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A comprehensive review by

Dr. R.V. S. N. Sarma, M.D., M.Sc.,

MetforminRevisited

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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

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.

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Diagnosis of Diabetes Mellitus

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

IGT

Normal

126

110

126

110

200

140

200

140

PPG75g of oral glucose – 2 hrs. after

DM

IFG

Normal

FPG

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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

IDDM Type - 1 DM

NIDDM Type - 2 DM

?IRDM

Type - 1½

2020 4040

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Hyperglycemia

Blood sugar rises above normal if1.↓ in insulin secretion (endogenous)2.↓ in insulin sensitivity (non-response)3.↑ increased hepatic production4.↓ decreased peripheral utilization5. Excessive CHO consumption6. A combination of any of the above

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Acute Chronic / Sustained

Stress Hyperglycaemia Diabetes Mellitus

Acute Chronic / Sustained

Stress Hyperglycaemia Diabetes Mellitus

Hyperglycaemia

GlucagonGlucagon GHGH Cortisol CatacholaminesCortisol Catacholamines

Differentiation: HbA1C / Fructosamine / Follow upDifferentiation: HbA1C / Fructosamine / Follow up

Insulin 120 mg %Insulin 120 mg %

80

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Diagnosis - Practical Points1. 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

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 Hg5. 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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TreatmentStrategiesTreatmentStrategies

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Treatment Strategy

Defect in insulin sensitivity1. Exercise - aerobic2. Weight reduction – Diet, drugs3. Thiazolidinediones - Glitazones4. Metformin

Defect in insulin secretion1. βcell stimulation - SU, Repaglinide2. Insulin exogenous supplimentation

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Increased hepatic glucose output 1. Metformin > Glitazones2. Insulin supplimentation, SU

Carbohydrate absorption (post-prandial hyperglycemia)

1. Acarbose

Treatment Strategy

Often the defects are multiple and hence the need for combination of the above

strategies

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Prevention ofComplicationsPrevention ofComplications

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How to prevention Complications of Diabetes ?

1. Weight reduction2. Exercise3. Strict control hyperglycemia 4. Improvement of lipid profile5. Smoking cessation6. Treatment of Hypertension7. Low dose aspirin therapy8. Early detection by evaluation

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MetforminMetformin

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History1. 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

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

Metabolic actions

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Metformin

1. Increased insulin binding2. Stimulation of insulin

receptor tyrosine kinase activity

3. Enhanced glucose transport (GLUT 4)

4. Increased glycogen synthase

5. Doesn't cause hypoglycemia

Cellular actions

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Actions of Metformin

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Metformin

1. Favorable lipid effects2. Weight loss3. Increased fibrinolytic activity4. Decreased platelet aggregability5. Favorable effect on

hypertension

Additional actions

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1. Obese diabetics2. Diabetics with

hypertension3. Diabetics with prominent

Dyslipidaemia4. Patients with IGT

MetforminPreferred choice

in

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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

Metformin - Pharmacokinetics

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Metformin - side effects

1. Nausea, vomiting, distension

2. Loss of appetite, diarrhoea3. Skin rashes, urticaria4. Increase in liver enzymes5. Rare – Lactic acidosis.

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1. Patients with Type I diabetes2. Patients with hepatic or renal

impairment3. Alcoholic liver disease4. Chronic obstructive airway disease5. Congestive heart failure, MI6. Pregnancy and lactation7. Peripheral vascular disease8. Any condition associated with hypoxia9. In patients > 70 yrs of age.10. Care while using diuretics

concomitantly

Metformin - contraindications

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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

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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Metforminmono therapy

Metforminmono therapy

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Metformin - Efficacy

Significantly lowers FPG

NIDDM Pts 29 week therapy

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Metformin - EfficacyNIDDM Pts

29 week therapy

Significantly lowers HbA1c

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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

UKPDS trial- Lancet 1998; 352: 837-853

Metformin – Efficacyin microvascular complications

1. 32% reduction in diabetes related endpoint

2. 42% reduction in diabetes related death3. 36% reduction in all cause mortality

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Metformincombined therapy

Metformincombined therapy

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Metforminwith Glyburide

Metforminwith Glyburide

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Objective To evaluate whether initial treatment with glyburide/metformin tablets is superior to monotherapy with eachDesign Randomized, parallel-group,

placebo-controlled, multicentre Patients 806 treatment naïve type 2diabeticsDuration 20 weeks Therapy Placebo, glyburide 2.5 mg,

metformin 500 mg, glyburide/metformin 1.25

+250/500 mg, once daily.

