Treating Diabetes

Dr. S. P. Mathew
M. D. [Med]
Ashok Hospital
Definition of Diabetes
 A syndrome caused by a decrease or total
lack of insulin or diminished effectiveness
of circulating insulin (insulin resistance)
 Characterised by hyperglycaemia
Case

A 45 yr old busy business who travels a lot,

BMI 27 kg/m2 and diabetic for 5 yrs presented
with tiredness. He is on T. Glipizide 5 mg BD
and T. Metformin 500 mg BD
Yesterdays lab reports:
FPG 225 mg/dl , PPG 302 mg/dl
& HbA1C 11.2%
Why treat Diabetes?
Change in risk P value

Any diabetes-related endpoint 12% 0.029

Diabetes-related deaths 10% NS
Myocardial infarction 16% 0.052
Microvascular disease 25% 0.0099
Stroke 14% NS
 Progression of OHA treated Diabetes

400

350

300

250
Insulin
Values

200 Fasting
Post Lunch
150

100

50

Time
How to diagnose?
Venous plasma glucose (mg/dl)
Fasting 2 hr after Lunch
Normal GT <110 <140
IFG 110-125 <140
IGT <110 140-199
IFG + IGT 110-125 140-199
DM >126 >200 (or Intermediate Value
>160)
Diagnosis of Diabetes

 For clinical purposes - the diagnosis of diabetes

should always be confirmed by repeating the
test on another day unless there is unequivocal
hyperglycaemia with acute metabolic
decompensation and obvious symptoms
WHO
Why is IGT important?
 IGT converts to Diabetes … therefore
Predictor of future Diabetes.
 IGT has high Cardiovascular risk
 IGT being a prediabetic state gives a
chance for primary prevention of Diabetes
Potential risk factors for Type 2
Diabetes
 Urbanization
 Lifestyle changes
 Positive family history of diabetes
 Age
 Obesity
 Physical inactivity
 High-fat diet
 Offspring of diabetic pregnancy
History Taking in Diabetes
 Duration of Diabetes and age at diagnosis
 Presenting complaints at the time of detection
 Family history
 Treatment of Diabetes
 Present complaints of the patient
 Associated illness and treatment
Initial work up
 FPG and PPG
 Hb A 1C
 12 hr Fasting lipid : TG, Cholesterol
 Urinalysis : Ketones, proteins, Pus cells,
microalbuminuria.
 Blood urea and serum creatinine.
 CBC, ESR
 ECG
 Fundus examination
 Foot and Oral examination
Treatment of Type 2
Diabetes
 Principles of Treatment:
 Keep the blood sugar as close to normal
as possible so as to delay complications of
Diabetes
Diabetes: Complications
Macrovascular Microvascular
Stroke Diabetic eye disease
(retinopathy and cataracts)

Heart disease and

hypertension
2-4 X increased risk
Renal disease

Peripheral
vascular disease Erectile Dysfunction

Peripheral Neuropathy

Foot problems

Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

Principles of Treatment
 Define target goal
 Diabetes education is essential
 Monitoring glycemic control is necessary
 Lifestyle modification
 Stepwise and combination pharmacologic
therapy
Sites of Action of Currently
Available Therapeutic Options ADIPOSE
LIVER
TISSUE

PANCREAS

GLUCOSE
PRODUCTION PERIPHERAL
Metformin GLUCOSE UPTAKE
Thiazolidinediones Thiazolidinediones
Metformin
INSULIN SECRETION
Sulfonylureas: Glyburide, Gliclazide, Glimepiride
Non-SU Secretagogues: Repaglinide, Nateglinide
INTESTINE

GLUCOSE MUSCLE
ABSORPTION
Alpha-glucosidase inhibitors

Adapted from Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5.
Therapeutic Agents for
Type 2 Diabetes
Mechanism of Action Agent
1. Sensitize the body to insulin  Thiazolidinediones,
Biguanides
2. Control hepatic glucose production  Biguanides,
Thiazolidnediones
3. Stimulate the pancreas to  Sulfonylureas
make more insulin Meglitinides
4. Slow the absorption of starches  Alpha-glucosidase
inhibitors
5. Decreases hepatic glucose  Insulin
production and increases
peripheral glucose uptake
Sulfonylurea: Glimepiride
(GLIMER)

 Glimepiride is efficacious and safe in type 2 diabetes patients

and 1-2 mg of Glimepiride appeared to be a sufficient dose for
most newly diagnosed type 2 diabetic patients. : J Med Assoc
Thai 2001 Sep;84(9):1221-8

 The long-term follow-up (457 patients) confirmed that

Glimepiride (1-8 mg) once daily provides equivalent
metabolic control to a higher dosage (2.5-20.0 mg) of
glibenclamide. : Horm Metab Res 1996 Sep;28(9):419-25
Insulin Sensitizers
Biguanide: Metformin

Glitazones: Rosiglitazone & Pioglitazone

Gliclazide + Metformin
(ZEFORMIN XR)
 The combination of an insulin sensitizer with an
insulin secretogogue is more additive than
synergistic.
The combination results in enhanced  peripheral
glucose metabolism.
 
