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5 Things a Cardiologist Needs to Know About Diabetes 1 This Document Was Prepared TABLE of CONTENTS: Based on Presentations Prepared for PACE-Cme.Org By: 1 5 Things1. Natural history of diabetes: focus on microvascular and macrovascular complications 2. HbA1c in CVD 3. Key classes of antidiabetic drugs 4. T2DM and CV outcomes a cardiologist5. Hypoglycemia in CV medicine – why worry? needs to know about diabetes 1 Natural history of diabetes: focus on microvascular and macrovascular complications 2 HbA1c in CVD 3 Key classes of antidiabetic drugs 4 T2DM and CV outcomes 5 Hypoglycemia in CV medicine – why worry? www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 1 This document was prepared TABLE OF CONTENTS: based on presentations prepared for PACE-cme.org by: 1. Natural history of diabetes: focus on microvascular and macrovascular complications . 3 Prevalence, risk factors, progression and impact of diabetes . 3 Prof Kausik Ray, MD Imperial College London, Macrovascular and microvascular complications and their relationship . 3 United Kingdom New glucose-lowering agents . 3 Prof Naveed Sattar, MD 2. HbA1c in CVD . 4 University of Glasgow, United Kingdom HbA1c to diagnose diabetes . 4 HbA1c and micro and macrovascular complications . 4 Prof Cliff Bailey Effects of lowering HbA1c . 4 Aston University, Birmingham, United Kingdom Glycemic targets and CVD risk . 5 Prof Lawrence Leiter, MD 3. Key classes of antidiabetic drugs . 5 St. Michael’s Hospital, Toronto, Multiple causes contribute to the development of T2DM . 5 Ontario, Canada Medical therapy . 5 Prof Guntram Schernthaner, Metformin . 5 MD Sulfonylureas . 6 Rudolfstiftung Hospital, PPAR-γ agonists . 6 Vienna, Austria Incretins . 6 Alpha-glucosidase inhibitors . 6 SGLT2 inhibitors . 6 Insulin . 6 4. T2DM and CV outcomes . 7 CV outcomes in DPP-4 inhibitors trials . 7 More variation in results of GLP-1RAs trials . 7 SGLT2 inhibitors and CV outcomes in trials . 7 Effects of new drugs in the real world . 8 5. Hypoglycemia in CV medicine – why worry? . 8 Epidemiology of severe hypoglycemia in diabetic patients . 8 Which diabetic patients are at risk for development of severe hypoglycemia . 8 Associations of severe hypoglycemia with CV events and all-cause and CV mortality . 9 Pathophysiological CV consequences of hypoglycemia . 10 Strategies to avoid severe hypoglycemia in the treatment of diabetic patients . 10 References . 11 www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 2 microvascular disease: retinopathy, nephropathy, and 1. Natural history of diabetes: neuropathy. In a large United Kingdom (UK) cohort of focus on microvascular and ~40000 individuals, the association between microvascular macrovascular complications disease and CV events was examined.4 Individuals with 1 microvascular complication had a 35-40% increased CVD (CV death, non-fatal MI, stroke) risk, regardless of Prevalence, risk factors, progression and impact type of microvascular complication. An increase in the of diabetes number of microvascular complications resulted in a The prevalence of type 2 diabetes (T2DM) is increasing: stepwise increase in the composite of CV death, non-fatal 150-200 million new cases are predicted in the next 10-15 MI, non-fatal stroke, and also in hospitalization for heart years with the heaviest burden in less developed countries. failure (HF), CV mortality and all-cause mortality. Thus, Insulin resistance starts with weight gain and obesity, and the prevention of microvascular disease is very important, can lead to hyperinsulinemia, hypertension, abnormal lipid as it is an independent risk factor for CV events. Although levels, and altered clotting that can finally lead to T2DM. good control of blood pressure (BP), lipids and glucose All of these factors increase cardiovascular (CV) risk in reduces CV risk in diabetes patients, including those these patients. with microvascular complications, it is more important to An analysis of the Nurses’ Health Study1 showed that prevent development of microvascular disease. patients with a history of diabetes at baseline had the highest CV risk and those free of diabetes at baseline had the lowest CV risk. Interestingly, the two middle New glucose-lowering agents groups in this study suggested a latent period; CV risk It used to be assumed that lowering glucose in diabetes increased by ~180% prior to the diagnosis of diabetes and patients could reduce their CV risk. However, the first increased again by ~180% after the diagnosis of diabetes. five trials with glucose-lowering agents did not show The only difference between these middle groups was a reduction in the composite of CV death, non-fatal MI the time of diabetes diagnosis, suggesting that diabetes and stroke. A meta-analysis showed that a reduction of is a progressive disease. Indeed, there is a latent period 0.9% in HbA1c over 4.7 years resulted in a 17% reduction in which genetic susceptibility, environmental factors, in non-fatal MI, a 15% reduction in fatal and non-fatal sedentary lifestyle, obesity and inactivity contribute to MI, no reduction in