Metformin in Clinical Use by Dr Shahjada Selim

Metformin in Clinical Uses by Dr Shahjada Selim

1. 4/16/2020 Dr S Selim 1 Clinical Uses of Metformin Dr Shahjada Selim Associate Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka Email: [email protected] , [email protected]

2. History of Metformin 4/16/2020 Dr S Selim 2 Biguanides- used in early medieval times- leguminosa Galega officinalis (goat's rue or French lilac) in Europe 1918-guanidine discovered as active glucose-lowering compound

3. History of Metformin 4/16/2020 Dr S Selim 3 3 biguanides available for medical use between 1957 & 1960- phenformin, metformin, buformin 1970s- phenformin and buformin withdrawn because of lactic acidosis

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. 4/16/2020 Dr S Selim 4

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 4/16/2020 Dr S Selim 5

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 4/16/2020 Dr S Selim 6

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8. The molecular mechanism of metformin is not completely understood. Multiple potential mechanisms of action have been proposed: 4/16/2020 Dr S Selim 8 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 posh phate 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. 4/16/2020 Dr S Selim 9 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 . 4/16/2020 Dr S Selim 10 …….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 . 4/16/2020 Dr S Selim 11 …….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. 4/16/2020 Dr S Selim 12 ….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%. 4/16/2020 Dr S Selim 13 ….Mechanism of Action

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15. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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 . M ore 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. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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 .

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20. Metformin use in diabetes 4/16/2020 Dr S Selim 20

21. Role of metformin in diabtes prevention Metformin reduces the risk of type2 DM It is cost effective 4/16/2020 Dr S Selim 21

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25. 4/16/2020 Dr S Selim 25 Metformin therapy for prevention of T2DM should be considered in those with prediabetes, especially for those with BMI ≥35 kg/m 2 (≥30 kg/m 2 for Asians) those aged, 60 years, and women with prior gestational diabetes mellitus ADA 2020

26. 4/16/2020 Dr S Selim 26 Metformin in the treatment of Diabetes

27. Metformin in combination therapy 4/16/2020 Dr S Selim 27 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

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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. 4/16/2020 Dr S Selim 29

30. Metformin and 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 type 2 diabetes (primary prevention) and those with cardiovascular complications (secondary prevention) 4/16/2020 Dr S Selim 30

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33. 4/16/2020 Dr S Selim 33 Cardiovascular effect of metformin in observational study

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36. 4/16/2020 Dr S Selim 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 Absorbed in upper small intestine Low bioavailability Increases glucose disposal by anaerobic metabolism of glucose Increases circulating levels of GLP-1 4/16/2020 Dr S Selim 37

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39. 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, 4/16/2020 Dr S Selim 39

40. 4/16/2020 Dr S Selim 40 Long-term use of metformin may b e associate d wit h bioc h emical v i t a mi n B1 2 d e fi ciency , an d periodi c mea s uremen t o f v i tamin B1 2 l e vel s sh o ul d b e c o nsider e d i n metformin-tr e a t e d patien t s, e s pecia l l y i n thos e w i t h anemia o r p eriph e ra l ne u ropat h y 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 A critical analysis of the relationship between metformin and lactic acidosis Renal impairment as a contraindication for metformin The therapeutic dosing profile and evidence base supporting use of metformin Evidence for a nephro -protective effect for metformin. 4/16/2020 Dr S Selim 41

42. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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 Prospective study from 1990, conducted in elderly patients who received metformin for two months. Mean monthly plasma metformin concentrations Remained within the usual range (<1.65 mg/L) Stage 1-2 CKD: 1,700 mg/day of metformin Stage 3 CKD : 850 mg/ day of metformin 4/16/2020 Dr S Selim 44

45. 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). 4/16/2020 Dr S Selim 45

46. Nephroprotective role of metformin 4/16/2020 Dr S Selim 46

47. Metformin and the Kidney 4/16/2020 Dr S Selim 47

48. 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/1.73m2) allow to administer metformin to patients across CKD stages 1–3, but not in 4 and 5. 4/16/2020 Dr S Selim 48

49. 4/16/2020 Dr S Selim 49 Summary of metformin use in type 2 diabetes Effective glucose lowering as monotherapy and in combination with other agents, including insulin Does not increase hypoglycaemia risk and is weight-neutral Possible cardiovascular benefits Maximally effective dose is usually 2000 mg daily Major side effect is GI disturbance Lactic acidosis risk is low; occurs mainly in those with advanced chronic kidney disease

50. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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 4/16/2020 Dr S Selim 52 A Cochrane review and meta-analysis of placebo-controlled trials

53. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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 4/16/2020 Dr S Selim 56 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. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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 4/16/2020 Dr S Selim 59

60. 4/16/2020 Dr S Selim 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.

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62. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 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. 4/16/2020 Dr S Selim 67 …..Carry Home Messages Metformin has proven efficacy in PCOS, ASCD and many cancers.