Metformin. Sulfonylurea. Thiazolidinedione. Insulin

Transcription

1 동아의대내분비내과박미경

2 Metformin Sulfonylurea Thiazolidinedione Insulin 요약

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4 markers of inflammation (hs-crp, TNF-a) markers of impaired endothelial function (VFW, scams, tpa, PAI-1) LDL-C, fasting and postprandial TGs, and free fatty acids HDL-C reactive oxygen species(ros) advanced glycosylation end product (AGE) Arterioscler Thromb Vasc Biol 2006, 26: J Am Coll Cardiol 2001, 37(5): J Intern Med 2005, 258: Metabolism 2001, 50: Curr Diabetes Rev 2008, 4:

5 UKPDS

6 (fatal or non-fatal myocardial infarction or sudden death) Intensive (metformin) vs. Conventional glucose control HR (95%CI)

7 Intensive (metformin) vs. Conventional glucose control HR (95%CI)

8 Metformin effects on vasculoprotection Diabetology & Metabolic Syndrome 2013, 5:6

9 Improved glycemic control Reduction in methylglyoxal levels Decrease in VLDL secretion and plasma triglyceride levels Reduced postprandial lipaemia Improved endothelial dysfunction Reduced plasminogen-activator inhibitor 1 (PAI-1) levels Modest weight loss (2 3 kg) Diabetology & Metabolic Syndrome 2013, 5:6

10 Total patients Retrospective, controlled, cohort study Records of the NACM, the largest Belgian mutual health insurer J Clin Endocrinol Metab 101: , 2016

11 Survival J Clin Endocrinol Metab 101: , 2016

12 A meta-analysis for mortality in users of metformin in patients with HF Metformin - significant decrease mortality (HR 0.86, 95 % CI ) all-cause hospital admissions (OR 0.85, 95 % CI ) BMJ 2007; 335

13 After a series of reassuring observational studies on the absence of association with lactic acidosis, and potentially signs of reduced mortality in the heart-failure setting, the absolute contraindication to metformin use in heart failure was removed by the FDA in A systematic review of observational studies including patients concluded that metformin should be considered the treatment of choice in patients with diabetes and heart failure. Diabetes Care 2005; 28: , J Card Fail 2010; 16: Diabetes Care 2005; 28: , Circ Heart Fail 2013; 6: Lancet 2015; 385:

14 Does not exert adverse effects on CVD in T2DM patients Improves some CVRFs, metformin may reduce CVD morbidity and mortality

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16 Sulfonylureas - Fail to improve CVRFs No change in markers of inflammation or endothelial function - weight gain & hypoglycemia (be associated with increased CVD risk)

17 Outcomes Increase CVD events and mortality Tolbutamide, glyburide Glipizide, glimepiride UGDP. Diabetes 1976; 25: Especially, pronounced after AMI or angioplasty Diabetes Care 2008; 31: J Clin Endocrinol Metab 2012; 97: Arch Med Sci 2014; 10:

18 DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) trial, the patients treated with a sulfonylurea at the time of myocardial infarction were those with the poorest outcome. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997; 314:

19 a Change in risk compared with group allocated to diet only (conventional therapy). Cardiovasc Drugs Ther (2008) 22:

20 DIGAMI 2 Study Mortality rates (total, CV or from malignancies) Metformin SU Insulin Any drugs Diabetologia (2011) 54:

21 Diabetes, Obesity and Metabolism 17: , 2015.

22 Effects of Metformin Compared With Sulfonylurea Monotherapy on Long-Term All-Cause Mortality and Cardiovascular Mortality and Morbidity RR = relative risk HR = hazard ratio 2RCTs; ADOPT study, SPREAD-DIACAD study Ann Intern Med. 2016;164: 19 April 2016.

23 UK Clinical Practice Research Datalink, cohort SU +MET vs DPP4i + MET Can J Diabetes 39 (2015)

24 Danish individuals patients (59% men, mean age 60±13 years) Diabetes, Obesity and Metabolism 16: , 2014.

25 MH-OR, Mantel-Haenszel odds ratio Diabetes, Obesity and Metabolism 15: , 2013.

26 Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study Administrative health records from Alberta, Canada In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae. Journal of Diabetes and Its Complications 29 (2015)

27 Metformin in combination with various insulin secretagogues in type 2 diabetes and associated risk of cardiovascular morbidity and mortality A retrospective nationwide study Nationwide administrative Danish registries d i a b e t e s r e s e a r c h a n d c l i n i c a l p r a c t i c e ( )

