inhibitor
Primary sites of action of currently available oral anti-
diabetic agents and non-insulin injectables

Adipose Muscle Blocks

Promotes
Metformin
Liver TZD

FFA
release

TZD
Circulatory System Metformin

Glucose
FFA
Intestinal
Glucose
absorption lipase inhibitor
Insulin
release Fat
Pancreas AGI

DPP-4 Carbohydrates Intestines

inhibitor
GLP-1 agonist

AGI: α-glucosidase inhibitors; DPP-4: dipeptidyl peptidase-4; FFA: free fatty acid; TZD: thiazolidinedione

Cheng A, Fantus G. Can Med Assoc J 2005;172:213–26.. Barnett A. Int J Clin Pract 2006;60:1454–70. Pérez López G, et al.
Nefrologia. 2010;30:618–25.
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.
 Class Generic Brand mg/tab Daily dose Initial Duration Frequency
dose of action /day
Sulfonyl Glibenclamide Daonil 2.5 , 5 2.5 – 15 2.5 12-24 1-2
urea Euglucon
Glipizide Minidiab 5, 10 5-20 5 10-16 1-2
Glucotrol XL
Gliclazide Diamicron 80 80-240 80 10-20 1-2
Gliquidone Glurenorm 30 30-120 30 - 1-3
Glimepiride Amaryl 1, 2, 3, 4 0.5
Non- Nateglinide Starlix 60, 120 TID with 60 6-8 With meal
sulfonyl meal
urea Repaglinide Novonorm 1, 2, 3, 4 TID with 1 6-8 With meal
meal
 Slide 34

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.
GLP 1 Agonist
Mode of Action

Glucagon-like peptide-1 (GLP-1) agonist activates the GLP

receptor in the pancreas. This increases insulin release from
the pancreatic β-cells, while inhibiting glucagon release by
the pancreatic α-cells

• Glucose-dependent insulin biosynthesis

β-cells and secretion
• β-cell proliferation

Pancreas
Net effect:
GLP-1 agonist blood glucose

• Glucagon secretion
α- • β-cell apoptosis
cell

GLP-1: glucagon-like peptide

1. Doyle ME, Egan JM. Pharmacol Ther 2007;113(3):546–93.

 Dosis
Golongan Generic Brand mg/tab Keterangan
Harian (mg)
Sulfonilurea
Glibenklamid Daonil 2.5 – 5 2.5 - 15 Sebelum makan
Glimepirid Amaryl, Solosa 1,2,3,4 1–6
Gliclazid Diamicron MR 30 - 60 30 - 120
Gliquidon Glurenorm 30 30 - 120
Glinid
Repaglinid Dexanorm 1 1.5 - 6
Nateglinid Starlix 120 360
Biguanid
Metformin Glucophage 500 - 850 250 - 3000 Bersama/sesudah makan
Tiazolidindione
Pioglitazone Actos 15 - 30 15 - 45 Tidak bergantung jadwal
makan
α-Glukosidase
inhibitor (AGI)
Acarbose Glucobay, Eclid 50 - 100 100 - 300 Bersama suapan pertama
DPP IV inhibitor
Vildagliptin Galvus 50 50 - 100 Tidak bergantung jadwal
Sitagliptin Januvia 25, 50, 100 25 - 100 makan
Saxagliptin Ongliza 5 5
Linagliptin Trajenta 5 5
 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
Pramlintide* 0.5–1.0 Weight loss Three injections daily, frequent GI
side effects, long-term safety not
established, expensive

Nathan, et al. Diabetes Care 2009;32: 193-203 *not yet available in Indonesia
 Properties of available glucose-lowering agents
that may guide treatment choice in Type 2
Diabetes
Class Compounds(s) Cellular Primary Advantages Disadvantages
mechanism Physiological
action(s)
Biguanides Metformin Activates Hepatic Glucose Extensive Gastrointestinal side
AMP-kinase Production  Experience effects
No weight gain Lactic acidosis risk
No hypoglycemia (rare)
Likely CVD Events  Vitamin B12
deficiency
Multiple
contraindications:
CKD, acidosis,
hypoxia,
dehydration etc.
Sulfonylureas Glibenclamide / Closes KATP Insulin secretion  Extensive Hypoglycemia
glyburide channels on experience Weight gain
Glipizide beta cell Microvascular Risk  Blunts myocardial
Gliclazide plasme (UKPDS) ischaemic
Glimepiride membranes preconditioning ?
Low durability
Meglitinides Repaglinide Closes KATP Insulin secretion  Postprandial Hypoglycemia
Nateglinide channels on glucose excursions  Weight gain
beta cell Dosing flexibility Blunts myocardial
plasme ischaemic
membranes preconditioning ?
Frequent dosing
schedule

