Metformin
Revisited
A comprehensive review by
Dr. R.V. S. N. Sarma, M.D., M.Sc.,
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Diabetes Mellitus
1. Type 2 DM (NIDDM)
2. Not merely “ SUGAR DISORDER”
3. Multi system disease – A syndrome
4. Metabolic – endocrine – vascular –
5. Cardiac – cerebral – renal – ophthalmic
From blood sugar to blood vessel
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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
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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
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Mandatory Examinations
1. H/o Smoking
1. Fasting and PP BG
2.
H/o IHD
2.
GHb A1c periodically
3.
Family H/o DM
3.
Microalbuminuria
4.
H/o Hypoglycemia
4.
Lipid profile
5.
Exam for all pulses
5.
ACR
6.
B.P recording
6.
ECG for LVH, IHD
7.
Foot exam - Trophic
7.
Echo for LV Dysfun.
8.
Autonomic neuropathy
8.
Stress test – ST Seg.
9.
Fundus exam for DR
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Diagnosis of
Diabetes Mellitus
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The questions ?
1. Does the patient have Diabetes
Mellitus ?
2. If so, what is the type of DM ?
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Does the Patient have Diabetes ?
“POLYS”
Loss of weight
Asymptomatic
Symptomatic
+ Unequivocal
Hyperglycaemia
on more than
one occasion
+ No unequivocal
Hyperglycaemia
Diabetes
Abnormal
GTT
Normal
Follow up
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Diagnosis – O-GTT
DM
DM
126
200
IGT
140
IFG
110
Normal
Normal
FPG
PPG
75g of oral glucose – 2 hrs. after
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Diagnosis – Criteria







R B G > 200 mg % on 2 occasions or
F B G > 126 mg % on 2 occasions or
P P B G > 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
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Diabetes Mellitus in India
20
40
IDDM
Type - 1 DM
NIDDM
Type - 2 DM
?
IRDM
Type - 1½
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Hyperglycemia
Blood sugar rises above normal if
1. ↓ in insulin secretion (endogenous)
2. ↓ in insulin sensitivity (non-response)
3. ↑ increased hepatic production
4. ↓ decreased peripheral utilization
5. Excessive CHO consumption
6. A combination of any of the above
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Hyperglycaemia
Acute
Chronic / Sustained
Stress Hyperglycaemia Diabetes Mellitus
Insulin
120 mg %
80
Glucagon
GH
Cortisol
Catacholamines
Differentiation: HbA1C / Fructosamine / Follow up
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Diagnosis - Practical Points
1. Do not label one a diabetic by glycosuria alone
For, one may have renal glycosuria
2. Benedict’s 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
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Diagnosis – New concept







Syndrome X
Metabolic syndrome
Insulin Resistance Syndrome
Pre CHD + Pre Diabetic state
It is very common in USA
- > 24% above 20 years of age.
Childhood overweight / obesity
PCOD is common association
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Metabolic Syndrome

