Glitazones like pioglitazone and rosiglitazone have been shown to increase the risk of fractures in women based on evidence from multiple clinical trials. The ADOPT trial found rosiglitazone use was associated with a higher risk of fractures compared to metformin or glyburide, especially in postmenopausal women. Subsequent studies confirmed this risk, finding about a 2-3 times increased risk of hip and wrist fractures with over 12-18 months of glitazone use. The exact mechanism is unclear but may involve effects on bone metabolism and formation. Ongoing monitoring of bone health is recommended for women with diabetes taking these drugs.

1. GLITAZONES & THEIR FRACTURE RISK Prof. P.K. Jain MD,MNAMS Professor & Head, Department of Medicine, M.L.B. Medical College, Jhansi, UP

2. Introduction Glitazones enhance insulin sensitivity in the adipose tissue, muscle and liver cells. Both Rosiglitazone and pioglitazone licensed as mono, dual and triple therapy. Pioglitazone also licensed as combination therapy with insulin in type 2 diabetes for whom metformin is inappropriate. Diabetes 2002;51:2796-803

3. GLITAZONES Sohda et al 1982 synthesised ciglitazone when looking for agent to reduce insulin resistance. Ciglitazone proved to be too toxic for humans but lead to development of troglitazone,rosiglitazone and pioglitazone. Troglitazone came with a bang and went out with a whimper and subsequently withdrawn because of hepatotoxicity.

4. GLITAZONE STRUCTURE

5. MECHANISM OF ACTION OF GLITAZONES

6. MECHANISM OF ACTION Glitazones bind to intracellular receptor PPAR gamma The resulting complex binds to sites in nucleus regulating gene expression in muscle & adipose tissue e.g. stimulate GLUT1 & GLUT4 gene expression (glucose transporter) and also hepatic glucokinase gene expression This results in enhanced insulin action e.g. increased entry of glucose into cells and reduced liver glucose release. NEJM 2002:356:437-40

9. Thiazolidinediones Reduce insulin resistance in muscle, adipose tissue and liver Adapted from Saltiel 1996, Jones 1999 Decrease circulating levels of insulin Decrease gluconeogenesis in liver Decrease blood glucose levels Adipose tissue Muscle Liver Blood glucose Pancreas

11. Glycaemic control As monotherapy, pioglitazone is comparable to both gliclazide and metformin in large studies. As dual therapy, no significant differences when compared to metformin or sulphonylurea. Significant improvement combined with insulin (v. Placebo) but four fold increase in oedema. Lancet 2005:352:854-65

13. REMEMBER WHERE GLITAZONES WENT WRONG!!

14. Glitazones-safety All are not recommended or contra-indicated in: Heart failure or history of heart failure Abnormal LFT’s Women with high risk of fracture Additionally glitazones are not recommended or contra-indicated in: Acute coronary syndrome Ischaemic heart disease Peripheral artery disease

15. Bone health and diabetes

16. Osteoporosis is a disorder of increased bone fragility and low bone mass with a consequent increase in fracture risk. Data from the third National Health and Nutrition Examination Survey (NHANES III) indicate that 13–18% of women in the United States over age 50 have osteoporosis Additional 37–50% have low bone mass at the hip. The disease results in more than 350,000 hip fractures alone each year in the United States. J Bone Miner Res 18:784–790, 2003

17. Copyright ©2007 Canadian Medical Association or its licensors Meymeh, R. H. et al. CMAJ 2007;177:723-724

18. Hip fractures are increased in patients with diabetes. Case-control studies of patients with hip fractures have found an excess of patients with diabetes, suggesting at least a twofold relative risk in all patients with diabetes. Women with type 1 diabetes had a 6.9- to 12-fold relative risk of hip fractures compared to women without diabetes. Arch Intern Med149:2445–2448, 1989

19. Diabetes is associated with an increased risk of fractures and this risk was demonstrated in WOMEN’S HEALTH INITIATIVE. The study involved >90000 women and were followed for 7years. 5 % of them were diabetic and it was found that diabetes was associated with a 20% increase in risk of fractures with the frequency of fracture increased in spine ,hip and sites in upper and lower limbs with an exception of lower arm,wrist and hand. Diabetologia 42:920–925, 1999

20. The Study of Osteoporotic Fractures in women older than 65 years with type 2 diabetes found an increased risk of hip and proximal humerus fractures despite a higher bone mineral density (BMD) in those patients. There was also a trend toward increased risk of vertebral, forearm, ankle, and foot fractures. In contrast, other investigators have found increased BMD at the spine in men and women with type 2 diabetes, with fewer fractures. Diabetes Care 24:1192–1197, 2001

21. The one site with an undisputed increased fracture risk is the foot, which may be related in part to obesity or neuropathy. Focal osteopenia and fractures associated with severe peripheral neuropathy (Charcot foot) are long recognized as a complication of any type of diabetes. Ann Intern Med 95:28–31, 1981

