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Hyperglycemia management in patients with CVD Hashemipour .S MD Endocrinologist Qazvin University of medical science Outline • Acute setting: • New hyperglycemia vs known diabetics • Complications • Management • Chronic setting: • • • • Sulfonylureas Metformin Thiazolidendiones DPP-IV inhibitors Acute hyperglycemia in patients with acute myocardial infarction Definition • Threshold glucose concentration used to define acute hyperglycemia has ranged from 108 mg/dl to 200 mg/dl • In most of the recent studies, blood glucose of 180-200 mg/dl on admission is used to define acute hyperglycemia Circulation J,2012; 76:563–571 Relationship between admission glucose and mortality after AMI Hyperglycemia and mortality Am Heart J 2005; 150:814 – 820 Diabetic patients vs non-diabetics In metaanalysis by Capes et al. : • In patients without history of diabetes, blood glucose on admission ≥108–144 mg/dl :3.9 times mortality • In patients with diabetes, blood glucose ≥180200mg/dl: 1.7 times mortality . • This meta-analysis, however, included mostly older studies from the pre-reperfusion era or in the thrombolysis era Lancet 2000; 355:773 – 778. Findings From the Japanese Acute Coronary Syndrome Study (JACSS) Am J Cardiol 2009; 104:769 – 774. Why mortality in hyperglycemic non-diabetic patients is higher than diabetic ones? Mortality id diabetic vs nondiabetic patients • Acute fluctuation of the blood glucose is important for some mechanisms augmenting myocardial damage • Another possible explanation is a paradoxical resistance of diabetic hearts to ischemic challenge. Circulation J,2012; 76:563–571 Does Acute Hyperglycemia in NonDiabetic Patients Represent Previously Undiagnosed Diabetes? Undiagnosed DM in hyperglycemic patients whithout history of DM Eur Heart J 2006; 27:2413 – 2419 Is Acute Hyperglycemia a Cause or a Consequence of Severe Myocardial Damage? LVEF and hyperglycemia Am Heart J 2003; 146:674 – 678 Mechanisms by Which Acute Hyperglycemia Exacerbates Myocardial Damage Inflammation 3 consecutive pulses of intravenous glucose separated by a 2-h interval show increasing levels of cytokines in normal and IGT subjects but returned to normal as glucose returned to normal levels. Interestingly, when the first elevation in the blood glucose level was maintained by subsequent continuous intravenous glucose infusion, plasma cytokine concentrations gradually returned to normal Levels despite hyperglycemia Circulation 2002; 106:2067 – 2072 Apoptosis Apoptosis is enhanced in human umbilical vein endothelial cells exposed to intermittent, rather than constant, high glucose concentrations Am J Physiol Endocrinol Metab2001; 281:E924 – E930 Other mechanisms • • • • • Oxidative stress Endothelial dysfunction Hypercoagolability Platelet hyperactivity Impaired recondition Management of acute hyperglycemia IV insulin therapy 2 major questions. • Is insulin infusion or GIK infusion preferable for the management of acute hyperglycemia in patients with AMI? • What is the optimal goal of the blood glucose level for patients with AMI? DIGAMI 1 • An RCT on patients admission glucose ≥198mg/dl to ≥24-h • insulin-glucose infusion followed by subcutaneous insulin or routine antidiabetic therapy • Blood glucose in insulin-glucose in fusion: 172.8±59.4 mg/dl, in controls :210.6±74.8 mg/dl J Am Coll Cardiol1995; 26:57 – 65 • Mortality during the 3.4 years was 33% in the insulin-glucose group and 44% in the control group (P<0.011). • The mortality reduction by insulin-glucose infusion was most obvious in baseline glucose level >297mg/dl J Am Coll Cardiol1995; 26:57 – 65 CREATE-ECLA study • An RCT on 20,201 patients to fixed dose of GIK for 24 h or usual care • Most patients did not have hyperglycemia • The mean of baseline BG was 162mg/dl • Mean BG at 24h in GIK: 154.8mg/dl and in control:135mg/dl JAMA 2005; 293:437 – 446 CREATE-ECLA study • Results : high-dose GIK infusion had a neutral effect on mortality, or complications in patients with acute ST-elevation MI JAMA 2005; 293:437 – 446 Conclusion These 2 studies, as well as the other previous studies, suggest that blood glucose control using insulin, but not metabolic modulation by GIK, is important to improve the outcomes of patients with AMI and acute hyperglycemia Glucose target Glucose target • Prior ACC/AHA Guidelines ,(until revised in 2009), recommended insulin infusion to normalize blood glucose level in patients with ST-elevation MI as Class I in patients with complicated course complicated course, and Class II in patients without a complicated course. • Metaanalysis of the 7 largest randomized trials, in 6 of which the target glucose level was 80–110 mg/L, showed that intensive insulin therapy provided no survival benefit, but rather was associated with a higher incidence of hypoglycemia and increased morbidity. Chest 2010; 137:544 – 551 Glucose targets The current AHA/ACC guideline recommends the use of an insulin-based regimen