5 Things1. Natural history of : 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, ) 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 (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 , 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. Day-to-day intra-individual variation in HbA1c is higher FPG the risk ratio is 1.05, as for 1 mmol/L higher very low, making it a robust test. HbA1c can be measured post-load glucose, while the risk ratio was 1.20 for 1% anytime during the day, and fasting is not necessary. higher HbA1c.12 Moreover, unlike glucose testing, HbA1c is accurate The evidence presented above has been implemented in after a recent event and can be done for example in the the guidelines of the European Society of Cardiology (ESC) coronary care unit, when the patient is typically not fasted. on diabetes, pre-diabetes, and CVD.6 These guidelines As a consequence, some authorities now recommend recommend that the diagnosis of diabetes is based on measuring HbA1c to diagnose diabetes.7, 8 Some concerns HbA1c and FPG combined or on an OGTT if still in doubt remain regarding the sensitivity of HbA1c tests in (class I, level B recommendation). In most clinical scenarios, predicting DM, especially when HbA1c is <6.5%.9 HbA1c is likely to be tested, as patients have not been fasting. Diagnostic criteria now use a cut-off value of HbA1c of ≥6.5% (≥48 mmol/mol) for diagnosis of diabetes. If a Effects of lowering HbA1c patient meets this criterion, the HbA1c measurement Once a patient has been diagnosed with T2DM, HbA1c should be repeated to confirm the finding, unless the can be used as a measure of diabetes control. Lowering patient has clear symptoms and FPG >11.1 mmol/L. FPG is HbA1c decreases the risk of microvascular disease such

www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 4 as kidney and eye disease, and nerve disease, although people with diabetes, and some medications require dose this takes several years, and a modest effect is seen on adjustment or termination. macrovascular risk. Newer drugs that lower HbA1c can lower CVD beyond the effects of glycemia reduction. Mechanisms that may be involved include hemodynamic effects, effects on the 3. Key classes of antidiabetic drugs vasculature, weight reduction and BP reduction. An added advantage may be that patients stop taking drugs that After diagnosis of diabetes, glucose control is not the carry a risk of causing hypoglycemia, thereby contributing only factor that needs consideration, as CV risk and co- to avoiding its occurrence. morbidities also require attention. The aim of therapy The modest CV effect that can be achieved with lowering for T2DM is to improve glycemic control to reduce HbA1c, becomes clear when comparing observations in microvascular risk, and to lower macrovascular risk, mostly a study of 200 T2DM patients treated for 5 years that by control of lipids and BP. In addition, co-morbidities lowering HbA1c by 0.9% with glucose-lowering drugs such as obesity, depression, fatty liver, and microvascular prevented about 2.9 events, while lowering LDL-c by 1 complications like kidney, eye and neuropathic diseases mmol/L prevented about 8.2 events, and each 4 mmHg should be managed. lower systolic BP prevented 12.5 CV events.5 Thus, statins and BP-lowering medication have a greater effect on Multiple causes contribute to the macrovascular CV events than does glucose-lowering per se. development of T2DM Insulin resistance and inadequate insulin production Glycemic targets and CVD risk and secretion, among other problems all contribute to An HbA1c target of <7.0% or <53 mmol/mol is associated development of T2DM.13 The liver produces too much with a decreased frequency and severity of microvascular glucose, while the muscle does not receive enough of that disease. For macrovascular disease, a specific target is less glucose due to its insulin resistance. Often, excess adipose compelling, but hyperglycemia is positively associated with tissue is seen, which contributes to the proinflammatory increased CVD risk. HbA1c of <7.0% or <53 mmol/mol may state. And, because more glucose is filtered through the be targeted in the majority of patients, acknowledging the kidney, the kidney tends to adapt by reabsorbing more individual needs of the patients. When a patient has just glucose. On the other hand, there is inadequate insulin been diagnosed and is free from significant CVD and has production and often also excess production of glucagon. a long life expectancy and no other concerns, one should Moreover, there are various defects associated with the aim for 6.0-6.5% or 42-48 mmol/mol. By contrast, in an incretin effect, the microbiome is altered and there are elderly patient with long-standing and/or complicated various autonomic changes in the control of glucose disease, relaxing the target to 7.5-8.0% or 58-64 mmol/ regulation.13 As the hyperglycemia in T2DM is the result mol may be wiser, given that the benefits in terms of life of multiple factors, bringing the glucose level down to expectancy are less relevant. as close to normal levels as possible, requires multiple therapies. The first approach in the management of All targets should be achieved without inducing hyperglycemia in T2DM is lifestyle improvement, through hypoglycemia or other adverse effects.6 Glycemic control diet, exercise, health education and weight control. should be individualized in each patient, considering its effects on quality of life, adverse effects on polypharmacy and the possible inconvenience of intensified control. In Medical therapy each patient, the best individual compromise between Metformin glucose control and vascular risk should be searched for. Patients should be informed on the risks and benefits of Metformin is generally the preferable first-line oral anti- intensified treatment. glycemic agent. Metformin can counter the action of insulin resistance. Its actions are partly insulin-dependent, In addition to hypoglycemia, which increases the risk of and partly insulin-independent. Metformin can reduce severe CVD events (read more in chapter 5), one should hepatic glucose production and has a modest effect in be aware of chronic kidney disease. This is common in enhancing the uptake and oxidation of glucose in the