Diabetes forum.com
Pioglitazone
(PIOZONE )

 Pioglitazone improves glycemic control through the dose-dependent

enhancement of ß-cell function and improved whole-body and hepatic
insulin sensitivity.: Diabetes Care 25:517-523, 2002

 Pioglitazone is effective for improving insulin sensitivity among patients

with recent TIA or stroke and impaired insulin sensitivity.: Stroke. 2003
Jun;34(6):1431-6. Epub 2003 May 01.

 Pioglitazone is effective for reducing Urinary albumin excretion and

podocyte injury in early-stage diabetic nephropathy. Metabolism 2001
Oct;50(10):1193-6
Choice of Oral Agents
Obese subjects ……………. Metformin
Nonobese…………………… Insulin Secretagogue
Combinations also work very well.
At onset most of type 2 subjects show good
response to any drug, because of
1. Relatively good beta cell function and
2. The reversibility of glucotoxicity

Do not forget. Lack of proper diet and exercise

may be the cause of lack of “response”
Indications for Insulin Therapy
in Type 2 Diabetes
 Poor response to two or three*
agents
 (SU or Repaglinide / Metformin /
Glitazone)
 * Triple option only for insulin refusing
patients - limited value
 Complications of Diabetes
Case - 1
 A 77 yr old female diabetic of 2 yr duration with BMI 23
kg/m2, presented with BP 130/80 and all systemic
examination within normal limits.
 She was on Tab, Glibenclamide ½ - 0 - ½ before food

1 month ago :
 FPG 94 mg/dl
 PPBS 143 mg/dl

On the day of hospital visit this time

 FPG 85 mg/dl
 PPG 110 mg/dl
 HbA1C is not available
Case - 1 Contd.

What is your advice ?

Would you like to change the OHA ?
Case - 1 Contd.

As this elderly lady of Type 2 diabetes is in risk of

frequent hypoglycemia due to Glibenclamide it is
better to change to Gliclazide or Glimepiride or
Glipizide. It is better to avoid tight Glycaemic Control
in elderly person with long acting Glibenclamide
Case - 2
A 45 yr old busy business who travels a lot,
BMI 27 kg/m2 and diabetic for 5 yrs presented
with tiredness. He is on T. Glipizide 5 mg BD
and T. Metformin 500 mg BD
Yesterdays lab reports:
FPG 225 mg/dl , PPG 302 mg/dl
& HbA1C 11.2%
Case - 2 Contd
What will you advice ?
Increase the present OHA dose ?
Or
Would you like to add third Oral Agent ?
Discuss the case
Case - 2 Contd.

 Since this obese gentleman is having short duration of

diabetes,
 He has insulin resistance and insulin reserve, therefore he may
be tried with same OHAs with increasing Metformin to 850 mg
BD.
Or
 A third agent like Pioglitazone 30 mg OD can be tried along
with previous combination
Profiles of Human Insulins and
Analogs
Aspart, lispro (4–6 hours)

Regular (6–10 hours)

NPH (12–20 hours)
Plasma insulin levels

Ultralente (18–24 hours)

Glargine (20-26 hours)

0 2 4 6 8 10 12 14 16 18 20 22 24
Hours
 Activity of a single injection of a
combination dose of insulin

NPH
Activity Level

Regular

i
0 3 6 9 12 15 18 21 24 Hours
BF Lunch Supper BT Snax
Activity of a split mix regime
Activity Level

NPH

Regular

i
0 3 6 9 12 15 18 21 24 Hours
BF Lunch Supper BT Snax
 Clinical advantages of short
acting analogues

 Better control of PP glycaemia

 Less episodes of hypos
 Flexibility in life style
 Safer in the elderly and in small children
 Initiation of insulin

Dose is dependent on severity of diabetes, the

quality and quantity and timing of meals and
physical activity.
Usually 0.2 units per kg upto 1 unit per kg per day
Impact of Therapies on A1C Levels
Therapy A1C Reduction

 Diet and Exercise 0.5 - 2.0%

 Sulfonylureas and Glitinides 1.0 - 2.0%
 Metformin 1.0 - 2.0%
 -Glycosidase Inhibitors 0.5 - 1.0 %
 Thiazolidinedione 0.5- 1.0%
 Insulin >5.0%