Inzucci SE, et al. Diabetologia. 2012

 Properties of available glucose-lowering agents
that may guide treatment choice in Type 2
Diabetes cont.
Class Compounds(s) Cellular Primary Advantages Disadvantages
mechanism Physiological
action(s)
Thiazolidinedi Pioglitazone Activates the Insulin Sensitivity  No hypoglycemia Weight Gain
ones Rosiglitazone nuclear Durability Oedema / Heart
transcription HDL-C  Failure
factor PPAR-y Triacylglycerols  Bone Fractures
(pioglitazone) LDL-C 
CVD Events ? (rosiglitazone)
Mn  (meta-
analyses,
rosiglitazone)
Bladder Cancer ?
(pioglitazone)
a-Glucosidase Acarbose Inhibits Slows intestinal No hypoglycemia Modest HbA1c
Inhibitors Migitol intestinal a- carbohydrate Postprandial efficacy
Voglibose glucosidase digestions / glucose Gastrointestinal side
absorption excursions  effects (flatulence,
CVD Events  diarrhoea)
Non-systemic Frequent dosing
schedule
DPP-4 Sitagliptin Inhibits DPP-4 Insulin secretion  No hypoglycemia Modest HbA1c
Inhibitors Vildagliptin activity, (glucose-dependent) Well tolerated efficacy
Saxagliptin increasing Glucagon secretion  Urticardia/Angio-
Linagliptin postprandial (glucose-dependent) oedema
Alogliptin active incretin Pancreatitis ?
(GLP-1, GIP)
concentrations

Inzucci SE, et al. Diabetologia. 2012

 Properties of available glucose-lowering agents
that may guide treatment choice in Type 2
Diabetes cont.
Class Compounds(s) Cellular Primary Advantages Disadvantages
mechanism Physiological
action(s)
GLP-1 Exenatide Activates GLP- Insulin secretion  No hypoglycemia Gastrointestinal side
Receptor Liraglutide 1 receptors (glucose-dependent) Weight reduction effects (nausea /
Agents Glucagon secretion  Improved beta vomiting)
(glucose-dependent) cell mass / Acute pancreatitis ?
Slows gastric function ? C cell hyperplasia /
emptying Cardiovascular medullary thyroid
Satiety  protective tumours
actions ? Injectable
Training
Requirements

Insulin Human NPH Activates Glucose disposal  Universally Hypoglycemia

Human Regular insulin Hepatic glucose effective Weight gain
Lispro receptors production  Theoretically Mitogenic effects ?
Aspart unlimited Injectable
Gluisine efficacy Training
Glargine Microvascular Requirements
Determir Risk  (UKPDS) ‘Stigma’ for patients
Pre-mixed
(several types)

Inzucci SE, et al. Diabetologia. 2012

SGLT-2 inhibitors
Mode of Action

NORMAL individuals :
• Filtered glucose load : ±180 g/day
• Urinary glucose : less than 0.5 g/day
• SGLT-s reabsorbs glucose from the nephron back
into the bloodstream
 Algoritma pengelolaan DM tipe 2 Tanpa Dekompensasi

DM Tahap -I Tahap -II Tahap -III

GHS

GHS
+
monoterapi

Catatan GHS
+
1. GHS = gaya hidup sehat
2. Dinyatakan gagal bila terapi Kombinasi 2 OHO
selama 2-3 bulan pada tiap
tahap tidak mencapai target
terapi HbA1c <7% Jalur pilihan alternatif, bila: GHS
3. Bila tidak ada pemeriksaan • tidak terdapat insulin +
HbA1c dapat dipergunakan • diabetisi betul-betul menolak Kombinasi 2 OHO
pemeriksaan GD.
Rata-2 hasil pemeriksaan insulin +
beberapa kali glukosa darah • kendali glukosa belum Basal insulin
sehari yang dikonversikan ke optimal
HbA1c menurut kriteria ADA,
2010
GHS
+ Insulin intensif*
Kombinasi 3 OHO

* Insulin intensif: penggunaan insulin basal bersamaan dengan insulin prandial

 Algoritma pengelolaan DM tipe 2 Tanpa Dekompensasi
Kadar HbA1c

<7% <7-8% <8-9% >9% 9-10% >10%

GSH GSH
+
Gaya Hidup
Sehat Monoterapi GSH
• Penurunan +
berat badan Met, SU,
• Mengatur diit GSH
AGI, Glinid, Kombinasi
• Latihan 2 obat +
TZD, DPP IV
jasmani
teratur Kombinasi GSH
Met, SU,
AGI, Glinid, 3 obat +
Catatan TZD, DPP IV
Met, SU, Kombinasi
1. Dinyatakan gagal bila dengan
AGI, Glinid, 2 obat
terapi 2-3 bulan tidak mencapai
target HbA1c <7% TZD, DPP IV
Met, SU,
1. Bila tidak ada pemeriksaan AGI, Glinid,
HbA1c dapat digunakan TZD
pemeriksaan GD.
Rata-rata glukosa darah sehari + GSH
GSH
dikonversikan ke HbA1c
menurut kriteria ADA 2010 Basal Insulin +