www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 5 muscle. It has an important effect on the intestine, to Altogether, these effects reduce hyperglycemia.14, 15 increase the anaerobic glucose metabolism and increase DPP-4 inhibitors are weight neutral, while the satiety that glucose turnover.13 is promoted with GLP-1RAs is helpful in achieving weight Advantages of metformin include that it does not cause loss. Both classes do not cause hypoglycemia. Potential CV weight gain and hypoglycemia. It tends to slightly lower benefits have been reported with DPP-4 inhibiting therapy basal insulin levels and it often improves the lipid profile and GLP-1RAs. Their use may, however, lead to pancreatitis and various vascular parameters. Metformin can cause and GLP-1RA treatment may also induce nausea.14, 15 some gastro-intestinal intolerance. When prescribing metformin, it is important to make sure that renal function Alpha-glucosidase inhibitors is adequate. If eGFR falls below 60 mL/min/1.73m² a dose Alpha-glucosidase inhibitors like acarbose are able to reduction should be considered, and treatment should be slow down the digestion of complex carbohydrates in the stopped when eGFR is below 30 mL/min/1.73m².13 intestine, which is another route to decreasing the post- Sulfonylureas prandial glucose excursion. Alpha-glucosidase inhibitors should be taken in Insulin secretion can be stimulated with sulfonylureas conjunction with a diet rich in complex carbohydrates. (SU) or meglitinides, of which the first ones are the Their advantages include that they do not cause weight longer acting ones, and the meglitinides the prandial gain, nor hypoglycemia. They may lower triglyceride levels. insulin releasers. These agents stimulate insulin secretion They can, however, cause gastro-intestinal disease and by acting on the K+ ATP channel on the surface of the flatulence.13 pancreatic β-cell. They induce weight gain and confer a risk of hypoglycemia SGLT2 inhibitors (see table 4).13 Sodium-glucose cotransporter-2 (SGLT2) inhibitors, act on PPAR-γ agonists the kidney. These glucosuric agents are able to suppress the reabsorption of glucose from the proximal tubule. Pioglitazone and other peroxisome proliferator-activated About 70-90 grams of glucose can be excreted via the receptor gamma (PPAR-γ) agonists mostly act on adipose urine per day, which not only reduces hyperglycemia in an tissue to increase adipogenesis and lipogenesis in insulin-independent way, but also lowers weight through peripheral adipose depots. In this process, by creating the loss of calories and it may create an osmotic diuresis, insulin-sensitive adipocytes, ectopic is taken away from which may contribute to the BP-lowering effect of SGLT2 other tissues. These agents increase insulin sensitivity inhibition.16 They do not cause hypoglycemia and have and rebalance the glucose-fatty acid cycle. They reduce potential beneficial effects on major adverse cardiac inflammation, and variable effects on lipids and reduction events and possibly on the kidney, as illustrated by the of some CV risk markers and events have been reported. effects on eGFR described above. The excreted glucose Adipogenesis results in weight gain. The onset of action is increases the risk of genital mycotic infections. Cases of slow, but there is no risk of hypoglycemia. Liver function diabetic ketoacidosis have been described when insulin should be checked, as well as NYHA risk. Fluid retention was reduced too much. In case of pioglitazone, a risk of HF 16 and edema can occur, and a risk of fractures and HF is has been described, as a consequence of edema. associated with the use of PPAR-γ agonists.13 Insulin Incretins If glycemic control cannot be achieved with each or all of Two types of incretins exist: the oral dipeptidyl the agents mentioned above, insulin therapy can be given. peptidase-4 (DPP-4) inhibitors (gliptins) and injectable Insulin affects many of the defects in T2DM; it lowers glucagon-like peptide-1 receptor agonists (GLP-1RAs). GLP- hepatic glucose production, increases glucose uptake in 1RAs not only enhance glucose-induced insulin secretion, the muscle, lowers lipolysis from adipose tissue, enhances but also suppress glucagon production and additionally protein anabolism and affects growth and differentiation. they have neural effects to promote satiety and to delay A disadvantage of using insulin is that it can induce gastric emptying. DPP-4 inhibitors prolong the life of hypoglycemia and that it causes weight gain. Insulin endogenous GLP-1 to increase the incretin effect. therapy should be correlated with diet and exercise,