Nathan, D. Oct 2002. N Engl J Med, Vol. 347, No.17

Strategy of Night
Dose of Insulin in
Type 2 Diabetes
BIDS Regimen
Bedtime insulin in combination with daytime
Sulphonylureas with or without metformin.
Advantages of BIDS Regimen
• Same type of control as with twice daily insulin therapy
• Less weight gain compared to multiple insulin injection therapy
• An acceptable method while introducing insulin therapy to a reluctant patient
Disadvantages
• Noctumal hypoglycemia because of the peak effect of the NPH insulin, since
peakless insulin (glargine) is available - such problems are less frequent
• Not all OHA failures will be adequately controlled with BIDS regimen - some
may require additional prandial insulin
Newer Modes of Insulin
Therapy Insulin Pen
 Benefits
 More accurate dosing mechanisms
 Faster and easier than conventional syringes
 Improved patient attitude and compliance
 Advantages of newer insulin pens
 LCD display to show dosage setting
 Dosage settings change quickly and easily
 Safety button automatically resets after drug delivery
 Insulin Pump
 Easy management of diabetes
 They are available in the size of a pager

Consists of
 A pump reservoir
 A small battery operated pump
 A computer chip to control insulin delivery
 It is all contained in a plastic case about the size of a
beeper
 It is presently very expensive

Advantages
 Helps to achieve smooth control of diabetes programmable
insulin delivery possible
 Major limiting factor is the cost (Rs. 1 Lac - Rs. 2.5 Lacs)
Insulin Inhalers
 Inhale therapeutic Systems Inc and
Pfizer
 Exubera : Dry powder form of insulin
that is
inhaled directly
into the lungs through inhale
therapeutic system
 Recently approved by US FDA
Complications of Insulin
Therapy
 Hypoglycaemia

 Local allergy

 Lipoatrophy

 Insulin Edema
Insulin therapy should aim to
 Normalize blood sugar and HbA1c levels
 Prevent complications of diabetes

Decision of choosing the right type of insulin rests upon

the Physician depending on
 Need of the hour
 Patient’s convenience
 Affordability

PLEASE DISCUSS OPTIONS WITH PATIENT

Other medical treatments:
 Anti-hypertensives
 Statins/fibrates
 Aspirin
 ACE inhibitors
 ARBs
Treat to Target
 HbA1C < 7%
 BP < 130/80
 Cholesterol <180 mg/dl
 HDL-C >45 / 55mg/dl
 Triglycerides <150mg/dl
Neuropathy
 Peripheral Neurop  Autonomic Neuropathy
 Femoral Amyotrophy Postural hypotension
 Mononeuritis Diarrhoea
multiplex Impotence
Atonic bladder
Sweating
Loss of hypo. awarenes
Vascular Disease
 PVD  Diabetes
 CVD  Hypertension
 CAD  Proteinuria
 Lipids
 Cigarettes
 Obesity
Peripheral Vascular Disease
 Intermittent  Doppler Studies
Claudication  Duplex Scanning
 Cold Legs  Angiography
 Pulseless Leg  Angioplasty
 Foot Ulcers  Treat risk factors
 Gangrene
Cerebro Vascular Disease
 TIAs  CT scan
 CVAs  Carotid Dopplers
 Dementia  Treat risk factors
 Carotid bypass
surgery
Coronary Artery Disease
 Angina  ECG
 MI  Cardiac enzymes
 Silent infarct  Troponin I
 CCF  Exercise stress test
 Echocardiography
 Angiography
 Angioplasty/CABG
Diabetic Foot
 Neuropathy  MRI
 PVD  Angiography
 Charcot Arthropathy
 Ulceration
Nephropathy
 Diabetic  Glycaemic control
glomerulosclerosis  BP control
 Microalbuminuria  CAPD
<300mg/l  Transplantation
 Proteinuria >300mg/l
 Nephrotic >3g/l
 Abnormal creatinine
INFECTIONS
 Rhinocerebral mucormycosis
 Malignant otitis externa,
 Pneumonia
 Urinary tract infections
 Skin, nail and soft tissue infections
 Teeth and gums
Screening [whom and what]
 BMI>30  Urinalysis
 Age >50  FBG
 Ethnic minorities  Random glucose
 Family history  OGTT
 GDM  Cost/benefit analysis
 Progression of OHA treated Diabetes

400

350

300

250
Insulin
Values

200 Fasting
Post Lunch
150

100

50

Time
 Time spent with Diabetic patient

Insulin
Specific complaints 4% Reassurance
8%
20%
Reassurance
Education Motivation
12%
Medications writing
Goal setting
Specialist referral Complications check
8%
Motivation Specialist referral
24%
Complications check
Education
8% Specific complaints
Goal setting
8%
Medications writing Insulin
8%
Summing up
 Treat the patient not the report
 Planned management helps for long term
benefits
 Education of doctor as well as patient is
the key to successful management
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