Insulin
intensif *

* Insulin intensif: penggunaan insulin basal bersamaan dengan insulin prandial

48
 Management of Hyperglycemia in
Type 2 Diabetes : A Patient-Centered Approach

Position Statement of the American Diabetes Association (ADA) and

the European Association for the Study of Diabetes (EASD)
Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efficacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs
Me ormin low

intolerance or If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
contraindica on Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy† dione inhibitor inhibitor agonist
Efficacy* high high intermediate intermediate high highest
Hypo risk moderate risk low risk low risk low risk low risk high risk
HbA1c Weight gain gain neutral loss loss gain
≥9% Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
Costs low low high high high variable

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i

Uncontrolled or GLP-1-RA or GLP-1-RA or Insulin§ or Insulin§ or GLP-1-RA

hyperglycemia or Insulin§ or Insulin§
(catabolic features,
BG ≥300-350 mg/dl,
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
HbA1c ≥10-12%) basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
+
Combination
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy‡
Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0
 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)
Key concepts in setting glycemic goals :
A1C is the primary target for glycemic control
• Goals should be individualized based on :
- duration of diabetes
- age/life expectancy
- comorbid condition
- known CVD or advanced microvascular complications
- hypoglycemia unawareness
- individual patient considerations
• More or less stringent glycemic goals may be appropriate for individual
patients

Postprandial glucose may be targeted if A1C goals are not met despite
reaching preprandial glucose goals

(Standard of Medical Care in Diabetes, ADA 2012)

Factors to Consider when Choosing
an Anti-hyperglycemic agent

Effectiveness in lowering glucose

Extraglycaemic effects that may reduce long-term

complications

Safety profile

Tolerability

Cost

Effect on body weight

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

The Principles of OAD Combination Theory

• Two (or more) oral blood glucose-lowering

medicines that have different mechanisms of
action
• Two medications is better rather than increase
in initial medicine to maximum dosage
• Fewer side effects than mono-therapy at higher
doses
Key concepts in setting glycemic goals :
A1C is the primary target for glycemic control
• Goals should be individualized based on :
- duration of diabetes
- age/life expectancy
- comorbid condition
- known CVD or advanced microvascular complications
- hypoglycemia unawareness
- individual patient considerations
• More or less stringent glycemic goals may be appropriate for individual
patients

Postprandial glucose may be targeted if A1C goals are not met despite
reaching preprandial glucose goals

(Standard of Medical Care in Diabetes, ADA 2012)

Diabetes in elderly people


• Always start with the lowest dose of
any blood glucose-lowering medicine
and increase gradually
• Using shorter-acting medicines that
reduces the risk of hypoglycaemia
• Hypoglycaemia may increase the risk
of falls and heart attack in older
people
Remember the possibility of
• Forgetfulness
• Poor motivation
• Depression
• Cognitive deficits
• Poly-pharmacy
• Reduced manual dexterity
• These factors impact on the ability
to maintain self-care and achieve
maximum benefits from blood
glucose-lowering medicines.
 Glycemic Target
Individualizing A1c target

Canadian Diabetes Association, 2013

 GLYCEMIC GOALS IN ADULT

IDF AACE ADA

HbA1C (%) < 6.5 ≤ 6.5 < 7.0
Fasting/preprandial glucose < 6.0 / < 110 < 6.0 / < 110 3.9-7.2/ 70-130
(mmol/L / mg/dL)
2-h postprandial glucose < 7.8 / < 140 < 7.8 / < 140 < 10.0 / < 180*
(mmol/L / mg/dL)

*ADA recommends that postprandial glucose measurements should be made

1- 2h after the beginning of the meal
IDF : International Diabetes Federation
AACE : American Association of Clinical Endocrinologist
 Correlation of A1C with Average Glucose

Mean plasma glucose

HbA1C (%) (mg/dl)
6 126
7 154
8 183
9 212
10 240
11 269
12 298

These estimates are based on ADAG data of ~2,700 glucose measurements over 3
months per A1C measurements in 507 adults with type 1, type 2, and no diabetes.
The correlation between A1C and average glucose was 0.92.