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29 all-cause mortality Cardiovascular death the composite endpoint of acute MI, stroke and cardiovascular death Diabetologia (2015) 58:50 58

30 All-cause mortality Lancet Diabetes Endocrinol 2015; 3: 43 51

31 CV related mortality Lancet Diabetes Endocrinol 2015; 3: 43 51

32 The new Dutch type 2 guidelines specifically advise gliclazide as the preferred second line drug instead of SUs as a class. The World Health Organization (WHO) has also included gliclazide in their Model List of Essential Medicines 2013 motivated by its safety data in elderly patients. Expert Review of Clinical Pharmacology, ISSN: (Print)

33 Gliclazide vs other SU Diabetes research and clinical practice 110 (2015) 75-81

34 SU receptors pancreas (SUR1) myocardium (SUR2A) and blood vessels (SUR2B) Gliclazide & Glipizide: specific for pancreatic SUR1 receptors Glimepiride & Glibenclamide: not pancreas specific While glibenclamide has been found to be associated in abolishing myocardial ischemic preconditioning, glimepiride does not appear to interfere with this.

35 Since other sulfonylureas are readily available, and at a similar cost to the patient, continuing to prescribe glibenclamide seems inappropriate in view of its higher risk of hypoglycaemia and ability to abolish ischaemic preconditioning, even if the jury is still out regarding whether or not it is associated with a higher risk of adverse cardiovascular outcomes or mortality versus other sulfonylureas. Kevin M Pantalone, Cleveland Clinic Lancet Diabetes-Endocrinology Vol 3 January 2015

36 Saskatchewan Health, Canada Increased likelihood of admission to hospital for heart failure in sulfonylurea users than metformin users Cleveland Clinic Study Metformin were at lower risk of developing heart failure than were those treated with a sulfonylurea (HR 0 76, 95% CI ; p=0 003) sulfonylurea or thiazolidinedione ~ similar UKPDS Compared with metformin, second-generation sulfonylureas were more likely to develop heart failure with HRs that varied from 1 30 (95% CI ) when adjusted for age, diabetes duration, and sex, down to an HR of 1 18 ( )

37 Some evidences of increased risk for CVD (observational studies) esp, vs MET, DPP4i - Blocked ischemic preconditioning, hypoglycemia, weight gain... There has never been a completed randomized controlled trial (RCT) that specifically addresses the cardiovascular risk of SU treatment. Recently, completed RCTs (ADOPT, APPROACH, DIGAMI 2) that have included SU monotherapy arms have reported CV endpoints as safety analyses and found no consistent harm with SUs.

38 TOSCA.IT trial CAROLINA trial Diabetes, Obesity and Metabolism 17: , 2015.

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40 Reduce carotid intimal medical thickness Reduce neointimeal/vsmc proliferation, macrophage migration, and foam-cell formation Improve vascular reactivity and endothelial function Decrease vascular in ammation, CRP, and MMP-9 levels Increase thrombolysis and decrease PAI-1 Decrease blood pressure and microalbuminuria J. Preventive Cardiology Vol. 4 No. 4 May 2015

41 Cause fluid retention to uncover or worsen heart failure Outcomes Markers Pioglitazone composite endpoint of MI, stroke and death LDL-C hs-crp, TNFa sicam, CIMT Rosiglitazone? risk of MI LDL-C hs-crp, TNF-a

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43 RECORD trial Higher risk of death or HF related hospitalization (HR: 2.10, 95% CI: ) In 2013, re-evaluation of the CV outome no excess risk of CV events between rosiglitazone vs metformin/su in terms of the composite of mortality, MI, or stroke (HR 0.95, 95 % CI ), RECORD. Joint meeting of the Endocrinologic and metabolic drugs advisory committee RECORD trial. Lancet. 2009; 373:

44 July 17, 2013 Volume 310, Number 3

45 Replicated the meta-analysis of 4 RCTs (ADOPT, DREAM, RECORD, the Dargie et al) of greater than 12-month follow-up no MI was (95% CI, to 1.000) no death from cardiovascular causes was (95% CI, to 1.003) Pharmacoepidemiology and drug safety 2015; 24: Dargie et al. J. Am. Coll. Cardiol. 2007; 49(16):

46 PROactive: Reduction in primary outcome All-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke Proportion of events (%) % Relative risk reduction HR* 0.90 ( ) P = Placebo (572 events) Pioglitazone (514 events) *Unadjusted Time from randomization Number at risk Pioglitazone Placebo Dormandy JA et al. Lancet. 2005;366:

