Old oral antidiabetic agents in the armamentarium of diabetes mellitus treatment: Safety and efficacy

Transcription

1 Old oral antidiabetic agents in the armamentarium of diabetes mellitus treatment: Safety and efficacy Melpomeni Peppa Assistant Professor of Endocrinology 2 nd Dept of Internal Medicine-Propaedeutic, Athens University Medical School, Attikon University Hospital, Athens, Greece

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3 Therapeutic options 3 injectable agents such as GLP-1 receptor agonists (incretins), amylin analogues and insulin 3 new oral agents such as - DPP-4 inhibitors, bile acid sequestrants, dopamine-2 agonists, gliflozins 5 old oral agents such as biguanides, sulfonylureas, thiazolidinediones meglitinides, (glitazones), alpha-glucosidase inhibitors

4 Guidelines ADA & EASD, 2015

5 Old Oral antidiabetic agents- Are we reaching the target? old oral agents biguanides, alpha-glucosidase inhibitors sulfonylureas, meglitinides thiazolidinediones (glitazones)

6 Metformin

7 Metformin & UKPDS Study 3867 newly diagnosed patients with type 2 diabetes, median age 54 years 7 4% vs 8% Lancet 1998; 352:

8 Lancet 1998; 352: Metformin & UKPDS Study

9 Diabetes as a component of metabolic syndrome Metformin positively affects all the components of metabolic syndrome (decreases triglycerides, increases HDL, decreases SBP, improves or prevents the progression FLD)

10 Metformin action Ladeiras-Lopes R. Expert Opin. Ther. Targets [Early Online]

11 Metformin novel actions Ladeiras-Lopes R. Expert Opin. Ther. Targets [Early Online]

12 Metformin and cancer Kasznicki J. Ann Transl Med 2014;2(6):57

13 Metformin-Conclusion Metformin is efficacious and safe in the management of DM Side effects gastrointestinal (could be a problem) Metformin affects positively various comorbidities in DM (metabolic syndrome, cancer) Well studied medication, with no surprises Cheap (8E/month)

14 Acarbose Standl E. Diabetes & Vascular Disease Research 9(3)

15 Acarbose Standl E. Diabetes & Vascular Disease Research 9(3)

16 Acarbose and CVD risk 1429 patients with IGT STOP-NIDDM trial Standl E. Diabetes & Vascular Disease Research 9(3)

17 Sulfonylureas Stephen C. Bain. Endocr Pract. 2009;15:

18 Sulfonylureas

19 UKPDS study 3867 newly diagnosed patients with type 2 diabetes, median age 54 years 7% vs 7.9% Lancet 1998; 352:

20 Lancet 1998; 352: Sulfonylureas-UKPDS study

21 Sulfonylureas-UKPDS study Increase body weight Hypoglycemia

22 Sulfonylureas- Is Hypoglycemia an issue? Metaanalysis of 25 studies. 10.1% 0.8% J. E. Schopman Diabetes Metab Res Rev 2014; 30:

23 Sulfonylureas Is the risk for CVD an issue? UKPDS, no difference in the rates of MI or diabetes-related death among subjects receiving chlorpropamide, glyburide, insulin ADVANCE, no significant differences between intensive glucose control involving gliclazide in major macrovascular events, death from cardiovascular causes, or death from any cause. RECORD, no significant differences in the risk for cardiovascular events among combination therapy with rosiglitazone and metformin, rosiglitazone and SU, or metformin and SU. ADOPT, no, lower rates of cardiovascular events in patients taking glyburide than in those taking either rosiglitazone or metformin.

24 A meta-analysis of 62 trials reporting major CVD events with sulfonylureas vs various comparators the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of major cardiovascular events appears to be unaffected Diabetes, Obesity and Metabolism 15: , 2013.

25 Sulfonylureas and myocardiocytes

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27 Lancet Diabetes Endocrinol 2015; 3: 43 51

28 Simpson SH. Lancet Diabetes Endocrinol 2015; 3: Sulfonylureas and all-cause mortality

29 Simpson SH. Lancet Diabetes Endocrinol 2015; 3: Sulfonylureas and CV mortality

30 Tissue specificity of different Sulfonylureas Sehra D. Expert Opin. Drug Saf. (2011) 10(6):

31 Sulfonylureas-Extrapancreatic effects? Sehra D. Expert Opin. Drug Saf. (2011) 10(6):

32 Sulfonylureas- Conclusion SUs are an outmoded class of agents. Known efficcacy and side effects New safety concerns are not likely to emerge. Low cost 15-20E/month Appropriate patient selection is important, (be careful in patients who are elderly or frail, have a history of hypoglycemia or hypoglycemia unawareness, or have renal dysfunction or other conditions or comorbidities likely to place them at high risk).

33 Meglitinides Stephen C. Bain. Endocr Pract. 2009;15:

34 Thiazolidinediones

35 TZDs and mitochondrial target regulation of insulin sensitivity J. R. Colca Diabetes, Obesity and Metabolism 16: , 2014.

36 Pioglitazone-PROactive Study

37 Pioglitazone-PROactive Study

38 Data were collated on 1.01 million persons over 5.9 million person-years. The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer Diabetologia (2015) 58:

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40 an increased risk of fractures in women, effects of rosiglitazone and pioglitazone are similar, fracture risk is independent of age fracture risk has no clear association with duration of TZD exposure. Bone 68 (2014)

41 Warning! For rosiglitazone OCTOBER SUSPENSION OF LICENCE. Avandia is being withdrawn because of an increased risk of heart problems, including heart attacks and heart failure U.S. Food and Drug Administration (FDA), prompted the FDA to lift its restrictions on this agent but maintain specific warnings related to increased risks for congestive heart failure and bone fractures

42 Thiazolidinediones-Conclusion A class of drugs with excellent metabolic profile due to the strong impact on the insulin resistance Cost 20-30E/month should be used with caution in older patients in patients with heart disease, and in patients who are risk for fall and/or fracture, particularly in postmenopausal women. will be considered as third- or fourth-line options after combinations of other agents.

43 Metabolic memory

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