22. Several subsequent studies found that the forearm BMD in children with only 4–6 years of type 1 diabetes was 20–50% lower than that in control subjects. Hence,BMD is lower in patients with type 1 diabetes than in subjects without diabetes. Ann Intern Med 122:409–414, 1995 In contrast, studies in women with type 2 diabetes, controlling for age and obesity, show BMD that is either the same or greater than that in normal subjects, even in patients treated with insulin. The Rancho Bernardo studies, a large population-based longitudinal cohort, also looked at men with type 2 diabetes and found that their BMD was similar to that of men with normal glucose tolerance. J Bone Miner Metab 17:119–124, 1999

23. J Bone Miner Metab 17:119–124, 1999

24. Is osteoporosis another complication of poor glycemic control? Diabetes complications also represent cumulative results of long-term poor control. Mathiassen et al. followed the BMD of 19 patients with type 1 diabetes (8 women), initially free of complications, and found that after 11 years, only those who developed retinopathy or proteinuria had worsening of their BMD. J Diabetes Complications 8:97–104, 1994 The presence of severe peripheral neuropathy in patients with type 1 diabetes have also been found to correlate with decreased BMD at all sites. J Intern Med 227:325–327, 1990

25. Hypercalciuria, a potential risk factor for osteoporosis, has long been noted in patients with poorly controlled type 1 diabetes or type 2 diabetes, and was shown to improve with lower A1C results. Thus, metabolic control appears to be a major factor in the increased incidence of osteoporosis in patients with diabetes. If the relationship between osteoporosis and diabetes were only related to hyperglycemia, one would expect a similar incidence of osteoporosis in patients with type 1 and those with type 2 diabetes, but most studies show more osteoporosis in patients with type 1 diabetes. J. Clin Endocrinol Metab 81:1152–1155, 1996

27. Treatments for hypertension and hyperlipidemia, which are associated with both types of diabetes, may also affect BMD. J Clin Endocrinol Metab 75:524–529,1992 Use of loop diuretics to treat hypertension can increase urinary loss of calcium, whereas thiazides may decrease it. Diabetes Res Clin Pract 40:31–38, 1998 Although case-control studies have suggested that treatment of hyperlipidemia with HMG CoA reductase inhibitors may increase BMD,these results have not been supported. Are treatment options resulting in low BMD?

28. Blow to glitazones

29. Have glitazones lost their sparkle?

30. June , 2007 A bad month altogether for glitazones

31. FDA link pioglitazone and fractures June 19, 2007 The American Food and Drugs Administration has issued a warning to healthcare professionals after an increased risk of fracture was seen in the clinical trial database of pioglitazone. The risk appears to be very similar to rosiglitazone . The risk appears to only affect women and the fractures are mainly located in the distal portion of the limbs , e.g. hand, foot, wrist, ankle, forearm, tibia and fibula.

32. GLITAZONES ‘ All that glitters is not gold’ The safety of new drugs has never been as well established as pharmaceutical company promotions may suggest. Now the thiazolidinediones, better known as 'glitazones', are under suspicion of causing serious, previously unsuspected adverse effects.

33. ADOPT Analysis Shows Rosiglitazone Increases Risk of Fracture in Women June 29, 2007 (Chicago) -- "In ADOPT, the increased risk of bone fractures in women with type 2 diabetes was accentuated with rosiglitazone," said during a late-breaking clinical-trials session at the American Diabetes Association 2007 Scientific Sessions.

34. Fracture In animals models, glitazones have been shown to decrease bone mineral density. Glitazones increase the rate of bone loss in women. ADOPT: increased fracture rate in women on rosiglitazone compared to metformin or glyburide.

35. Fracture risk should be considered during medication reviews for female patients already on glitazones. In patients whose type 2 diabetes is poorly controlled the pros and cons of each of the available hypoglycaemic agents should be considered and discussed with the patient before any treatment is started.

36. The manufacturer recommends that, “ the risk of fracture should be considered in the care of female patients with type 2 diabetes mellitus who are currently being treated with pioglitazone, or when initiation of pioglitazone treatment is being considered “.

37. It appears to increase fractures principally in the upper and lower limbs, and there was no observed increase in spinal fractures with glitazone. It would appear that this is a class effect .

38. Possible mechanisms still not clear but there are certain postulated theories. The PPAR-gamma, the molecular target of the TZDs currently in clinical use, is expressed in skeletal tissue Evidence from preclinical studies has demonstrated that activation of PPAR-gamma Inhibits bone formation by diverting mesenchymal stem cells from the osteogenic to the adipocytic lineage. May increase bone resorption by stimulating the development of osteoclasts. There is also potential for indirect adverse skeletal effects of PPAR-gamma activation by modulation of circulating levels of hormones and cytokines known to influence bone metabolism. Clin Calcium:2008 May;18(5):650-5

39. Are the adverse effects of glitazones linked to induced testosterone deficiency?

40. Glitazones induce androgen deficiency in patients with Type 2 Diabetes Mellitus resulting in pathophysiological changes in multiple tissues and organs which may explain their observed clinical adverse effects .