www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 6 and requires monitoring of blood glucose. Various differences in the results of the trials testing them. formulations (rapid or short-acting and intermediate or The ELIXA trial on lixisenatide was done in post-ACS long-acting) and delivery devices exist.13, 15 patients21, the LEADER trial evaluated liraglutide22, and the SUSTAIN-6 trial tested semaglutide, which is given Thus, multiple treatment options should be employed once weekly.23 Both the LEADER and SUSTAIN-6 trials to get the glucose level as close to normal as possible, included patients with established CVD (80%) and patients and should be started as soon as possible in order to at high-risk for CV events (20%). The EXSCEL trial tested defer or prevent the development of microvascular exenatide, given once weekly, in patients with high risk complications and to contribute to the long term reduction for CVD.24 Thus, the study populations were fairly similar, in macrovascular complications. except that in ELIXA all patients had ACS and in the other trials 70-80% of patients had a history of CVD.

The ELIXA trial showed CV safety, but no superiority for lixisenatide, in contrast to the LEADER and SUSTAIN-6 4. T2DM and CV outcomes trials that showed significant reduction in the MACE endpoint. The LEADER showed a significant 14% reduction Since the US Food and Drug Administration (FDA) in the MACE endpoint for liraglutide, a significant mandated demonstration of CV safety for new reduction in CV mortality, and a non-significant reduction antihyperglycemic drugs, various trials evaluating DPP-4 in MI and stroke. A 25% reduction in the MACE endpoint inhibitors, GLP-1RAs and SGLT2 inhibitors on CV outcomes was observed in the SUSTAIN-6 trial for semaglutide. No have been completed or are ongoing. Results will be significant difference was seen in CV mortality. MI was briefly discussed and are summarized in table 1. significantly reduced and stroke was also reduced, but not significantly. No superiority was observed for exenatide in CV outcomes in DPP-4 inhibitors trials the EXSCEL trial in MACE, nor were CV mortality, MI and The DPP-4 inhibitors were the first class to have completed stroke altered. CV safety trials: the SAVOR trial testing saxagliptin, the Ongoing trials with GLP-1RAs are the FREEDOM trial EXAMINE trial with alogliptin, and the TECOS trial with evaluating a subdermal infusion pump, which is inserted sitagliptin.17-19 Although the populations in these studies every 3-6 months. A smaller phase 3 trial testing this were slightly different, all patients were at high risk for device demonstrated CV safety, but no superiority, CVD and the primary endpoint in these trials was major however the details of the trials are not published yet. adverse cardiovascular events (MACE) or MACE plus. The Other ongoing trials in high-risk populations are the overall results were quite consistent; HRs were (around) REWIND trial testing dulaglutide and the HARMONY 1.00. The drugs showed no superiority, but demonstrated OUTCOMES trial evaluating albiglutide given once-weekly. CV safety, thus complying with the FDA request. Completion of these studies is expected in the next 1 to 2 years. One difference between the results of these trials was the risk for HF; a significant increase was observed with SGLT2 inhibitors and CV outcomes in trials the tested drug in the SAVOR trial, the EXAMINE trial Two trials evaluating SGLT2 inhibitors have been showed a non-significant increase for HF, and in the completed to date: the EMPA-REG OUTCOME25 testing TECOS trial the HR for HF was 1.00.17, 18, 20 This difference empagliflozin and CANVAS26 testing canagliflozin. The in safety for HF is not understood. Two ongoing trials EMPA-REG OUTCOME exclusively included patients with with DPP-4 inhibitors are the CARMELINA study testing a history of CVD and in the CANVAS trial about two thirds linagliptin and the CAROLINE study evaluating linagliptin of patients had a history of CVD and one third were at risk vs. the SU glimepiride. The latter is the only trial of a new of CV events. In the EMPA-REG OUTCOME, the primary antihyperglycemic drug with an active comparator. outcome of 3-point MACE was significantly reduced by 14%, CV death was significantly reduced by 38%, non-fatal More variation in results of GLP-1RAs trials MI was non-significantly reduced and non-fatal stroke was GLP-1RAs show more pharmacological differences non-significantly increased. When looking at the graphs for amongst the drugs than other classes, resulting in more the incidence of CV death, over time an early separation of

