Clinical Uses of Metformin by Dr Shahjada Selim

1. Clinical Uses
of Metformin
Dr Shahjada Selim
Associate Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka
Email: selimshahjada@gmail.com, info@shahjadaselim.com

2. History of Metformin
•Professor Jean Sterne introduced Metformin into
clinical practice in Hospital Laennec in Paris in
1957.
•Between 1965 and 1977- Metformin combined
with a Sulfonylurea had synergistic properties in
lowering blood glucose
•Approval of the drug by the US Food and Drug
Administration in 1995

3. •The results of the United Kingdom
Prospective Diabetes Study (UKPDS) in
1998 changed the status of Metformin
dramatically, by showing that metformin
therapy was associated with a reduction in
heart attacks and all-cause mortality in
overweight, newly-diagnosed people with
type 2 diabetes.

4. • The molecular mechanism of metformin is not
completely understood.
• Multiple potential mechanisms of action have been
proposed: inhibition of the mitochondrial respiratory
chain (complex I), activation of AMP-activated protein
kinase (AMPK), inhibition of glucagon-induced
elevation of cyclic adenosine
monophosphase (cAMP) with reduced activation of
protein kinase A (PKA), inhibition of mitochondrial
glycerophosphate dehydrogenase, and an effect
on gut microbiota.
Mechanism of Action

5. Ultimately, it decreases gluconeogenesis (liver
glucose production).
It also has an insulin-sensitizing effect with multiple
actions on tissues including the liver, skeletal
muscle, endothelium, adipose tissue, and the
ovary.
The average patient with type 2 diabetes has three
times the normal rate of gluconeogenesis;
metformin treatment reduces this by over one-third.
Mechanism of Action

6. Metformin and other biguanides may
antagonize the action of glucagon, thus
reducing fasting glucose levels.
Metformin also induces a profound shift in the
fecal microbial community profile in diabetic
mice and this may contribute to its mode of
action possibly through an effect on glucagon-
like peptide 1 secretion.
…..Mechanism of Action

7. AMPK probably also plays a role in increased
peripheral insulin sensitivity, as metformin
administration increases AMPK activity in skeletal
muscle.
AMPK is known to cause GLUT4 deployment to the
plasma membrane, resulting in insulin-independent
glucose uptake.
….Mechanism of Action

9. Dosage and Administration
In order to minimize GI side effects, metformin should
be taken with meals and initiated at a low dose,
typically 500 mg once daily [XR formulation may be
safer] with gradual increases.
This may be gradually increased as necessary to a
maximum 2550mg daily in divided doses in the USA,
although dosages of up to 3 g/day are used in some
countries.

10. ….Dosage and Administration
More than 50% of the drug’s efficacy is observed at
1000 mg.
Accordingly, in those patients having difficulty with
higher doses, daily amounts of 1000–1500 mg should
be considered substantially effective.

11. ……Dosage and Administration
• Metformin XR, and related products, is an
extended-release formulation, available in 500,
750 and 1000 mg tablets.
• It has a dual polymer matrix, which slowly releases
the active drug.
• It enables slower drug absorption in the upper GI
tract, providing a once-daily dosing option, while
also decreasing the frequency and severity of GI
side effects.

13. Metformin use in diabetes

14. Role of metformin in diabtes
prevention
•Metformin reduces the risk of type 2 DM
•It is cost effective

18. Metformin therapy for prevention of T2DM should
be considered in those with prediabetes, especially
for those with BMI ≥35 kg/m2 (≥30 kg/m2 for Asians)
those aged, 60 years, and women with prior
gestational diabetes mellitus
ADA 2020

19. Metformin in the
treatment of Diabetes

20. Metformin in combination therapy
Once initiated, metformin should be continued as
long as it is tolerated and not contraindicated; other
agents, including insulin, should be added to
metformin.
Pharmacologic Approaches to Glycemic Management:
Standards of Medical Care in Diabetes - 2020. Diabetes Care 2020;43(Suppl. 1):S98-S110

22. Metformin in combination therapy
•Combinations of higher doses of metformin with
newer classes of OADs (DPP4 inhibitors,SGLT2
inhibitors) are likely to be more effective than
combinations involving lower metformin
•Combination tablets have the potential to simplify
the delivery of antihyperglycemic therapy,
maintaining better glycemic control compared with
monotherapy, while reducing the burden of
polypharmacy and supporting better adherence to
therapy.

