Metformin by Dr Sarma

1
Metformin Revisited
A comprehensive review by Dr. R.V. S. N. Sarma,
M.D., M.Sc.,

2
Diabetes Mellitus

• Type 2 DM (NIDDM)
• Not merely SUGAR DISORDER
• Multi system disease A syndrome
• Metabolic endocrine vascular
• Cardiac cerebral renal ophthalmic
• From blood sugar to blood vessel

3
Prevention of Diabetes

• How we have grown ?
• Prevention holds the key no users ?
• Diabetic care is Life long
• Nutrition Excercise Education - DM
• How about NOW or never ?
• 1,49, 806 studied 1 kg ? - 9 ? DM

4
Should we wait ? and

• Pay heavily on
• ICUs, transplant units, amputation units
• Laser therapy, physio therapy units
• Or pay very little now
• By preventing the epidemic rise in DM
• Clinical diabetes ADA Apr/June 2001

5
Mandatory Examinations

1. H/o Smoking
2. H/o IHD
3. Family H/o DM
4. H/o Hypoglycemia
5. Exam for all pulses
6. B.P recording
7. Foot exam - Trophic
8. Autonomic neuropathy
9. Fundus exam for DR

1. Fasting and PP BG
2. GHb A1c periodically
3. Microalbuminuria
4. Lipid profile
5. ACR
6. ECG for LVH, IHD
7. Echo for LV Dysfun.
8. Stress test ST Seg.

6
(No Transcript)
7
The questions ?

1. Does the patient have Diabetes Mellitus ?
2. If so, what is the type of DM ?

8
Does the Patient have Diabetes ?
Unequivocal Hyperglycaemia on more
than one occasion No unequivocal
Hyperglycaemia
POLYS Loss of weight Asymptomatic Symptomati
c
Diabetes Abnormal GTT Normal Follow
up
9
Diagnosis O-GTT
DM IGT Normal
DM IFG Normal FPG
200 140
126 110
PPG
75g of oral glucose 2 hrs. after
10
Diagnosis Criteria

• R B G gt 200 mg on 2 occasions or
• F B G gt 126 mg on 2 occasions or
• P P B G gt 200 mg on 2 occasions
• Never make a diagnosis on single test
• Never diagnose based on glycosuria
• Glucometer is not ideal for diagnosis
• Screening, Diagnosis and Monitoring

11
Diabetes Mellitus in India
20
40
IDDM Type - 1 DM
NIDDM Type - 2 DM
? IRDM Type - 1½
12
Hyperglycemia

• Blood sugar rises above normal if
• ? in insulin secretion (endogenous)
• ? in insulin sensitivity (non-response)
• ? increased hepatic production
• ? decreased peripheral utilization
• Excessive CHO consumption
• A combination of any of the above

13
Hyperglycaemia
Acute Chronic / Sustained Stress
Hyperglycaemia Diabetes Mellitus
Insulin 120 mg
80
Glucagon
Cortisol Catacholamines
GH
Differentiation HbA1C / Fructosamine / Follow up
14
Diagnosis - Practical Points
1. Do not label one a diabetic by glycosuria
alone For, one may have renal
glycosuria 2. Benedicts shows any reducing
substance. Glucose oxidase test strips
confirm glucosuria 3. Do not neglect urine test
for acetone 4. Never base Dx on a single blood
sugar test 5. O-GTT is the gold standard for
diagnosis DM 6. HbA1C - of use in DD of stress
hyperglycemia 7. All diabetics need not be
symptomatic One may present first time with
complications
15
Diagnosis New concept

• Syndrome X
• Metabolic syndrome
• Insulin Resistance Syndrome
• Pre CHD Pre Diabetic state
• It is very common in USA
• - gt 24 above 20 years of age.
• Childhood overweight / obesity
• PCOD is common association

16
Metabolic Syndrome

• NECP ATP III criteria 3 or more below
• Abdominal obesity W.C (cm) gt 88 ?, 102 ?
• ? in Triglycerides gt 150 mg
• ? in HDL lt 50 mg for ?, lt 40 mg for ?
• Blood pressure gt 130 / 85 mm Hg
• IFG FPG gt 110 or IGT PPBG gt 140 mg
• WHO criteria (in addition to above)
• ACR gt 30 mg/g
• Micro-Albuminuria gt 20 µgs / min