www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 7 curves is apparent for empagliflozin vs. placebo; already ~17000 patients and the CREDENCE trial testing the effect within a few months empagliflozin gives reduction in of canagliflozin on renal outcomes. CV mortality.25 Similar results were observed for both empagliflozin doses tested (10 and 25 mg). Hospitalization Effects of new drugs in the real world for HF was significantly reduced by 35% and again an It is important to note that these studies were done early separation of curves for empagliflozin vs. placebo primarily in patients with known CVD. In the real world, only was observed. Safety data in the EMPA-REG OUTCOME 20% of patients with diabetes have a history of CVD.27 It trial showed a small increase in genital yeast infection, will be interesting to see the results of primary prevention both in men and women, no significant increase in volume of CV events in patients in the real world. The finding that depletion symptoms, no increase in acute kidney injury, no some new diabetes drugs give reduction in CV outcomes 25 differences in fractures/amputations. (canagliflozin, empagliflozin, liraglutide, semaglutide) should be translated to clinical practice: patients with diabetes and The CANVAS program, consisting of the pooled CANVAS known CVD should be prescribed therapies for which there is and CANVAS-R trials, showed a 14% reduction in the evidence of CV benefit. primary outcome.26 The individual components, CV death, non-fatal MI and non-fatal stroke were all reduced with canagliflozin, although non-significantly because there was not enough power. A significant reduction of 33% for HF hospitalization was seen with canagliflozin. In the CANVAS program, safety data showed an increase 5. Hypoglycemia in CV medicine – in genital yeast infections, a significant increase of why worry? symptoms of volume depletion, a two-fold increased risk of lower limb amputations and an increase in fractures.26 Epidemiology of severe hypoglycemia in Ongoing trials with SGLT2 inhibitors are the VERTIS study diabetic patients testing ertugliflozin in ~8000 patients at high risk for CV A recent study conducted in diabetes centers in Germany events, the DECLARE study evaluating dapagliflozin in and Austria evaluated the rate of severe hypoglycemia (SH) in 29 485 patients with T2DM treated with SUs.28 2.8% Of patients showed SH in their last year of SU treatment, Table 1 | Overview of trials with new classes of with an adjusted SH event rate of 3.9 (3.7-4.2) events per antihyperglycemic drugs and CV outcomes. 100 patient-years. Event rates for coma and hospitalization Class Trial Tested drug Primary CV were 1.9 and 1.6, respectively. SH event rates were highest endpoint superiority in patients who received SU and insulin (6.7), and lower DPP-4 in- SAVOR Saxagliptin 3-point No with SU and another oral antidiabetic drug (3.1) than with hibitors MACE SU alone (3.8). Risk for SH was particularly high in patients EXAMINE Alogliptin 3-point No with impaired renal function: the event rate was 7.7 in MACE those presenting with eGFR ≤30 mL/min/1.73m², 4.8 in TECOS Sitagliptin 4-point No those with eGFR between 30 and 60 mL/min/1.73m² and MACE 3.9 if eGFR was >60 mL/min/1.73m². Based on the data, GLP-1RAs ELIXA Lixisenatide 4-point No the authors noted that high risk of SH was associated with MACE lack of diabetes education, older age, decreased eGFR, but LEADER Liraglutide 3-point Yes MACE also with lower BMI, suggesting that SU treatment in those patients should be considered with caution.28 SUSTAIN-6 Semaglutide 3-point Yes MACE EXSCEL Exenatide 3-point No Which diabetic patients are at risk for MACE development of severe hypoglycemia SGLT2 in- EMPA-REG Empagliflozin 3-point Yes The Risk in Communities (ARIC) study hibitors OUTCOME MACE provided more insight into risk factors for developing SH CANVAS Canagliflozin 3-point Yes in adults with diabetes.29 In 1206 patients from the ARIC MACE study, 185 SH events were seen over a follow-up period

