1. 1. Insulin sensitizers Metformin: The Gold Standard By Prof. Adel A El-Sayed MD Chairman Elect Middle East and North Africa (MENA) Region International Diabetes Federation (IDF) Professor of Internal Medicine Sohag Faculty of Medicine Sohag-EGYPT
2. 2. No Conflict Of Interest
3. 3. Pathophysiology of Type 2 Diabetes Insulin resistance. Beta cell dysfunction.
4. 4. Pathophysiology of Type 2 Diabetes Insulin Resistance Insulin Resistance starts very early in the course of the disease. insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion.
5. 5. Pathophysiology of Type 2 Diabetes Insulin Resistance It is now generally believed that T2DM occurs when the beta cell mass is unable to increase the insulin secretion to meet the demands put on them by the insulin resistance. Insulin resistance is related to most of the markers of CV diabetic complications.
6. 6. Insulin resistance and adverse cardiovascular outcomes 0 1 2 3 4 5 6 7 CHD events All-cause mortality RR 2.18 (95% CI 1.82 to 3.87( RR 1.62 (95% CI 1.03 to 2.55( Incidence/1000patient-years Prospective cohort study in Malm, Sweden (n=4748( +Insulin resistance Insulin resistance Hedblad B et al. Diabet Med 2002;19:47.
7. 7. Insulin sensitizers Metformin. Thiazolidinediones.
8. 8. Metformin The blood glucose-lowering actions of metformin result primarily from an amelioration of insulin resistance, mainly in liver and muscle, with a less marked effect on adipose tissue. (Giannarelli, Diabetes Metab2003) Within the liver, the principal effect of metformin is a reduction in hepatic glucose output.
9. 9. The Metformin Problem Biguanides: Metformin and phenformin. Discovered in US and became available in the market in 1959. Widely used between 1960 and 1978. Phenformin had been accompanied with development of the serious and potentially fatal lactic acidosis. Both drugs were withdrawn from US market in 1978. Metformin remained widely used in Canada and Europe.
10. 10. Cardiovascular Benefits With Metformin UKPDS In newly-diagnosed type 2 diabetic patients followed for a median of 11 years in the UKPDS, (UK Prospective Diabetes Study Group, Lancet 1998) patients who received metformin benefited from clinically and statistically significant improvements in CV complications of DM (the risk of all-cause death, diabetes related death, myocardial infarction, and in a composite measure of 21 diabetes- related complications). other intensive therapies delivered a similar level of glycaemic control without those CV benefits
11. 11. In 1995 metformin was FDA approved
12. 12. Cardiovascular Benefits With Metformin Several observational analyses have suggested significant cardioprotective benefits with metformin in patient populations with more severe cardiovascular disease at baseline. (Kao et al, Am J Cardiol 2004)
13. 13. Metformin and Lipid Profile Numerous studies have demonstrated improved lipid profiles in dyslipidaemic patients.(Despres, Diabetes Metab 2003) Modest improvements in levels of total cholesterol, low-density lipoprotein (LDL)- cholesterol and triglycerides are observed, though little or no change in high-density lipoprotein (HDL)-cholesterol is usually seen.
14. 14. Metformin and Adiposity The modest reductions in body weight often observed with metformin are associated with redistribution of fat from visceral deposits to subcutaneous deposits .(Kurukulasuriya et al, Diabetes 1999)
15. 15. Metformin and C-Reactive Protein Patient Group Type 2 1 Type 2 + MS 2 PCOS 3 n 12 65 32 Dose (mg( 2500 2500 2000 CRP 33% 33% 50% 1 Chu. Diabetes Care 2002; 25: 542-549 2 Akbar. Endocrine 2003; 20: 215-218 3 Morin-Papunen. JCEM 2003 Duration 4m 3.5y 6m P-value >0.01 0.01 >0.01 Metformin
16. 16. Inhibition of glycoxidation Metformin inhibits the formation of advanced glycation endproducts (AGE) both indirectly through improved glycaemia and directly through reaction with, and neutralization of highly reactive radicals involved in AGE formation.
17. 17. Metformin and Improved Haemostasis Metformin reduces levels or activity of plasminogen activator inhibitor-1 (PAI-1), (Grant et al, Diabetes Metab 2003) and sometimes increases the activity of tissue plasminogen activator (tPA). Other antithrombotic mechanisms of metformin include stabilisation of reduced aggregation of platelets in response to stimuli and reduction of the activity of clotting Factor VII and Factor XIII, which are involved in thrombus formation and stabilisation, respectively.