NECP ATP III criteria – 3 or more below
1. Abdominal obesity –W.C (cm) > 88 ♀, 102 ♂
2. ↑ in Triglycerides > 150 mg%
3. ↓ in HDL < 50 mg% for ♀, < 40 mg% for ♂
4. Blood pressure > 130 / 85 mm Hg
5. IFG = FPG > 110 or IGT = PPBG > 140 mg%
 WHO criteria (in addition to above)
1. ACR > 30 mg/g
2. Micro-Albuminuria > 20 μgs / min
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Treatment
Strategies
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Treatment Strategy
Defect in insulin sensitivity
1. Exercise - aerobic
2. Weight reduction – Diet, drugs
3. Thiazolidinediones - Glitazones
4. Metformin
Defect in insulin secretion
1. βcell stimulation - SU, Repaglinide
2. Insulin exogenous supplimentation
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Treatment Strategy
Increased hepatic glucose output
1. Metformin > Glitazones
2. Insulin supplimentation, SU
Carbohydrate absorption
(post-prandial hyperglycemia)
1. Acarbose
Often the defects are multiple and hence the need
for combination of the above strategies
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Prevention of
Complications
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How to prevention
Complications of Diabetes ?
1.
2.
3.
4.
5.
6.
7.
8.
Weight reduction
Exercise
Strict control hyperglycemia
Improvement of lipid profile
Smoking cessation
Treatment of Hypertension
Low dose aspirin therapy
Early detection by evaluation
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Metformin
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History
1.
2.
3.
4.
Biguanides- used in early medieval timesleguminosa Galega officinalis (goat's rue or
French lilac) in Europe
1918-guanidine discovered as active
glucose-lowering compound
3 biguanides available for medical use
between 1957 & 1960- phenformin,
metformin, buformin
1970s- phenformin and buformin withdrawn
because of lactic acidosis
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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
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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
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Actions of Metformin
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Metformin
Additional actions
1.
2.
3.
4.
5.
Favorable lipid effects
Weight loss
Increased fibrinolytic activity
Decreased platelet aggregability
Favorable effect on hypertension
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Metformin
Preferred choice in
1. Obese diabetics
2. Diabetics with hypertension
3. Diabetics with prominent
Dyslipidaemia
4. Patients with IGT
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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
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Metformin - side effects
1.
2.
3.
4.
5.
Nausea, vomiting, distension
Loss of appetite, diarrhoea
Skin rashes, urticaria
Increase in liver enzymes
Rare – Lactic acidosis.
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Metformin - contraindications
1. Patients with Type I diabetes
2.
3.
4.
5.
6.
7.
8.
9.
10.
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 > 70 yrs of age.
Care while using diuretics concomitantly
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1. Metformin mono therapy in DM
2. Metformin in combination with
1. Glyburide
2. Pioglitazone
3. Insulin
3. Metformin in sec. OHA failure
4. Metformin I.G.T
5. Metformin in P.C.O.D
6. Metformin in Metabolic Syndrome
7. Metformin in obesity
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Metformin
mono therapy
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Metformin - Efficacy
NIDDM Pts
29 week
therapy
Significantly lowers FPG
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Metformin - Efficacy
NIDDM Pts
29 week
therapy
Significantly lowers HbA1c
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Metformin – Efficacy
in microvascular complications
1. 1704 obese type 2 diabetics with FPG > 6
mmol/lit after dietary trial
2. Randomised to metformin to maintain FPG
<6 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
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Metformin
combined therapy
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Metformin
with Glyburide
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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 May;4(3):201-8
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Metformin – Glyburide
glyburide/ glyburide/
metformin metformin Placebo
Glyburide
1.25/250 mg 2.5/250 mg
Metformin
0
-0.2
-0.21 *
-0.4
-0.6
-0.8
-1.24 **
-1.0
-1.03 ***
-1.2
-1.48
-1.4 P<0.001 *
-1.6 P=0.016 *
P<0.001 *
-1.53
*
* P<0.001
**
* *P=0.004
P<0.001
Garber AJ et al. Diabetes Obes Metab 2002 May;4(3):201-8
Week 20
***
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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 pathophysiological defects of type 2 diabetes.
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Metformin
with Pioglitazone
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Metformin – Pioglitazone
Design
Double blind Randomized
placebo controlled clinical trial
Duration 16 weeks
Patients
328 patients with poorly
controlled DM - HbAlc > 8.0%,
Rx.
Metformin  30 days
Later Pioglitazone 30mg + Met (n=168)
Placebo + Metformin (n=160)
Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409
or
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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
* p<0.05
Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409
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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
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Metformin in Sec. OHA
failure
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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
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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,
P=0.001)
- lower HbA1c values (8.13+/-0.89 v/s 9.05+/1.30%, P=0.003)
Withdrawal of metformin therapy
caused deterioration in HbA1c
(P=0.001)
Tong PC et al. Diabetes Res Clin Pract 2002 Aug; 57(2):93-8
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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
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Metformin
in I. G. T.
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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
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Metformin in I G T
Design
Objective
Patients
Therapy
Duration
Randomized double blind
To evaluate effect of metformin
on glucose metabolism & rate of
conversion to DM
70 patients with IGT
Placebo (n = 37) or metformin
(n= 33) 250 mg three times daily
12 months
Li CL et al. Diabet Med 1999 Jun;16(6):477-81
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Metformin in
PCOD
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What is PCOD ?
1.
2.
3.
4.
Poly Cystic Ovarian Disease
Common form of female infertility
Poor conception rates
Pregnancy loss rates are high (30-50%)
during the 1st trimester
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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 Apr;77(4):669-73
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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 Apr;77(4):669-73
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Metformin in PCODEarly 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 Feb;87(2):524-9
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Metformin prevents early Preg. loss
Early Preg. Loss Rate
41.9 %
50
60
40
P < 0.001
P < 0.002
30
20
10
58.3 %
50
40
30
In prior h/o Miscarriage
20
8.8 %
11.1 %
10
0
0
Metformin
Placebo
Metformin
Jakubowicz DJ et al. J Clin Endocrinol Metab 2002 Feb;87(2):524-9
Placebo
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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 Feb;87(2):524-9
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Metformin in
Insulin resistance
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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
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Insulin Sensitizers
1. Exercise
2. Weight reduction
3. Metformin
4. Glitazones
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Metformin
in Obesity
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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)
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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 (n=69)
Metformin XL* 1000 mg OD (n=72)
Duration
24 weeks
Physician’s Desk Reference 2002 Pg. 1083
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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
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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
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DIE
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WHO recommendation -Diet
CARBOHYDRATES : 50-60%
- mainly from complex carbohydrates
FATS : 30%
- saturated 10%
- poly-unsaturated 10%
- mono-unsaturated 10%
- cholesterol < 300 mg/day
PROTEINS : 12-20%
SODIUM : < 6 g/day
- hypertensive diabetic, < 3 g/day
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Managing Diabetes
Follow a Healthy Meal Plan
Eat Least
Eat Moderately
Sugar, Fat, Alcohol, Salt
Protein Foods
Eat More
Carbohydrate Foods
Eat Most
Vegetables
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EXERCISE
Benefits
•
•
•
•
•
Reduces weight
Improves cardiovascular function
Increases fitness
Increases physical working capacity
Improves sense of well-being /quality of life
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Let us together
win the war
against Diabetes
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