www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 8 of 15.2 years. After multivariable adjustment, important Associations of severe hypoglycemia with CV risk factors for developing SH were found, as summarized events and all-cause and CV mortality in table 2. When individualizing diabetes care for older Another analysis of the ARIC study data revealed that patients, these risk factors should be considered in the 3-year cumulative incidence of CHD after an SH event hypoglycemia risk assessment. A study in 58 223 Japanese was 10% and of mortality was 28.3%.32 Adjusted analyses patients with T2DM also assessed associations between revealed the increased risks of CV outcomes as shown in risk factors and SH events to elucidate potential predictors table 3. Hypoglycemia was not associated with stroke, HF, of SH.30 As in the American studies, age (multi-variable atrial fibrillation or non-CV and non-cancer mortality.32 adjusted HR per 10 years: 1.24, 95%CI: 1.02-1.52), diabetes duration (HR: 1.58, 95%CI: 1.14-2.20) and insulin treatment (HR: 7.05, 95%CI: 4.68-10.6) were associated with a Table 3 | Associations of severe hypoglycemia and CV statistically significantly higher risk for SH. In this study, outcomes in adults (mean age 64 years) with diabetes, based 32 the risk of SH was decreased in patients who received on the ARIC study. metformin (HR: 0.53, 95%CI: 0.35-0.80), pioglitazone (HR: Associations of severe Hazard ratio 95% Confidence 0.62, 95%CI: 0.39-0.96) or a GLP-1RA (HR: 0.26, 95%CI: hypoglycemia and CV Interval 0.04-1.85).30 outcomes