to achieve and maintain a blood glucose level <180 mg/dl, avoiding hypoglycemia in patients with STEMI with either a complicated or uncomplicated course. J Am Coll Cardiol2009; 54:2205 – 2241 IV insulin infusion • Infusion Initiation: Start infusion at rate of 1–5 units per hour, depending on degree of hyperglycemia and insulin resistance Transferring a patient from SQ to IV insulin: divide 50% of the total daily insulin dose by 24 hrs for an hourly rate (depending on patient status/condition). IV insulin infusion • When patient is NPO :D5W solution at 75–125 cc/hr (unless patient is still very hyperglycemic i.e., >200 mg/dL) • Check BG Q1 hr for first 4–6 hrs until stable, then Q2 hrs. For prolonged infusions, if very stable, can decrease BG checks to Q4 hrs. Starting IV infusion Joslin Diabetes Center publication 2009 IV insulin infusion Joslin Diabetes Center publication 2009 Key massages • Complications of AMI are higher in patients wit new hyperglycemia vs known diabetics • BS fluctuations has detrimental effect on myocard • Beneficial effects of IV insulin is related to glucose control, not insulin per se • Glucose target<180mg/dl is appropriate for AMI setting Non-acute setting HbA1C target in patients with CVD Myocardial Infarction and Microvascular Disease UKPDS 10 years follow up Incidence per 1000 patient-years 80 60 Microvascular disease 40 Myocardial infarction 20 0 0 5 6 7 8 9 10 11 Updated mean HbA1c (%) UKPDS 35. BMJ 2000; 321: 405-12 HBA1C and CVD In ACCORD study, patients showed increased mortality when randomized to intensified treatment regimens that targeted normal A1C levels (<6.0%) with one or more of the following drugs taken alone or in combination: metformin, SFUs, TZDs, and insulin HbA1C target in patients with CVD Higher HbA1c goals (7.5–8.0%) or even slightly higher are appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced complications , established vascular disease Diabetes Care June 2012 , 6 1364-1379 Sulfonylureas • These agents induce closure of the adjacent potassium ATP-dependen receptors.While SUR1 is expressed in beta cells, SUR2A are expressed in cardiomyocytes. • The K- ATP channel in cardiomyocytes has an important function in its adaptation to cardiac ischemia. • Detrimental effect of Glibenclamide has been shown on cardiomyocyte adaptation to ischemia in animal models DIABETES CARE, 2009,s337-341 Sulfonylureas • In the UKPDS, combination therapyof metformin and sulfonylureas was associated with an increased risk of fatal MI (HR 1.79) • In a recent cohort study, sulfonylurea therapy was associated with 2.1 and 1.3 increased cardiovascular mortality with a for older sulfonylurea agents and glibenclamide respectively Sulfonylureas • The second mechanism for the higher risk of adverse cardiovascular effects associated with sulfonylurea involves hypoglycaemia—a common, well known adverse effect of sulfonylurea treatment. • Episodes of hypoglycaemia can prolong the QT interval and are associated with cardiac ischaemia Sulfonylureas • The third cause could be attributed to the weight gain and worsening obesity , together with the adverse consequences of this undesirable side effect All-cause mortality and sulfonylureas Lancet Diabetes Endocrinol 2014 Cardiovascular mortality and sulfonylureas Lancet Diabetes Endocrinol 2014 • Several limitations should be considered when interpreting our findings: First and foremost, selection bias could have affected the reported associations because data for these network meta-analyses were taken mainly from cohort studies. Glibenclamide & Glipizide : Interact with the cardiac and vascular SUR2A/B Glimepiride & Gliclazide : show very little interaction with SUR2A/B Metformin UKPDS Metformin Substudy Design Aim: to determine effect of metformin on outcome in overweight patients with type 2 diabetes Main Randomization 4209 Overweight 1704 Conventional Policy 411 Nonoverweight 2505 Intensive Policy 1293 Insulin or Sulfonylurea 951 UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Metformin 342 Metformin: post trial study • In the UKPDS, Metformin monotherapy in conjunction with diet decreased MI rates by 39% , compared with conventional therapy alone in overweight patients • Increased insulin sensitivity and enhanced fibrinolytic activity are possible explanations for this beneficial effect Thiazolidinediones Mechanism of action Thiazolidinediones • In PROactive study pioglitazone was examined for secondary prevention in patients with established macrovascular disease. • Post hoc analysis of the subgroup with previous MI demonstrated significant risk reduction of recurrent MI, or acute coronary syndrome Thiazolidinediones • Pioglitazone therapy is associated with reduced carotid IMT and reduced stent restenosis • However, cardiovascular outcome results can not be extrapolated from these data Thiazolidinediones • The meta-analysis by Nissen demonstrated an increased incidence of MI in patients treated with rosiglitazone