23. Metformin and the heart
•Clinical evidence from randomised, controlled
trials and from observational studies supports the
potential of metformin to improve clinical
cardiovascular outcomes in people with diabetes
•These benefits are present in those with newly
diagnosed T2DM (primary prevention) and those
with cardiovascular complications (secondary
prevention)

24.  Clinical evidence from randomised trials and
observational studies supports improved long-
term macrovascular outcomes in people with
type 2 diabetes treated with metformin.
 Multiple biological mechanisms contribute to
these benefits, which are still being studied
intensively today.

25. Metformin and the Gut
•Absorbed in upper small intestine
•Low bioavailability (40-60% bioavailability, better
when taken fasting)
•Increases glucose disposal by anaerobic
metabolism of glucose
•Increases circulating levels of GLP-1

27. Metformin and vitamin B12 deficiency
•A randomised, placebo-controlled trial in 390
insulin-treated type 2 diabetes patients reported
a mean decrease of 19% in B12 levels, and a
7.2% increase in the proportion with B12
deficiency
Mechanisms:
Altered small bowel motility causing bacterial
overgrowth, alterations in intrinsic factor levels
and interaction with an endocytic receptor for
B12.

28. Long-term use of metformin may be
associated with biochemical vitamin B12
deficiency, and periodic measurement of
vitamin B12 levels should be considered in
metformin-treated patients, especially in
those with anemia or peripheral neuropathy
Pharmacologic Approaches to Glycemic Management:
Standards of Medical Care in Diabetes - 2020. Diabetes Care 2020;43(Suppl. 1):S98-S110

30. Recently 65 studies rigorously examined the risk of
lactic acidosis in moderate to severe CKD patients
over the period of 1950–2014.
The risk of lactic acidosis is essentially nil in the
context of clinical trials, including those that did not
specify kidney disease as an exclusion criterion.

31. As long as kidney function is stable and the patient
is observed closely, metformin is unlikely to
measurably increase the risk of lactic acidosis in
patients with moderate CKD (i.e., eGFR 30-60
mL/min/1.73 m2).
Metformin and the Kidney

32. Metformin dose and CKD
•Maximum daily metformin doses were suggested
by Schernthaner in a meta-analysis:
1700–2000 mg/day in CKD 3A with a significant
benefit on all-cause mortality (HR 0.87;95%CI
0.77-0.99; p<0.05)
1000 mg/day in CKD stage 3B with no increase
risk on all-cause mortality (HR 1.04; 95% CI 0.84-
1.24).

33. Metformin and Kidney
•Recent authorizations from the European
Medicines Agency (EMA) and the US Food and
Drug Administration (FDA) for the relaxed use of
metformin in patients with diabetes and CKD
stage 3 A and B (eGFR 59–30 mL/min/1.73 m2)
allow to administer metformin to patients across
CKD stages 1–3, but not in 4 and 5.
•ADA 2020 recommends not to use metformin in
eGFR <30 mL/min/1.73 m2

34. Summary of metformin use in type 2
diabetes
1.Effective glucose lowering as monotherapy and in
combination with other agents, including insulin
2.Does not increase hypoglycemia risk and is weight-
neutral
3.Possible cardiovascular benefits
4.Maximally effective dose is usually 2550 mg daily
5.Major side effect is GI disturbance
6.Lactic acidosis risk is very low; occurs mainly in
those with advanced chronic kidney disease

35. Metformin was the first insulin sensitizing drug (ISD)
to be investigated in PCOS with the role of improving
insulin resistance [Velazquez et al. 1994].
Several effects have been reported as related to
metformin in PCOS patients including restoring
ovulation, reducing weight, reducing circulating
androgen levels, reducing the risk of miscarriage
and reducing the circulating insulin levels.
Metformin in Polycystic ovary
syndrome

36. Metformin and steroidogenesis
The effect of metformin on androgen production has
been controversial [Arlt et al. 2001].
It may be argued that the metformin effect on
circulating androgen is a byproduct of ovulation
resumption. However, in vitro experiments
demonstrated that metformin significantly inhibited
both androstenedione and testosterone production
by the theca cells [Attia et al. 2001].
Further, it has been suggested that
metformin reduces hyperandrogenism
through its effect on both the ovary and
adrenal gland suppressing their
androgen production, reducing pituitary
LH and increases the production of
SHBG by the liver [Bailey and Turner,
1996].