17
(No Transcript)
18
(No Transcript)
19
Treatment Strategy

• Defect in insulin sensitivity
• Exercise - aerobic
• Weight reduction Diet, drugs
• Thiazolidinediones - Glitazones
• Metformin
• Defect in insulin secretion
• ßcell stimulation - SU, Repaglinide
• Insulin exogenous supplimentation

20
Treatment Strategy

• Increased hepatic glucose output
• Metformin gt Glitazones
• Insulin supplimentation, SU
• Carbohydrate absorption
• (post-prandial hyperglycemia)
• Acarbose

Often the defects are multiple and hence the need
for combination of the above strategies
21
(No Transcript)
22
(No Transcript)
23
How to prevention Complications of Diabetes ?

1. Weight reduction
2. Exercise
3. Strict control hyperglycemia
4. Improvement of lipid profile
5. Smoking cessation
6. Treatment of Hypertension
7. Low dose aspirin therapy
8. Early detection by evaluation

24
(No Transcript)
25
History

1. Biguanides- used in early medieval times-
   leguminosa Galega officinalis (goat's rue or
   French lilac) in Europe
2. 1918-guanidine discovered as active
   glucose-lowering compound
3. 3 biguanides available for medical use between
   1957 1960- phenformin, metformin, buformin
4. 1970s- phenformin and buformin withdrawn because
   of lactic acidosis

26
Metformin
Metabolic actions

1. Reduction of excessive Hepatic Glucose Output
2. Stimulation of insulin-mediated muscle glucose
   uptake -glycogen synthesis is increased
3. Inhibition of lipolysis and of FFA availability

27
Metformin
Cellular actions

1. Increased insulin binding
2. Stimulation of insulin receptor tyrosine kinase
   activity
3. Enhanced glucose transport (GLUT 4)
4. Increased glycogen synthase
5. Doesn't cause hypoglycemia

28
Actions of Metformin
29
Metformin
Additional actions

1. Favorable lipid effects
2. Weight loss
3. Increased fibrinolytic activity
4. Decreased platelet aggregability
5. Favorable effect on hypertension

30
Metformin
Preferred choice in

1. Obese diabetics
2. Diabetics with hypertension
3. Diabetics with prominent Dyslipidaemia
4. Patients with IGT

31
Metformin - Pharmacokinetics
Bio-avalability ( of dose) 50 to 60
C max (?g/ml) 1.0 to 1.5
t max (in hours) 1.9 to 3.0
Plasma ½ life (t ½) 2.0 to 5.4
Renal clearance (ml/min) 400 to 600
Total clearance (ml/min) 1,300
32
Metformin - side effects

1. Nausea, vomiting, distension
2. Loss of appetite, diarrhoea
3. Skin rashes, urticaria
4. Increase in liver enzymes
5. Rare Lactic acidosis.

33
Metformin - contraindications

• Patients with Type I diabetes
• Patients with hepatic or renal impairment
• Alcoholic liver disease
• Chronic obstructive airway disease
• Congestive heart failure, MI
• Pregnancy and lactation
• Peripheral vascular disease
• Any condition associated with hypoxia
• In patients gt 70 yrs of age.
• Care while using diuretics concomitantly

34

1. Metformin mono therapy in DM
2. Metformin in combination with
3. Glyburide
4. Pioglitazone
5. Insulin
6. Metformin in sec. OHA failure
7. Metformin I.G.T
8. Metformin in P.C.O.D
9. Metformin in Metabolic Syndrome
10. Metformin in obesity

35
(No Transcript)
36
Metformin - Efficacy
37
Metformin - Efficacy
38
Metformin Efficacy in microvascular
complications

1. 1704 obese type 2 diabetics with FPG gt 6 mmol/lit
   after dietary trial
2. Randomised to metformin to maintain FPG lt6 vs
   conventional Rx with diet
3. 10 year follow-up

1. 32 reduction in diabetes related endpoint
2. 42 reduction in diabetes related death
3. 36 reduction in all cause mortality

UKPDS trial- Lancet 1998 352 837-853
39
(No Transcript)
40
(No Transcript)
41
Metformin Glyburide

• Objective To evaluate whether initial treatment
  with glyburide/metformin tablets is superior
  to monotherapy with each
• Design Randomized, parallel-group,
  placebo-controlled, multicentre
• Patients 806 treatment naïve type 2diabetics
• Duration 20 weeks
• Therapy Placebo, glyburide 2.5 mg, metformin
  500 mg, glyburide/metformin 1.25 250/500
  mg, once daily.