Coronary heart disease 2.02 1.27-3.20 In the ACCORD, ADVANCE and VADT studies, the intensive All-cause mortality 1.73 1.38-2.17 glucose control arms were associated with a significant CV mortality 1.64 1.15-2.34 increase of SH, as compared with standard glucose control Cancer mortality 2.49 1.46-4.24 (ACCORD: 16.2% vs. 5.1% in intensive vs standard glucose control, ADVANCE: 2.6% vs. 1.5%, VADT: 21.2% vs. 9.9%). The SH events seemed related to the use of insulin In the Japanese study mentioned earlier, a multivariate (ACCORD: final % on insulin therapy: 77% vs 55% with Cox proportional hazard model showed that SH was intensive vs standard glucose control, ADVANCE: 40% strongly and positively associated with the risk of CVD vs. 24% and VADT: 89% vs. 74%). The type of SUs used in (adjusted HR: 3.39, 95%CI: 1.25-9.18). They also evaluated the studies varied: glimepiride in ACCORD and VADT, and the association of SH with CVD risk in a propensity gliclazide in ADVANCE.31 score-matched cohort of patients with similar baseline characteristics for patients with SH and those without, and found that SH was indeed strongly associated with the risk of CVD (HR: 7.31, 95%CI: 1.87-28.6).30 Table 2 | Risk factors for severe hypoglycemia in adults (mean age 64 years) with diabetes, based on the ARIC In ADVANCE, the outcome of patients with SH was quite study.29 alarming: patients with SH showed a 3-4-fold risk of all-cause death (HR: 3.27, 95%CI: 2.29-4.65) and of CVD Risk factor for Hazard ratio 95% Confidence death (HR: 3.79, 95%CI: 2.36-6.08).33 Similarly, in the developing severe Interval hypoglycemia Veteran’s VADT study, SH was a strong predictor of CV death (HR: 4.04, 95%CI: 1.45-11.28) (unpublished data). In 5 Years increase in age 1.24 1.07-1.43 a large retrospective study conducted at the Mayo-Clinic Black race 1.39 1.02-1.88 in 1013 diabetic patients (79% Type 1 DM [T1DM], 21% Any insulin use vs. no 3.00 1.71-5.28 T2DM, mean age: 60.5 years and mean HbA1c: 7.3%), about medication 7.5% of patients reported SH.34 After 5 years of follow- Oral medication only vs. no 2.20 1.28-3.76 up, patients who reported SH showed a 3.4-fold higher medication mortality rate as compared with those who reported no or 34 Poor vs. good glycemic 2.60 1.70-4.10 mild hypoglycemia. In yet another study, the cumulative control incidence rate of CVD events in veterans was found to

Macroalbuminuria 1.95 1.23-3.07 be higher in those with vs. without hypoglycemia (both groups n=761, 1-year rate: 19.5% vs. 9.6%, 2-year rate: Poor cognitive function 1.57 1.33-1.84 29.10% vs. 15.9%, 3-year rate: 34.5% vs. 22.0%).35

www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 9 Although the increased incidence of SH in the ORIGIN trial levels of C-reactive protein, vascular endothelial growth in patients treated with insulin glargine as compared with factor and interleukin-6. These processes, together with controls (6.3% vs 1.8%) was not considered a big problem the sympathoadrenal response with increased level at the time of presentation of the results, study data were of epinephrine that lead to rhythm abnormalities and published later that showed that SH was significantly hemodynamic changes, may explain why hypoglycemia is associated with increased risks of CV death or nonfatal MI harmful for patients with established CVD.31, 40 or stroke (HR: 1.59, 95%CI: 1.24-2.03), total mortality (HR: 1.75, 95%CI: 1.39-2.19), CV death (HR: 1.71, 95%CI: 1.27- Strategies to avoid severe hypoglycemia in the 2.30) and arrhythmic death (HR: 1.77, 95%CI: 1.17-2.68). treatment of diabetic patients Interestingly enough, the relative risk of CV outcomes The question then rises whether the link between with hypoglycemia was lower with insulin glargine-based hypoglycemia and CV risk or mortality is causal or merely glucose-lowering therapy than with standard glycemic a correlation. In some cases a causal link between SH and control with metformin and SU. Thus, the ORIGIN results acute death indeed seems likely, for instance in case of would have been very different if patients in the control the ‘dead-in-bed-syndrome’. The two-fold increased risk group had received different antidiabetic drugs that do not of sudden death in patients with T2DM after MI could also induce hypoglycemia.36 be linked to SH. Moreover, the ADVANCE study has shown that diabetic patients with SH have a higher vulnerability UK Observational data show that both in patients with for all-cause and CVD mortality as well as for severe T1DM and T2DM, those who experienced hypoglycemia vascular complications. had a higher risk of experiencing CV events and all-cause mortality, irrespective of whether patients had a history of Irrespective of whether the association is causal; CVD.37 A retrospective cohort study evaluated the risk of preventive strategies to avoid SH are mandatory. This is stroke, CHD, congestive HF and mortality in 46135 patients particularly important in high risk situations of patients with CKD (of whom 85% had diabetes) who had two or with T2DM, including long duration of diabetes, presence more SH events. The risks of all these conditions were of macrovascular complications, acute MI/stroke, greatly increased in those with at least two SH events: impaired renal function (CKD), coronary revascularization, stroke HR: 11.6, CHD HR: 9.4, congestive HF HR: 11.2 and admission to intensive care unit, in case of unawareness to mortality HR: 33.0.38 hypoglycemia and finally at high age with hypovigilance.

