Metformin by Dr Sarma

							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”        + Unequivocal     Diabetes
Loss of weight
               Hyperglycaemia   Abnormal
Asymptomatic      on more than
                  one occasion
Symptomatic                      GTT
               + No unequivocal
                 Hyperglycaemia Normal

                                       Follow up
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             Diagnosis – O-GTT

                               DM          200

         DM                    IGT
                                           140
126
         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
                                  Dr.Sarma@works
    diagnosis
         Diabetes Mellitus in India

              20               40

   IDDM                               NIDDM
Type - 1 DM                         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
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7. All diabetics need not be symptomatic
     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            Dr.Sarma@works
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Prevention of
Complications




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         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
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Metformin




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                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

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


                                    Dr.Sarma@works
            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       50% to 60%
dose)
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.   Nausea, vomiting, distension
2.   Loss of appetite, diarrhoea
3.   Skin rashes, urticaria
4.   Increase in liver enzymes
5.   Rare – Lactic acidosis.



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        Metformin - contraindications

1. Patients with Type I diabetes
2.    Patients with hepatic or renal impairment
3.    Alcoholic liver disease
4.    Chronic obstructive airway disease
5.    Congestive heart failure, MI
6.    Pregnancy and lactation
7.    Peripheral vascular disease
8.    Any condition associated with hypoxia
9.    In patients > 70 yrs of age.
10.   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

                                       Dr.Sarma@works
 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     Dr.Sarma@works
   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, 2002 May;4(3):201-8
Garber AJ et al. Diabetes Obes Metabonce daily.       Dr.Sarma@works
                       Metformin – Glyburide
            glyburide/ glyburide/
            metformin metformin Placebo
                                      Glyburide             Metformin
           1.25/250 mg 2.5/250 mg
       0
    -0.2                              -0.21 *
    -0.4
    -0.6
    -0.8
                                                            -1.03 ***
    -1.0                                         -1.24 **
    -1.2   -1.48
    -1.4 P<0.001 *           -1.53
                                                            Week 20
    -1.6 P=0.016 *       * P<0.001 * *
                            P=0.004 *
         P<0.001 *       ** P<0.001 * * *
Garber AJ et al. Diabetes Obes Metab 2002 May;4(3):201-8         Dr.Sarma@works
            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.                            Dr.Sarma@works
   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)
                   or Placebo + Metformin (n=160)


Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409   Dr.Sarma@works
                                 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     Dr.Sarma@works
                   Metformin – Pioglitazone
       Open label extension of the study
       Metformin + 30/45 mg
       Pioglitazone
       154 patients
       72 weeks in HbAlc: – 1.36%
            Fall
                 Fall in FPG: – 63.0 mg/dl
                 Excellent tolerability
                 No hepatotoxicity seen
Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409
                                                       Dr.Sarma@works
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 PC et al. Diabetes Res Clin Pract 2002 Aug;withdrawn.
Tong phase Metformin was 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   Dr.Sarma@works
                       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 Jun;16(6):477-81
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Metformin in
 PCOD




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           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



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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
  Heard MJ et al. Fertil Steril 2002 Apr;77(4):669-73
   wks.                                                       Dr.Sarma@works
                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   Dr.Sarma@works
                         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 Feb;87(2):524-9
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                  Metformin prevents early Preg. loss
Early Preg. Loss Rate                        In prior h/o Miscarriage
                                                                      58.3 %
50                      41.9 %                60

40                                            50

      P < 0.001                               40       P < 0.002
30
                                              30
20
                                              20
10      8.8 %                                         11.1 %
                                              10
 0                                              0
     Metformin          Placebo                     Metformin         Placebo
Jakubowicz DJ et al. J Clin Endocrinol Metab 2002 Feb;87(2):524-9   Dr.Sarma@works
                                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
                                                                    Dr.Sarma@works
 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


                                Dr.Sarma@works
  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
                                           Dr.Sarma@works
            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

                                             Dr.Sarma@works
           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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D I E


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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                                 Sugar, Fat, Alcohol, Salt


Eat Moderately                                      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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