Diabetes Mellitus:

Treatment Based on Pathophysiology

of Hyperglycemia

Djoko Wahono
Soeatmadji

Division of Diabetes and Endocrinology,

Department of Medicine, Dr. Saiful Anwar
Hospital, Medical Faculty, Brawijaya University
 The New Paradigm of (Type 2)
Diabetes Treatment
• Aggressive Treatment – Driven by
Target (AIC < 7%)
• Early Combinations (including with
insulin)
• Agressive Insulin Treatment
 Rationale for
Aggressive Treatment

r:ndei:6855:slides:bernsteintitle
 Type 2 diabetes is NOT a mild
disease
Stroke
Diabetic 2 to 4 fold increase in
cardiovascular
Retinopathy mortality and stroke3
Leading cause
of blindness
in working age Cardiovascular
adults1
Disease
8/10 diabetic patients
die from CV events4

Diabetic
Nephropathy Diabetic
Leading cause of
Neuropathy
end-stage renal disease2 Leading cause of
non-traumatic lower
extremity amputations5

1
Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98.
3
Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5
Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.
 Serious Complications of Type 2
Diabetes are Present at Diagnosis
Complication Prevalence
(%)*
Any complication 50
Retinopathy 21
Abnormal ECG 18
Absent foot pulses ( 2) and/or ischaemic feet 14
Impaired reflexes and/or decreased vibration sense 7
Myocardial infarction/angina/claudication ~2–3
Stroke/transient ischaemic
* Some patients had more attack at time of diagnosis
than one complication ~1
ECG = electrocardiogram

Adapted from UKPDS Group. UKPDS 6. Diabetes Res 1990; 13:1–11.

 DCCT: Results Summary
Improved control of blood glucose
reduces the risk of clinically meaningful
 Retinopathy 76% (P0.002)
 Nephropathy 54% (P<0.04)
 Neuropathy 60% (P0.002)

Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:9
 The UKPDS
Type 2 diabetes
> 5,000 patients; 14 years
1% Life-style vs oral vs
HbA1c insulin

35%  microvascular complication

14%  myocardial infarction
 UKPDS Results:
Tight Blood Pressure Control
Risk Reduction*
P=0.0046 P=0.019 P=0.013 P=0.0092 P=0.0038 P=0.0036 P=0.0043
0
10
24% 32
20 % 37% 34%
44%
47%
30 56%

40
50
60
Any Diabetes- Stroke Micro- Retinopathy Deterioration Heart
diabetes- related death vascular progression of vision failure
related endpoints
endpoint
*Compared with less tight control. Captopril and atenolol were
equally effective in reducing risk and were equally safe in patients
with diabetes. UKPDS Group. BMJ. 1998;317:703-713.
ADA, AACE and IDF glycemic goals
Biochemical index ADA1,2 AACE3 IDF4
(Global)

HbA1c (%) <7 < 6.5 < 6.5

mg/dl mmol/l mg/dl mmol/l mg/dl mmol/l

Fasting/preprandial 5.0–7.2 < 110 < 6.0

90–130 < 110 < 6.0
plasma glucose

Postprandial
plasma glucose < 180 < 10.0 < 140 < 7.8 NA NA

Bedtime plasma
glucose 110–150 6.0–8.3 NA NA NA NA

American Diabetes Association. Diabetes Care 2004; 27:S15–S35.

1

American Diabetes Association. Diabetes Care 2002; 25:S35–S49.

2

3
American Association of Clinical Endocrinologists. Endocrine Pract 2002; 8 (Suppl. 1):40–82.
4
http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf.
PHARMACOTHERAPY

Oral Diabetic Medications

 Primary sites of action of oral
anti-diabetic agents
Biguanides
Muscle
Thiazolidinediones

Adipose
tissue Liver
DPP-4
inhibitors

Pancreas
DPP-4 Stomach
Insulin
Glucose
GLP-1
Gut
Sulphonylureas and a-glucosidase inhibitors
GLP-1 meglitinides
analogues
Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1(Suppl. 1):S32–S40.
Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
Pratley RE & Salsali A. Curr Med Res Opin 2007; 23:919–931.
Todd JF & Bloom SR. Diabet Med 2007; 24:223–232.
Treatment Based on the Pathogenic
Mechanisms of Diabetes
 Treatment Based on the
Pathogenic Mechanisms of Type
2 Diabetes

-cell dysfunction Insulin resistance

Insulin Insulin
Insulin Secretagogues Insulin Sensitizer
SU Metformin
Glinide Glitazone
Acarbose
In Europe and the USA, insulin
resistance with obesity is the
predominant pathological
manifestation of diabetes,
whereas impaired insulin
secretion predominant in Asia
Seino Y and Yamada Y, 2006
 Early Combinations
(Including with insulin)
ORAL DIABETIC MEDICATION
HAS ITS LIMITATIONS
 Cross-sectional and 10-Year Cohort Data:

Patients on SU/Insulin vs Conventional

FPG Treatment HbA 1c
200 9

180
8
Median Median
160
FPG HbA1c
(mg/dL) (%)
140 7

120
6
100 0

Time from randomization (y) Time from randomization (y)