39 Very recently, the DEVOTE study randomized 7637 Table 4 | Glucose-lowering drugs and the risk of patients with T2DM to insulin degludec or insulin glargine. hypoglycemia. SH occurred less frequent in the degludec than in the glargine group (4.9% vs. 6.2%, OR: 0.73, P<0.001 for Glucose-lowering drugs NOT Glucose-lowering drugs superiority). The risk of all-cause mortality and CV death associated with hypoglycemia associated with hypoglycemia was significantly higher in patients who had vs. who did Metformin Insulin not have SH (HR: 2.51, 95%CI: 1.79-3.50 and HR: 2.14, DPP-4 inhibitors Sulfonylureas 95%CI: 1.37-3.31, respectively). The risk of death was GLP-1RAs Glinides highest in the short term after SH (e.g. HR: 4.20, 95%CI: Pioglitazone 1.35-13.09 at 15 days after the SH event), and declined Acarbose/miglitol over time but remained statistically significantly elevated SGLT2-inhibitors throughout the study.39 A recent review41 discusses strategies to avoid SH in older Pathophysiological CV consequences of patients with T2DM. It states that the heterogeneity of hypoglycemia older patients must be considered and a need exists to Hypoglycemia induces abnormalities in blood coagulation, individualize all therapeutic strategies based on hyperactivation of platelets, neutrophil activation and specific factors that predict benefits and risks, including an increase of factor VIII. Endothelial dysfunction also the functional and cognitive status and the burden takes place, which reduces vasodilation. Finally, there is of co-morbidities. Nowadays, a number of glucose- an increase in inflammation, as reflected by increased lowering drugs are available that are not associated with

www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 10 hypoglycemia (summarized in table 4). These agents are References the preferred therapies in elderly patients with impaired kidney function who are at increased risk for SH, in order 1. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis to avoid the risk of CV events and mortality associated of type 2 diabetes. Diabetes Care. 2002;25(7):1129-34. with SH. 2. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56(4):686-95.

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5. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta- analysis of randomised controlled trials. Lancet. 2009;373(9677):1765- 72.

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12. Sarwar N, Aspelund T, Eiriksdottir G, Gobin R, Seshasai SR, Forouhi NG, et al. Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik prospective study and systematic review. PLoS Med. 2010;7(5):e1000278.

