dr.sarma@works a comprehensive review by dr. r.v. s. n. sarma, m.d., m.sc., metformin revisited
TRANSCRIPT
Dr.Sarma@works
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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