Patients followed for 10 years All patients assigned to regimen
Conventional Glibenclamide (glyburide) Conventional Glibenclamide
Chlorpropamide Insulin Chlorpropamide Insulin
UKPDS Group. Lancet. 1998;352:837-853.
 Efficay of Pharmacological
Treatment Options
Agent Men lowering of initial
HbA1c (%)
-glucosidase inhibitors 0.5 – 1.0
Biguanides 1.0 – 1.5
Sulfonylurea 1.0 – 1.5
Glinides 0.5 – 1.5
Glitazone 1.0 – 1.5
Insulin* 1.0 – 2.0
* Unlimited dose, potentially normalized
Reyden L. Eur Heart J 2007; 28: 88-136
 ORAL AGENT FAILURE RATES
Agent Primary failure Secondary
rate failure rate
Sulfonylurea 15 – 30% 5 – 10%/year

Glinide ? ?

Biguanides < 10% 5 – 10%/year

-Glucosidase Dependent on diet Unknown

inhibitor adherence

Thiazolidinedione As high as 25% Unknown

s

Feingloss,1999
 When to start combination ?

Any single oral therapy is unlikely to

lower A1c >1.5 – 2.0%, it is logical
to consider initial combination
therapy for patients presenting with
an A1c 8.0–9.0%
Dailey GE. Diabetes Care 2005; 28:220-221
RULE OF COMBINATION
Use combinations of oral
antidiabetic agents with
complementary
mechanisms of action
 Two (or more ?) Oral Hypoclycaemic
Agents with Different Class of Action
SU Met TZD Glinide Acarbose
SU

Met

TZD

Glinide

Acarbose

Insulin
Combine Do not combine
 The Idial Combination

 Insulin secretion  Insulin sensitivity

More than 50 years proven safety and efficacy

• Safe
• Better glycaemic control than
monotherapy
• Does not require maximal oral
hypoglycaemic dose
 …such an aproach is logical and will
likely result in quicker achievement of
target glucose levels, particularly in
those with greatest degree of baseline
glycemia…

Kimmel B and Inzuchhi SE. Clinical Diabetes 2005; 23: 64 – 76 .

 Treatment Based on the
Pathophysiology of Hyperglycemia
 The Physiological Requirement for Insulin

Basal

Pancreatic output :
basal  prandial

• Basal insulin : the amount of insulin necessary to prevent fasting

gluconeogenesis (fasting hyperglycemia) and ketogenesis

• Prandial insulin : the amaount of insulin necessary to cover meals

without development of posprandial hyperglycemia
Physiologic Plasma Glucose and Insulin Secretion:
24-hour profile
Meals

 
Prandial insulin

Basal insulin

Prandial glucose
                                                                                                                                                         

Basal glucose
                          
Insulin and Glucose Patterns in Type 2 Diabetes :
Basal vs Mealtime

■ Basal hyperglycemia ■ Mealtime hyperglycemia

                                                                                                                                                           

                          
 Treatment Based on the
Pathophysiology of Hyperglycemia
in Type 2 Diabetes

Fasting Hyperglycemia Prandial Hyperglycemia

Insulin long-acting Insulin prandial

(Insulin basal) Short-acting Insulin
Long-acting SU Short-acting SU
Metformin Glinide
Glitazone Glitazones
Acarbose
 Policy for the Selection of
Glucose Lowering Therapy
Glucometabolic Situation
Postprandial
hyperglycemia
Fasting hyperglycemia
Insulin resistant
Insulin deficiency
Policy
-glucosidase inhibitors,
Short-acting SU, Glinides,
Short-/rapid-acting insulin
Biguanides, long-acting
SU, glitazones, long-acting
insulin
Biguanides, glitazones,
-glucosidase inhibitors
SU, glinides, insulin

Reyden L. Eur Heart J 2007; 28: 88-136

 Potential Downsides of Pharmacological
Treatment Modalities in Type 2 diabetes
Potential Problems Avoid or reconsider

Weight gain SU, glinides, glitazones, insulin

GI symtoms Biguanides, -glucosidase

inhibitors
Hypoglycemia SU, glinides, insulin

Impaired kidney Biguanides, SU

function
Imapired liver function Glinides, glitazones, biguanides, -
glucosidase inhibitors
Impaired cardio- Biguanides, glitazones
pulmonary function
Reyden L. Eur Heart J 2007; 28: 88-136
We must learn to live together as
brothers or perish as fools
 The ADA and EASD Management
Algorithm (2006)
Lifestyle and intervention and metformin

If HbA1c > 7%*

Add basal insulin Add sulfonylurea Add TZD

(most effective) (least expensive) (no hypoglicemia)

If HbA1c > 7%

Intensify Add TZD Add basal Add

insulin** insulin sulfonyluera

If HbA1c > 7%

Add
Intensify insulin

Intensive insulin + metformin +/- TZD

* Check HbA1c every 3 months until HbA1c < 7% and than at least 6 months
** Preferred based on effectiveness and expense
 Hypoglycemia in patients receiving
monotherapy for 6 years in the UK Prospective
Diabetes Study
Principal Diabetes Management
(The Asia-Pacific Type 2 Diabetes Policy group)

(A1C >7.4%)