stroke, and no reduction in all-cause an increased CV risk. Although it was initially thought mortality.5 It is possible that undesirable effects, such that diabetes is a CVD risk equivalent, it turns out that as weight gain and hypoglycemia associated with older this is not true in the early phase after diagnosis.2 This treatments may have offset some of their benefits is important, because in the beginning, it is possible to resulting in an increase in CV events. As a consequence, alter the course and trajectory of disease, for example by it is now requested that safety of novel glucose-lowering improving glycemic control. agents is demonstrated in large trials. The therapeutic When diagnosed with diabetes at the age of 40 years, a actions and CV outcomes of these new antidiabetic agents person loses half a decade of life, with half of the adverse are discussed in detail in chapter 3 and 4. events being vascular events.3 If one develops diabetes at Novel drug classes show a modest glucose-lowering effect. 90 years, there are fewer life years to lose. Therefore, a The results suggest that it matters how glucose is lowered. different therapeutic approach may apply to older patients While lowering glucose with insulin, sulfonylureas (SU) who are more vulnerable and frail compared to younger or DPP-4 inhibitors has not resulted in CV benefit, some patients, who have much more to gain in number of life newer agents have additional effects and favorably affect years. CV death, non-fatal MI and stroke. Microvascular disease in diabetes can be prevented by Macrovascular and microvascular complications blocking the renin-angiotensin system, either with an and their relationship ACE inhibitor or ARB. These drugs cause efferent arterial Chronic complications in diabetes include macrovascular vasodilation, resulting in reduced glomerular pressure disease: myocardial infarction (MI), stroke, need for and slowing down of the progression of nephropathy. The revascularization, and peripheral vascular disease; and SGTL2-inhibitor empagliflozin has a different mechanism www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 3 of action than ACE inhibitors and ARBs: a change in also recommended as a first line diagnostic test. If HbA1c hemodynamics delivers sodium to the distal convoluted testing is not possible, for instance if the patient has tubule, resulting in juxtamedullary apheresis and afferent hemoglobinopathy or abnormal red blood cell turnover vasoconstriction, which reduces the pressure on the (e.g in advanced renal disease or severe anemia), FPG is glomerulus. In the EMPA-REG OUTCOME trial, initially a recommended. rapid decline in estimated glomerular filtration rate (eGFR) Patients are considered at high-risk for DM if their HbA1c was observed, similar to that achieved with ACE inhibitors, is between 6.0% and 6.4% in the UK, and between 5.7% after which eGFR levels stabilized. This is in contrast with and 6.4% in the USA. At these values, patients should traditional glucose-lowering therapy, which shows a steady be informed about it and they should be given advice or progression and decline in eGFR. guided to make lifestyle changes to prevent the onset of diabetes, irrespective of whether they have existing CVD. HbA1c and micro and macrovascular complications 2. HbA1c in CVD In a curve displaying the prevalence of retinopathy at varying levels of FPG, the point of inflection above which 10 HbA1c is a measure used in diagnosis and management retinopathy starts to develop, is at 6.5-7% , while the of diabetes. HbA1c is glycated hemoglobin, which refers cut-off point in the diagnostic criteria is 7%. In a similar curve for HbA1c levels, the inflection point is around to hemoglobin bound to glucose. Measurement of HbA1c 6.5%, which concurs with the diagnostic criteria. 2-Hour levels reflects the average glucose level of the last 2-3 glucose levels do not show a clear inflection point.10 These months, since red blood cells survive for 8 to 12 weeks data show that HbA1c is a good demarcator for the risk before they are renewed. of developing retinopathy, which defines the diagnostic criteria for diabetes, as it reflects end-organ damage. A HbA1c to diagnose diabetes post-hoc analysis of the ADVANCE study has shown that To diagnose diabetes, three measurements can be microvascular event risk begins above HbA1c of 6.5%11, performed: fasting plasma glucose (FPG), HbA1c and oral again concurring with diagnostic criteria. 6 glucose tolerance test (OGTT). In the past decade, new HbA1c assays with better quality control and international For macrovascular event risk, inflection of the curve was standardization (to intra-assay coefficients of variation of seen at around 7%, and the risk increased at higher HbA1c typically less than 5%) have become available. levels.11 In patients without known diabetes, post-load An HbA1c assay is performed by collecting blood in EDTA, glucose is considered the best method to predict CHD. which remains stable during transportation for up to seven A meta-analysis has, however, shown that per 1 mmol/L days.
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