1. Metformin was introduced in 1957 and is effective for lowering blood glucose levels as monotherapy or in combination with other agents. 2. It works by decreasing hepatic glucose production and increasing insulin sensitivity. Common side effects include gastrointestinal issues. 3. Metformin is recommended for preventing type 2 diabetes in prediabetic patients and is the first-line treatment for type 2 diabetes.

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

3. History of Metformin

4. History of Metformin
•Professor Jean Sterne introduced Metformin into
clinical practice in Hospital Laennec in Paris in
1957.
•The initial lack of well-controlled clinical trials led to
the drug being regarded as less effective than the
Sulfonylureas.

5. …..History of Metformin
•Between 1965 and 1977- Metformin combined
with a Sulfonylurea had synergistic properties in
lowering blood glucose
•Metformin to be equivalent to sulfonylureas in
lowering blood glucose in obese subjects with type
2 diabetes with better weight reduction

6. •Metformin was equally effective compared
to sulfonylureas in blood glucose control in
non-obese patients with T2DM.
•Approval of the drug by the US Food and
Drug Administration in 1995

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

9. •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

10. •In addition to suppressing hepatic glucose
production, metformin increases insulin
sensitivity, enhances peripheral glucose
uptake (by inducing the phosphorylation
of GLUT4 enhancer factor), decreases
insulin-induced suppression of fatty acid
oxidation, and decreases absorption of
glucose from the gastrointestinal tract.
…….Mechanism of Action

11. •Increased peripheral use of glucose may be
due to improved insulin binding to insulin
receptors. The increase in insulin binding
after metformin treatment has also been
demonstrated in patients with NIDDM.
…….Mechanism of Action

12. •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. Some metabolic actions of
metformin do appear to occur by AMPK-
independent mechanisms.
….Mechanism of Action

13. •Metformin has indirect antiandrogenic effects
in women with insulin resistance, such as
those with polycystic ovary syndrome, due to
its beneficial effects on insulin sensitivity. It
may reduce testosterone levels in such
women by 50%.
….Mechanism of Action

15. Dosage and Administration
Therapy with metformin should be initiated with a
dosage of 50mg/day, with or after meals.
This may be gradually increased as necessary to a
maximum of five 500mg or three 850mg tablets daily
in the USA, although dosages of up to 3 g/day are
used in other countries.
The drug may be administered with a SUs, DPP4s
and others when needed.

16. ….Dosage and Administration
In order to minimise 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.
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.

17. 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.

18. Dosage and Administration
In a randomised, double-blind trial involving
701 participants, the efficacy and safety of the
extended-release formulation was found to be
similar to the twice-daily immediate release
drug.

20. Metformin use in diabetes

21. Role of metformin in diabtes
prevention

25. 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

26. Metformin in the
treatment of Diabetes

27. 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

29. 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.

30. Metformin and heart

33. Cardiovascular effect of metformin in observational study

36.  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.

37. Metformin and the Gut

39. Metformin and vitamin B12 deficiency

40. 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

41. Metformin and the Kidney

42. 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.

43. The incidence of lactic acidosis in the setting
of metformin therapy is low, and the drug is not
necessarily responsible when lactic acidosis
occurs in patients taking this medication
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).

44. Metformin Dose and kidney

45. Metformin dose and CKD

46. Nephroprotective role of metformin

47. Metformin and the Kidney

48. Metformin and Kidney

49. 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 hypoglycaemia risk and is
weight-neutral
3.Possible cardiovascular benefits
4.Maximally effective dose is usually 2000 mg daily
5.Major side effect is GI disturbance
6.Lactic acidosis risk is low; occurs mainly in those
with advanced chronic kidney disease

50. 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

51. 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].

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

53. 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

54. 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

55. 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.

56. 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.

57. 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].

58. ….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.

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

60. 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.

62. 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.

63. …..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.

64. ….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.

65. 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.

66. …..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.

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