18. 18. Prevention of Diabetes - Diabetes Prevention Program. - Prevention of Gestational Diabetes
19. 19. Gestational Diabetes in 40 Women with PCOS Previously without metformin In 52 livebirth pregnancies With metformin In 40 livebirth pregnancies GD 13% GD 31% X2 =4.3, p=0.039 McNemar S=8.3, p=0.039 Glueck. Human Reproduction 2004; 19: 510-521
20. 20. Metformin Mechanism of Action Recent reports suggested that increase in the circulating concentration of glucagon- like peptide-1 (GLP-1) may contribute to the metabolic effects metformin. (Lindsay et al, Diabet Med 2005 - Sinha Roy et al, Diabetologia 2007) This might arise from increased secretion of GLP-1 rather than inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4). (Sinha Roy et al, Diabetologia 2007)
21. 21. Metformin in combination The glucose-lowering extent of metformin is additive when used in combination with every known antidiabetic drug: a sulphonylurea,(Blonde et al, Diabetes Obes Metab 2002) a meglitinide, (Marre et al, Diabetes Obes Metab 2002) a thiazolidinedione (Charbonnel et al, Diabetologia 2005) an - glucosidase inhibitor (Chiasson et al, Diabetes Care 2001 Phillips et al, Diabetes Care 2003) a GLP-1 analogues, exenatide (DeFronzo et al, Diabetes Care 2005) liraglutide, (Naucket al, Exp Clin Endocrinol Diabetes 2006) DPP-4 inhibitors, vildagliptin (Ahren et al, Diabetes Care 2005) or sitagliptin. (Hermansen et al, Diabetes Obes Metab 2007) and insulin-based regimens .(Ryysy et al, Diabetes Care 2001) The additive antihyperglycaemic efficacy of these combinations relates to different cellular modes of action of metformin compared with each of the other classes of agents.
22. 22. Metformin and Weight Metformin is widely recognized to have either little effect on body weight or to facilitate modest weight loss in type 2 diabetes. (Golay, Int J Obes 2008) There is no major effect of obesity status on the antihyperglycaemic effect of metformin but a slightly larger glucose-lowering effect of metformin has been observed as body mass index (BMI) decreases. (Donnelly et al, Diabet Med 2006) Thus, body weight should not unduly influence the decision whether to prescribe metformin.
23. 23. Metformin safety with pregnancy Metformin has long been reported to be safe with pregnancy. Recently, in June 2008 the first results of the MIG Trial was published in the N Engl J Medicine. It demonstrated that metformin is as safe as insulin in women with gestational diabetes. In the NICE guidelines (2008), and Canadian guidelines (2009) metformin has been mentioned as a safe and effective substitute for insulin in treatment of gestational diabetes.
24. 24. Potential clinical uses beyond type 2 diabetes Diabetes prevention. Polycystic ovary syndrome. Other conditions associated with insulin resistance Non- alcoholic fatty liver disease (NAFLD) and the related non-alcoholic steatohepatitis (NASH) and in patients receiving highly active antiretroviral therapy (HAART) for HIV are at risk of lipodystrophy syndrome. Anti-Cancer by activating the enzyme AMPK:Two observational studies in patients with type 2 diabetes have demonstrated a significantly lower risk of cancer in patients receiving metformin relative to other treatments. (Evans et al, BMJ 2005) (Bowker et al, Diabetes Care 2006)
25. 25. Metformin In The International Guidelines The recommendations of the American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD) (ADA/EASD consensus, Diabetologia 2006 updated on 22/10/2008), and the International Diabetes Federation (IDF) 2005 place metformin as first-line therapy for type 2 diabetic patients irrespective of age, body weight and severity of hyperglycaemia.
26. 26. Thiazolidinediones Thiazolidinediones TZDs were developed in 1997. There first member troglitazone was withdrawn from the market in the year 2000 due to hepatotoxicity. Pioglitazone and rosiglitazone appeared in the market in 1999. Glitazones act predominantly by enhancing peripheral insulin sensitivity, offering promising perspectives in terms of -cell preservation [Buchanan et al, Diabetes 2002 Ovalle and Bell, Diabetes Obes Metab 2002] and cardiovascular protection [Suwattee et al, Endocrinologist 2002 Dormandy et al, Lancet 2005].
27. 27. Thiazolidinediones Mechanism of Action The primary effect of TZDs is peripheral, with increasing insulin sensitivity and increased glucose uptake with much less effect on hepatic insulin sensitivity. Seventy percent of the insulin resistance seen in patients with T2DM is in the periphery and this shows the important role which the glitazones can play as compared to metformin which has its major action on the liver which accounts for only 30% of the insulin resistance.
28. 28. The Glitazones And The Beta Cell Beta cell failure begins more than a decade before diabetes is diagnosed [Kahn, Cell 1998 - Donath and Halban, Diabetologia 2004] Two mechanisms related to insulin resistance: glucotoxicity, lipotoxicity. glitazone therapy: - Delay or prevent beta cell failure? - growing body of evidence that TZDs rejuvenate beta-cells and improve their function [Bell, Am J Med 2003].