Metformin – Glyburide

Garber AJ et al. Diabetes Obes Metab 2002 May;4(3):201-8

Dr.Sarma@worksGarber AJ et al. Diabetes Obes Metab 2002 May;4(3):201-8

P<0.001 *P=0.016 * *P<0.001 * * *

0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

-1.4

-1.6

glyburide/ metformin

1.25/250 mg Placebo

Glyburide

-1.48-1.53

-0.21 *

-1.24 **

glyburide/ metformin

2.5/250 mg

-1.03 ***

Week 20

P<0.001 *P=0.004 * *P<0.001 * * *

Metformin

Metformin – Glyburide

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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. 

Metformin – GlyburideConclusions

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Metforminwith

Pioglitazone

Metforminwith

Pioglitazone

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Design Double blind Randomized placebo controlled clinical

trialDuration 16 weeksPatients 328 patients with poorly

controlled DM - HbAlc > 8.0%,Rx. Metformin 30 daysLater Pioglitazone 30mg + Met (n=168) or Placebo + Metformin (n=160)Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409

Metformin – Pioglitazone

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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

Einhorn D et al Clin Ther 2000 Dec; 22(12): 1395-409

* p<0.05

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Open label extension of the study

Metformin + 30/45 mg Pioglitazone

154 patients

72 weeksFall in HbAlc: – 1.36%

Fall in FPG: – 63.0 mg/dl

Excellent tolerability

No hepatotoxicity seen

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

Metformin – Pioglitazone

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Metformin in Sec. OHA

failure

Metformin in Sec. OHA

failure

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Design Randomised, open and parallel studyNumber Fifty-one subjects Patients Type 2 diabetes with secondary oral hypoglycaemic agent failure Therapy1st phase 36 weeks- Combined therapy of

sulphonylureas and nocturnal insulin, with or without metformin2nd phase Metformin was withdrawn. Tong PC et al. Diabetes Res Clin Pract 2002 Aug; 57(2):93-8

Combination in Sec. OHA failure

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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

Combination in Sec. OHA failure

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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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Metforminin I. G. T.

Metforminin I. G. T.

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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

IGT to Type 2 DM

Raman PG et al. Asian J Diabetol 2002 June-July; 4(4): 37-42

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Metformin in I G T

Design Randomized double blindObjective To evaluate effect of metformin on glucose metabolism & rate of conversion to DMPatients 70 patients with IGTTherapy 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 inP C O D

Metformin inP C O D

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What is PCOD ?

1. Poly Cystic Ovarian Disease2. Common form of female

infertility 3. Poor conception rates4. Pregnancy loss rates are high

(30-50%) during the 1st trimester

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Metformin in PCODObjective 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. Metforminstarted 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 PCOD- Early Pregnancy loss

1. Retrospective study 2. Women with PCOD who became

pregnant 3. Duration of enrollment- 4.5 yr ,

OPD setting4. 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. lossEarly Preg. Loss Rate

50

40

30

20

10

0Metformin Placebo

8.8 %

41.9 %

In prior h/o Miscarriage

60

50

40

30

20

10

0Metformin Placebo

11.1 %

58.3 %

P < 0.001 P < 0.002

Jakubowicz DJ et al. J Clin Endocrinol Metab 2002 Feb;87(2):524-9

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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 inInsulin

resistance

Metformin inInsulin

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 ObesityMetformin 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 weeksPhysician’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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D I ED 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 More Carbohydrate Foods

Eat Least Sugar, Fat, Alcohol, Salt

Eat Moderately Protein Foods

Eat Most Vegetables

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EXERCISEBenefits

• 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 waragainst

Diabetes

Let us together

win the waragainst

Diabetes

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