47 PROactive: Reduction in secondary outcome All-cause mortality, MI (excluding silent MI), stroke 25 Proportion of events (%) % Relative risk reduction HR* 0.84 ( ) P = Placebo (358 events) Pioglitazone (301 events) Number at risk Time from randomization Pioglitazone Placebo *Unadjusted Dormandy JA et al. Lancet. 2005;366:

48 PERISCOPE study Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation study Regression of coronary atherosclerosis as measured by a 0.16 % decrease in percent atheroma volume (PAV) compared with a 0.73 % increase with glimepiride (p=0.002) JAMA. 2008;299:

49 ACTOS Now for Prevention of Diabetes trial Decrease in CIMT progression ( mm/year) as compared to placebo group ( mm/year; p=0.01) Arterioscler Thromb Vasc Biol. 2013;33(2):393 9

50 IRIS Trial Investigators N Engl J Med 2016;374:

51 Primary outcome (fatal or nonfatal stroke or fatal or nonfatal myocardial infarction) N Engl J Med 2016;374:

52 N Engl J Med 2016;374:

53 Nutrition, Metabolism & Cardiovascular Diseases (2015) 25, 697e705

54 TZDs Signals of the potential CV harm (esp, rosiglitazone) reassurance except heart failure Pioglitazone Beneficial effect on CV risk (esp, ischemic strokes) Differences between rosiglitazone vs pioglitazone - Differences in lipid profiles? - Differences in potency of anti-inflammatory effects?

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56 Insulin is thought to enhance atheroma formation via increases in smooth muscle cells, LDL synthesis, and elevations in smooth muscle-lipid interactions. Insulin is also associated with weight gain, sodium retention, and elevated blood pressure. Diabetes Care. 1990;13(6): Diabetes Spectrum 2007, Volume 20, Number 3 N Engl J Med. 2005;353(25):

57 Insulin showed increased CV morbidity and mortality as compared to patients treated with diet, metformin, or sulfonylureas in patients with myocardial infarction and left ventricular dysfunction. Arch Intern Med. 2004;164: Insulin had an increased risk of CV mortality, all-cause mortality, and hospitalized HF in patients with chronic heart failure. Eur Heart J. 2006;27:65 75

58 UKPDS Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)

59 UKPDS (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI)

60 1 st Co-primary: MI, Stroke, or CV Death 2nd Co-Primary: MI, Stroke, CV Death, Revascularization, Heart Failure Adjusted HR = 1.02 ( ) P=0.63 by log-rank test Adjusted HR = 1.04 ( ) P=0.27 by log-rank test

61 Diabetes Care Volume 38, November 2015

62 insulin-treated vs non-insulin treated Conclusion Insulin treatment in these DM patients was associated with a significantly higher short and long-term adverse cardiovascular outcomes after PCI compared to those DM patients not treated by insulin therapy. Cardiovasc Diabetol (2015) 14:135

63 Short term CV outcomes <1 year Cardiovasc Diabetol (2015) 14:135

64 Long term CV outcomes 1 year Cardiovasc Diabetol (2015) 14:135

65 Several observational studies with insulin - more likely to develop heart failure - worse prognosis Eur Heart J 2006;27: Pacing Clin Electrophysiol 2008; 31: Arch Intern Med 2004; 164: Am Heart J 2005; 149:

66 UKPDS No difference in the incidence of HF standard vs intensive glycemic control groups SU/INS vs Metformin UKPDS 33. Lancet 1998; 352: UKPDS 34. Lancet 1998; 352:

67 BARI-2D trial No difference in the risk of heart failure insulin provision (SU/INS) vs insulin sensitisation (metformin/tzd) N Engl J Med 2009; 360:

68 2 RCTs and 6 cohort studies Different insulin regimens BMJ Open 2015;5:e

69 BMJ Open 2015;5:e006341

70 2 RCTs and 6 cohort studies Different insulin regimens Conclusion There is a need for more consistent high-quality evidence investigating the impact of insulin use on cardiovascular outcomes in patients with type 2 diabetes BMJ Open 2015;5:e

71 Some signals of the potential CV harm in several observational trials No increase risk in RCTs Very limited data on differences between insulin regimens

72 Metformin may have cardioprotective benefits Sulfonylurea suggested worsened outcomes ~ controversy suggested difference between SUs -- no RCT, need future studies

73 Thiazolidenedione Signals of the potential CV harm (Rosiglitazone) reassurance except heart failure Difference between rosiglitazone vs pioglitazone Insulin Some signals of the potential CV harm in observational trials No increase risk in RCTs

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75 Beyond metformin, there are limited data on the CVD outcomes.

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