37. Metabolic effect of metformin in PCOS
A Cochrane review and meta-analysis of placebo-controlled trials

38. Observational studies have suggested that
metformin administration reduced the risk of
miscarriage among PCOS sufferers [Thatcher
and Jackson, 2006; Glueck et al. 2002;
Jakubowicz et al. 2002].
In a meta-analysis, Palomba and colleagues
reported that metformin had no beneficial effect
on the miscarriage rate [Palomba et al. 2009].
Gestational di
Metformin and pregnancy

39. PCOS sufferers have a higher risk of developing
GDM [Boomsma et al. 2006]. Further, it has been
reported that the risk of PCOS is significantly high at
40% among women with a previous history of GDM.
GDM is associated with high perinatal mortality and
morbidity for the fetus and both short- and long-term
complications for the mother [The HAPO Study
Cooperative Research Group, 2008; Pettitt et al.
1980].
Gestational diabetes mellitus

40. Endometrial cancer
Metformin may reduce the risk of endometrial
cancer [Ben Sahra et al. 2008], and the logical
yet theoretical benefits of metformin in
preventing endometrial cancer, it is difficult to
justify its prophylactic use in PCOS patients
without firm evidence addressing efficacy and
cost implications.

41. Place of Metformin in treatment of
PCOS in different guidelines
National Institute for Health and Care Excellence (NICE) i:
Clomiphene and/or metformin as first-line pharmacologic
therapies, depending on individual circumstances, after
intervention to achieve weight loss, and prescribed by a
specialist.
The Endocrine Society in the USA:
Clomiphene as the first-line treatment for PCOS, with possible
use of metformin for women with PCOS who have type 2
diabetes or impaired glucose tolerance, again after a trial of a
lifestyle intervention.

42. Non-glycaemic effects
Once the cardiovascular benefits of metformin were
suggested following clinical trials, interest into the
pleiotropic effects of the drug arose. It has been proposed
that its overall benefits are not solely the consequence of
improved glucose control. This was evidenced in the
UKPDS [27].

43. ….Non-glycemic effects
Furthermore, in short-term studies, weight loss of up to 2-
4 kg after 16–29 weeks of treatment with metformin has
been reported [28, 29]. This effect may be mediated
through carbohydrate malabsorption, enhanced
carbohydrate utilization in the GI tract itself, or reduced
calorie intake from mild anorexia [30]. In the longer-term
UKPDS study, metformin was merely weight neutral, yet,
this was in contrast to the predictable weight gain
observed in those assigned to sulfonylureas or insulin.

44. Metformin and cancer
There are evidence of benefit in
preventing and treating these cancers
with metformin
•Colorectal
•Breast
•Liver
•Pancreas

45. Metformin inhibits mTOR activity by activating
ATM (ataxia telangiectasia mutated) and LKB1
(liver kinase B1) and then adenosine
monophosphate-activated kinase (AMPK), and
thus prevents protein synthesis and cell growth.
Metformin can activate p53 by activating AMPK
and thereby ultimately stop the cell cycle and
inhibits carcinogenesis.

47. Metformin intolerance
Metformin treatment is frequently associated with
GI side effects (20–30% of patients) with severe
side effects resulting in metformin discontinuation
in ~5% of patients. The mechanism by which
metformin causes GI side effects remains
uncertain.

48. …..Metformin intolerance
However, there are a number of putative
mechanisms; the side effects may simply relate to
the high concentration of metformin in intestinal
enterocytes, potentially explaining why slow-
release formulations of metformin, which disperse
slowly and reduce local luminal metformin
concentrations, reduce GI intolerance.
GI effects The most common side effects of
metformin are GI in nature: diarrhoea, nausea
and/or abdominal discomfort.

49. ….Adverse effects
They are usually mild, transient and dose-related,
but can occur in up to 50% of patients taking the
medication. About 5% of individuals cannot
tolerate the drug, even at low doses . Symptoms
can be mitigated by gradual titration or reduction
in dose. These side effects may relate to drug
accumulation in the enterocytes of the small
intestine.

50. Carry Home Messages
 The metabolic and vasculo-protective profiles of
metformin have been recognised in treatment
guidelines for T2DM
 The recommendations of the ADA, EASD, IDF
place metformin as first-line therapy.

51. …..Carry Home Messages
 The drug is suitable irrespective of age, body
weight and severity of hyperglycemia (except
patients with symptoms necessitating
insulin).
 Metformin complements lifestyle
management throughout the treatment of
T2DM and forms a convenient
pharmacological foundation for combined
therapy with other antidiabetic therapies,
including insulin.

52. …..Carry Home Messages
 Metformin has proven efficacy in PCOS,
ASCD and many cancers.

53. ধন্যবাদ