Although not statistically non-significant, a trend of increased cardiovascular death (P 0.06) is a cause for concern. • In a subsequent meta-analysisby Singh et al. the data on increased MI was confirmed Weight gain, Edema & CHF with thiazolidinediones Weight gain Median weight gains with pioglitazone of 0.9, 1.0, and 2.6 kg at the 15, 30, and 45mg daily doses, respectively When pioglitazone added to insulin: Median weight gains of 2.3 and3.6 kg (or as high as 5.4 kg in some studies) occurred at 15 and 30 mg daily Edema • Mono-therapy: the incidence of pedal edema ranges from 3% to 5% for each of the TZDs. • The incidence is greater when the drugs are used in combination with other glucose lowering agents (6-7.5% with other OHA and 15% with insulin) • Higher incidence (up to 18%) when older age or comorbidities (HTN,IHD,CRF)exist DIABETES CARE,2004,27,256-263 Causes of edema • Increased plasma volume : may result from a reduction in renal excretion of sodium • TZDs may interact synergistically with insulin to cause arterial vasodilatation, leading to sodium reabsorption. • Increased sympathetic nervous system activity endothelial permeability DIABETES CARE,2004,27,256-263 CHF • In clinical trials using TZDs, the incidence of CHF was 1% for rosiglitazone monotherapy or in combination with sulfonylurea or metformin, and was similar to thatobserved during treatment with a placebo DIABETES CARE,2004,27,256-263 CHF in combination with insulin • Combination therapy of rosiglitasone 4mg or 8mg with insulin : CHF increased to 2% and 3% , respectively ( compared with 1% in the group treated with insulin alone) TZD in patients with CHF in another observational analysis of patients with class I to III CHF, and an ejection fraction of <45% who were treated with thiazolidinedione over a 2year period. Fluid retention: 17% Worsening CHF: 5.4% (worsening jugular venous distension) J Am Coll Cardiol41:1394–1398, 2003 PATHOGENESIS OF CHF WITH TZD USE • Increase in plasma volume is the main pathophysiology, either alone or superimposed on preexisting heart disease • Pioglitazone to a maximum dose of 60 mg q.d. for up to 48 weeks had no adverse effect on cardiac structure and function as evaluated by echocardiography. Diabetes 2000-(Suppl.1):A124 • Indeed ,improvement of left ventricular remodeling and partially normalized systolic function in mice after extensive anterior myocardial function after receiving pioglitazon is reported Circulation106:3126–3132, 2002 Recommendation Instruct the patient to report any new sign or symptom during the course of treatment: • Weight gain 3 kg • Pedal edema (particularly if the onset is acute and the amount progresses rapidly) • Shortness of breath or fatigue without other apparent cause Use of TZDs in Patients With Heart Disease In patients who are not functional class III & IV CHF but are known to have a depressed ejection fraction (e.g <40%), TZDs may be used at the lower dosage range of each drug and increased gradually during months with monitoring edema and other symptoms of CHF DPP-IV inhibitors Diabetes is a Multi-System Disorder: “The Incretin Effect” Liver Pancreas Suppressed postprandial glucagon Decreased Glucose Output Enhanced Insulin secretion GLP-1 release Food GLP-1 and other gut hormones released in response to food: “entero-insular axis” This ability is reduced or lost in type 2 diabetes Slowed gastric emptying Increased Satiety Actions of GLP-1 The Problem • Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme (very short half-life in plasma - requires continuous IV infusion). Who is ideal candidate for using DPP-4 Inhibitors? • Excellent in patients with mild hyperglycemia(especially postprandial hypoglycemia) requiring insulin secretagogue • Can be used in renal insufficiency without risk of hypoglycemia or lactic acidosis • Patients with heart failure ( no risk of edema or lactic acidosis) • Regarding relative short history of GLP1 and DDP4 inhibitors compared with other OAD, safety issues do not completely understood. GLP-1 and heart Data from animal models and pilot clinical studies have indicated that native GLP-1 may have cardioprotective effects in the setting of ischaemia, or following ischaemic injury Cardiovascular Diabetology2013,12:130 DPP-4 inhibitors and HEART • DPP-4 inhibitors do not have major effects on weight • Limited evidence suggests that sitagliptin may reduce systolic blood pressure • Can reduce postprandial hyperlipidemia • These drugs are not associated with QT interval prolongation DPP-4 inhibitors and HEART • Data about long term effects of DPP-IV inhibitors and cardiac outcome are very limited Key massages • Hb A1C target is higher in patients with CVD. • Sulfonylureas (especially older generations ) may has detrimental effect on CVD events • Metformin has beneficial long term effect on MI rate and all cause mortality • Data shows beneficial effects of pioglitazone on surrogate cardiac outcomes • Data about DPP-4 inhibitors is very limited