41. Effects on Bone Because osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, increased adipogenesis may occur at the expense of osteoblasts, leading to bone loss. RGZ and PGZ usage were associated with more than doubling of fractures of the hip and wrist, increasing with the dose of either thiazolidine .

43. An analysis from A Diabetes Outcome Progression Trial (ADOPT) ADOPT was a randomized, controlled clinical trial comparing the effect of the rosiglitazone, the metformin, and the glyburide on glucose control in drug-naive patients recently diagnosed with type 2 diabetes. It was shown that treatment with rosiglitazone produced more durable glycemic control than metformin or glyburide as measured by fasting glucose and A1C. While a review of adverse events of special interest uncovered an increase in the number of fractures in women taking rosiglitazone. Diabetes care 25:1737-1743,2002

44. 4,360 individuals with type 2 diabetes naive to oral hypoglycemic drugs were randomly assigned. 1,456 subjects were assigned to rosiglitazone, 1,454 to metformin, and 1,441 to glyburide therapy. It was large multi centre trial. The initial daily doses were 4 mg rosiglitazone, 500 mg metformin, and 2.5mg glyburide, and the dose was titrated to the maximum effective daily dose (4 mg rosiglitazone twice daily, 1 g metformin twice daily, and 7.5 mg glyburide twice daily). The median duration of follow-up was 4.0 years for the rosiglitazone group.

45. 200 reported a fracture during the course of the study The Kaplan-Meier estimated cumulative incidence of a fracture (95% CI), reaching 9.8% at 5 years with rosiglitazone, 5.6% with metformin, and 5.7% with glyburide as shown in figure. Amongst the men, there was no significant difference in fracture risk between different treatment groups. Whereas in women, the cumulative incidence of a fracture reached 15.1% at 5 years with rosiglitazone, 7.3% with metformin, and 7.7% with glyburide. The fracture incidence was more after 12 months of treatment and more in the postmenopausal women.

46. Kaplan Meier estimates of cumulative incidence of fractures at 5 yrs. In All Patients.

47. Kaplan Meier estimates of cumulative incidence of fractures at 5 yrs. In MEN

48. Kaplan Meier estimates of cumulative incidence of fractures at 5 yrs. In WOMEN

49. Among women in the rosiglitazone group, mostly reported fractures in lower limb & upper limbs as compared to other treatment groups. There was no difference in the proportion of women who reported a spinal fracture. A difference in the proportion experiencing fractures was observed in the foot ( P< 0.05 for rosiglitazone compared with metformin and glyburide). Humerus ( P< 0.05 for rosiglitazone compared with metformin and glyburide). Hand ( P> 0.05 for rosiglitazone compared with metformin and glyburide).

52. The Health Canada advisory was based on an unpublished, manufacturer-led review of double-blind randomized controlled trials of pioglitazone use in diabetic patients. There was no apparent increase in fracture risk among men. Among women, 2.6% of those in the pioglitazone group experienced fractures, as compared with only 1.7% in the comparison group. Fractures occurred in 1 of 52 patients taking pioglitazone for a year, as compared with placebo or another diabetes drug. Most of the fractures occurred in distal upper and lower limbs and, to a lesser degree, in the hip and spine J Clin Endocrinol Metab 2006; 91: 3349-54

53. Another landmark trial which was done by Christopher Meier et al in university of Basel provided further evidence . The odds for fracture were increased among patients who took the drugs for approximately 12 to 18 months and the risk was highest for those with two or more years of therapy. Fractures of the hip and wrist were most notable . Arch Intern Med. April 28, 2008;168(8):820-825

54. Odds Ratios for users of 8 or more thiazolidinedione prescriptions (corresponding to approximately 12-18 months of therapy) compared with nonuse was 2.43 . Rosiglitazone (OR, 2.38)and pioglitazone (OR, 2.59) were used more frequently by case patients with fracture (predominantly hip and wrist fractures) than by controls. Hence Glitazones usage is associated with an approximately 2- to 3-fold increased risk of hip and nonvertebral osteoporotic fractures. In this particular trial risk of fracture was same amongst women and men which was in contrast to ADOPT trial. J Clin Endocrinol Metab. 2007;92(4):1305-1310

56. Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for 2 Diabetes (RECORD TRIAL)) Upper and distal lower limb fracture rates were increased mainly in women randomly assigned to glitazone.

58. However, in the light of above discussion the current recommendations regarding use of Glitazones are questionable. The gold standard will be long term, large, multicentric, controlled, adequately powered, prospective studies with clearly identifiable end-points. But these are difficult to carry after the furore raised in the literature recently. The last word on Glitazones has not yet been said in the literature, but for the treating physicians, the last word has already been heard.

59. Take Home Message

60. Special attention should be paid to bone health in women with type 2 diabetes who are receiving thiazolidinediones

61. With Glitazones-Do Routine BMD

62. No Glitazones-No BMD