29. 29. The Glitazones And Diabetes Prevention TRIPOD (Azen et al, Control Clin Trials1998) and PIPOD (Xiang et al, Diabetes2006) studies.
30. 30. Glitazones and hypertension insulin resistance plays a role in leading to hypertension (Reaven et al, N Engl J Med 1996) (Natali et al, Endocrinol Metab Clin North Am 2004) the decrease in insulin resistance brought about by the glitazones should lead to a lowering of the raised blood pressure levels Studies carried out in patients with T2DM have shown a lowering of the blood pressure levels although this may not have been to a very significant extent (Rizza et al, Diabetes Care 2005) (Scherbaum et al, Diabetes 2001)
31. 31. Glitazones and inflammation Inflammations are thought to be one of the leading, if not the main, predisposing factors in the causation of atherosclerosis (Libby et al, Circulation 2002) (Mendall et al, Eur Heart J 2000) and even T2DM (Roivanen et al, Diabetologia 1998) (Pradhan et al, JAMA 2001) Pro-inflammatory markers such as hs-CRP, interleukin- 6, tumor necrosis factor-alpha and adipokines are associated with insulin resistance Glitazones have been shown in clinical studies to be associated with a significant lowering of these proinflammatory risk markers (Wang et al, Am J Cardiol 2004) (Satoh et al, Diabetes Care 2003).
32. 32. Glitazones and coagulopathy Insulin resistance and T2DM are associated with a pro-coagulant and anti- fibrinolytic status This is closely related to the early onset and rate of progression of macrovascular disease and increased cardiovascular risk (McGill et al, Diabetes 1994) (Imperatore et al, Diabetes Care 1998). Studies have shown that glitazones can improve these markers. (Kruszynska et al, Diabetes 2000) (Freed et al, Diabetologia 2000)
33. 33. Glitazones and the endothelium Insulin resistance in animals and humans has been shown to be associated with endothelial dysfunction. (van Oostrom et al, JR Soc Med 2002) (Celermajer, J Am Coll Cardiol 1997 Many studies have reported that the use of insulin sensitizers, especially the glitazones show a salutary effect on the various manifestations and consequences of endothelial dysfunction (Bagi et al, Am J Physiol Heart Circ Physiol 2004) (Cominacini et al, Cell Adhes Commun 1999) Interestingly, in a short trial, Murakami et al. reported that administration of troglitazone was associated with a substantial reduction in the frequency of episodes of angina in patients with coronar artery disease and T2DM (Murakami et al, Am J Cardiol 1999). . Moreover, these investigators found that the decrease in episodes of pain was correlated with angiographic (coronary) improvement in endothelial function.
34. 34. TZDs Problems Glitazones And CV Diseases IHD However, in the meta-analysis of the trials investigating the effect of rosiglitazone on CV end points, an increase of the risk of myocardial infarction by 43% was observed in patients treated with this medication (Nissen et al, N Engl J Med 2007).
35. 35. TZDs Problems Glitazones And CV Diseases Heart Failure Two meta-analyses were published in the September 12, 2007 issue of the Journal of the American Medical Association The first about pioglitazone included 19 randomized trials (Lincoff et al, JAMA 2007; 298:1180-1188 ) and the second about rosiglitazone included four randomized trials (Singh et al, JAMA 2007; 298:1189-1195 ) Both meta-analyses demonstrated highly significantly increased risk of serious heart failure with the use of the studied drug.
36. 36. Glitazones and the bones December 2006, the ADOPT trial reported a higher risk of fractures in diabetic women randomized to rosiglitazone than in women randomized to metformin or glyburide (Kahn et al, N Engl J Med 2006). This had been proved to be true in almost all big trials with glitazones. This has lead to both GSK as well as Takeda, manufacturers of rosiglitazone and pioglitazone, respectively, to issue warnings that these medications may cause an increased risk of fracture in women (GlaxoSmithKline, www.fda.gov {accessed 15 May 2007})
37. 37. ADA/EASD Consensus Statement Updated on Management of Type 2 Diabetes October 22, 2008 the tier 1 algorithm consisting of well- validated core therapies: Step 1 is lifestyle intervention and use of metformin Step 2 is to add another medication, either insulin or a sulfonylurea Step 3 involves starting or intensifying insulin therapy
38. 38. ADA/EASD Consensus Statement Updated on Management of Type 2 Diabetes October 22, 2008 The tier 2 algorithm consists of less well- validated therapies In these patients, adding exenatide or pioglitazone may be considered, although rosiglitazone is not recommended.
39. 39. 2010 Rosiglitazone was practically withdrawn Pioglitazone has been under investigations for a probable relationship with cancer bladder
40. 40. The Lessons The evidence should be derived from clinical studies with solid clinical end points rather than surrogate markers. The honor of time should be always respected.
41. 41. THANK YOU