Garber AJ et al. Diabetes Obes Metab 2002
May4(3)201-8
42
Metformin Glyburide
glyburide/ metformin 1.25/250 mg
glyburide/ metformin 2.5/250 mg
Placebo
Metformin
Glyburide
0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 -1.6
-0.21
-1.03
-1.24
-1.48
-1.53
Plt0.001 P0.016 Plt0.001
Week 20
Plt0.001 P0.004 Plt0.001
Garber AJ et al. Diabetes Obes Metab 2002
May4(3)201-8
43
Metformin Glyburide
Conclusions
Initial combination treatment with glyburide
metformin tablets produces greater improvements
in glycaemic control than either glyburide or
metformin alone. The superiority of initial
therapy with glyburide metformin tablets may
arise from simultaneous treatment of both
patho-physiological defects of type 2 diabetes. 
44
(No Transcript)
45
Metformin Pioglitazone
Design Double blind Randomized placebo
controlled clinical trial Duration 16
weeks Patients 328 patients with poorly
controlled DM - HbAlc gt 8.0, Rx. Metformin
? 30 days Later Pioglitazone 30mg Met (n168)
or Placebo Metformin (n160)
Einhorn D et al Clin Ther 2000 Dec 22(12)
1395-409
46
Results
Compared to placebo combination caused Fall in
HbAlc (- 0.83) Fall in FPG (-7.7mg/dl) Fall
in TG levels (-18.2) Rise in HDL 8.7 Decrease
in FPG levels occurred as early as 4th weeks
plt0.05
Einhorn D et al Clin Ther 2000 Dec 22(12)
1395-409
47
Metformin Pioglitazone
Open label extension of the study Metformin
30/45 mg Pioglitazone 154 patients 72 weeks
Fall in HbAlc 1.36 Fall in FPG 63.0
mg/dl Excellent tolerability No hepatotoxicity
seen
Einhorn D et al Clin Ther 2000 Dec 22(12)
1395-409
48
(No Transcript)
49
Combination in Sec. OHA failure

• Design Randomised, open and parallel study
• Number Fifty-one subjects
• Patients Type 2 diabetes with secondary oral
  hypoglycaemic agent failure
• Therapy
• 1st phase 36 weeks- Combined therapy of
  sulphonylureas and nocturnal insulin, with or
  without metformin
• 2nd phase Metformin was withdrawn.

Tong PC et al. Diabetes Res Clin Pract 2002 Aug
57(2)93-8
50
Combination in Sec. OHA failure

• Subjects on metformin
• - used less insulin to maintain glycaemic control
  (13.7/-6.8 vs. 23.0/-9.4 U/day, P0.001)
• - lower HbA1c values (8.13/-0.89 v/s
  9.05/-1.30, P0.003)
• Withdrawal of metformin therapy
• caused deterioration in HbA1c
• (P0.001)

Tong PC et al. Diabetes Res Clin Pract 2002 Aug
57(2)93-8
51
Conclusion

• This study confirms that metformin plays an
  important role in the success of the combination
  therapy.
• The rational use of metformin and sulphonylurea
  together with insulin will help to improve
  metabolic control in Type 2 diabetes patients who
  have secondary drug failure.

Tong PC et al. Diabetes Res Clin Pract 2002 Aug
57(2)93-8
52
(No Transcript)
53
IGT to Type 2 DM

• Plasma glucose level at initial O-GTT,
• Body mass index
• Family history of DM,
• Hypertension
• Raised basal plasma insulin/ proinsulin
• Lower post-load insulin/glucose ratio
• Abnormal lipid profile
• Abnormal serum creatinine

Raman PG et al. Asian J Diabetol 2002 June-July
4(4) 37-42
54
Metformin in I G T
Design Randomized double blind Objective To
evaluate effect of metformin on glucose
metabolism rate of conversion to
DM Patients 70 patients with IGT Therapy
Placebo (n 37) or metformin (n
33) 250 mg three times daily Duration 12 months
 Li CL et al. Diabet Med 1999 Jun16(6)477-81
55
(No Transcript)
56
What is PCOD ?