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www.pace-cme.org 5 Things a cardiologist needs to know about diabetes 11 17. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. 33. Zoungas S, Chalmers J, Kengne AP, Pillai A, Billot L, de Galan B, et Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. al. The efficacy of lowering glycated haemoglobin with a gliclazide N Engl J Med. 2015;373(3):232-42. modified release-based intensive glucose lowering regimen in the ADVANCE trial. Diabetes Res Clin Pract. 2010;89(2):126-33. 18. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 34. McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, diabetes mellitus. N Engl J Med. 2013;369(14):1317-26. Smith SA. Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes Care. 2012;35(9):1897-901. 19. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 35. Zhao Y, Campbell CR, Fonseca V, Shi L. Impact of hypoglycemia diabetes. N Engl J Med. 2013;369(14):1327-35. associated with antihyperglycemic medications on vascular risks in veterans with type 2 diabetes. Diabetes Care. 2012;35(5):1126-32. 20. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, 36. Investigators OT, Mellbin LG, Ryden L, Riddle MC, Probstfield et al. Heart failure and mortality outcomes in patients with type 2 J, Rosenstock J, et al. Does hypoglycaemia increase the risk of diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, cardiovascular events? A report from the ORIGIN trial. Eur Heart J. randomised, double-blind trial. Lancet. 2015;385(9982):2067-76. 2013;34(40):3137-44. 21. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, et 37. Khunti K, Davies M, Majeed A, Thorsted BL, Wolden ML, Paul SK. al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Hypoglycemia and risk of cardiovascular disease and all-cause Syndrome. N Engl J Med. 2015;373(23):2247-57. mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study. Diabetes Care. 2015;38(2):316-22. 22. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 38. Yu TM, Lin CL, Chang SN, Sung FC, Kao CH. Increased risk of stroke in Diabetes. N Engl J Med. 2016;375(4):311-22. patients with chronic kidney disease after recurrent hypoglycemia. Neurology. 2014;83(8):686-94. 23. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 39. Pieber TR, Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson Diabetes. N Engl J Med. 2016;375(19):1834-44. SS, et al. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia. 24. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, 2018;61(1):58-65. Buse JB, et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(13):1228-39. 40. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events. Diabetes Care. 2010;33(6):1389-94. 25. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 41. Schernthaner G, Schernthaner-Reiter MH. Diabetes in the older Diabetes. N Engl J Med. 2015;373(22):2117-28. patient: heterogeneity requires individualisation of therapeutic strategies. Diabetologia. 2018. 26. Neal B, Perkovic V, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(21):2099.

27. Iglay K, Hannachi H, Joseph Howie P, Xu J, Li X, Engel SS, et al. Prevalence and co-prevalence of comorbidities among patients with type 2 diabetes mellitus. Curr Med Res Opin. 2016;32(7):1243-52.

28. Schloot NC, Haupt A, Schutt M, Badenhoop K, Laimer M, Nicolay C, et al. Risk of severe hypoglycemia in sulfonylurea-treated patients from diabetes centers in Germany/Austria: How big is the problem? Which patients are at risk? Diabetes Metab Res Rev. 2016;32(3):316-24.

29. Lee AK, Lee CJ, Huang ES, Sharrett AR, Coresh J, Selvin E. Risk Factors for Severe Hypoglycemia in Black and White Adults With Diabetes: This document has been prepared and published by MEDCON The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. International (Publisher) on behalf of the PACE Foundation. No 2017;40(12):1661-7. part of this document may be used or reproduced or transmitted in any form or by any means without prior written permission of 30. Goto A, Goto M, Terauchi Y, Yamaguchi N, Noda M. Association the Publisher. Reprints may be requested with the Publisher. Between Severe Hypoglycemia and Cardiovascular Disease Risk in Japanese Patients With Type 2 Diabetes. J Am Heart Assoc. 2016;5(3):e002875. The educational program this report describes was independently developed under auspices of the PACE Foundation. This work was 31. Frier BM, Schernthaner G, Heller SR. Hypoglycemia and cardiovascular sponsored by an unrestricted educational grant provided by MSD risks. Diabetes Care. 2011;34 Suppl 2:S132-7. and Pfizer. The views expressed in this report are those of the individual 32. Lee AK, Warren B, Lee CJ, McEvoy JW, Matsushita K, Huang ES, et al. presenters and do not necessarily reflect the views of the PACE The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes. Diabetes Care. Foundation, the sponsor or the Publisher. For more information, 2018;41(1):104-11. videos of the lectures and speakers, visit PACE-cme.org.

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