1. Poly Cystic Ovarian Disease
2. Common form of female infertility
3. Poor conception rates
4. Pregnancy loss rates are high (30-50) during
   the 1st trimester

57
Metformin in PCOD

• Objective Assess pregnancy outcome pts with
• polycystic ovary syndrome
  (PCOS)
• Design Case series, Outpatient.
• Patients Anovulatory patients (n 48) with a
  diagnosis of PCOD enrolled over 15 m.
• Rx. Metformin started at 500 mg b.i.d. for 6
  weeks and increased to 500 mg t.i.d. if no
  ovulation occurred. Clomiphene citrate 50 mg
  added if no ovulatory response after 6 wks.

Heard MJ et al. Fertil Steril 2002
Apr77(4)669-73
58
Metformin - Effective in PCOD

1. 40 patients resumed spontaneous menses with
   metformin alone
2. 31 required CC (50 mg) in conjunction with
   metformin therapy
3. 67 of combination therapy had evidence of
   ovulation
4. Overall 42 conceived with a median time of 3 m
   for conception

Heard MJ et al. Fertil Steril 2002
Apr77(4)669-73
59
Metformin in PCOD- Early Pregnancy loss

1. Retrospective study
2. Women with PCOD who became pregnant
3. Duration of enrollment- 4.5 yr , OPD setting
4. Sixty-five women received metformin during
   pregnancy (metformin group) and 31women did not
   (control group).

Jakubowicz DJ et al. J Clin Endocrinol Metab
2002 Feb87(2)524-9  
60
Metformin prevents early Preg. loss
Early Preg. Loss Rate
In prior h/o Miscarriage
58.3
41.9
50 40 30 20 10 0
60 50 40 30 20 10 0
P lt 0.001
P lt 0.002
8.8
11.1
Metformin
Placebo
Metformin
Placebo
Jakubowicz DJ et al. J Clin Endocrinol Metab
2002 Feb87(2)524-9  
61
Conclusion

• Metformin administration during pregnancy
  reduces 1st trimester pregnancy losses in women
  with Polycystic ovary syndrome. 

Jakubowicz DJ et al. J Clin Endocrinol Metab
2002 Feb87(2)524-9  
62
(No Transcript)
63
Metabolic syndrome

1. Exercise
2. Weight reduction
3. Diet modification
4. Control of blood pressure
5. IFG or IGT may be treated with Metformin 250 to
   500 mg b.i.d

64
Insulin Sensitizers

1. Exercise
2. Weight reduction
3. Metformin
4. Glitazones

65
(No Transcript)
66
Metformin in obesity

• In childhood over weight and obesity
• Its action of interfering with glucose absorption
  in the intestine
• Anorexio-genic action
• No effect on normal blood sugar non hypoglycemic
  (only anti hyperglycemic)

67
Metformin XL vs Plain

• Design Double blind randomized
• Patients Type 2 DM on Metformin 500 mg BID for
  8 weeks with FPG ? 200 mg/dl and HbA1c ? 8.5
  
• Therapy Plain metformin 500mg BID (n69)
  Metformin XL 1000 mg OD (n72)
• Duration 24 weeks

Physicians Desk Reference 2002 Pg. 1083
68
Advantages of Metfromin SR

• Convenience
• ONCE DAILY dosing simplifies treatment regimen
• Reduces number of tablets to be consumed
• To be taken conveniently at - DINNER
• Compliance
• Adverse effects such as Nausea / Vomiting (due to
• gastritis) and diarrhea - less likely with SR
• Preparation Better tolerated than plain metformin
• Control
• Comparable to that of plain metformin b.i.d /
  t.i.d

69
Metformin SR with evening meal
Evening dosing takes advantage of slow GI transit
while patients are sleeping This allows tablet to
move slower through GI tract than when patients
are awake
70
(No Transcript)
71
WHO recommendation -Diet

• CARBOHYDRATES 50-60
• - mainly from complex carbohydrates
• FATS 30
• - saturated 10
• - poly-unsaturated 10
• - mono-unsaturated 10
• - cholesterol lt 300 mg/day
• PROTEINS 12-20
• SODIUM lt 6 g/day
• - hypertensive diabetic, lt 3 g/day

72
Managing Diabetes Follow a Healthy Meal Plan
73
EXERCISEBenefits

• Reduces weight
• Improves cardiovascular function
• Increases fitness
• Increases physical working capacity
• Improves sense of well-being /quality of life

74
(No Transcript)
75
(No Transcript)