Does a GLP1 agonist, Liraglutide, or a SGLT inhibitor, Empagliflozin, have a lower risk of cardiovascular events and mortality in a type 2 diabetics with established atherosclerotic cardiovascular disease?Abstract:Practicing medicine is an art. Type 2 Diabetes Mellitus is a disease where clinicians exercise their artistic skills in choosing antihyperglycemic drugs to control patient’s blood sugars. How does a provider choose a 2nd line drug for a type 2 diabetic with uncontrolled blood sugars? The American Diabetes Association states patients with diabetes mellitus type 2 and established atherosclerotic cardiovascular disease, needs anti-hyperglycemic therapy starting with lifestyle management and Metformin and subsequently incorporate an agent proven to reduce major adverse cardiovascular events and mortality (currently empagliflozin and liraglutide). This paper discusses which is better, GLP1 agonist to SGLTi, for 2nd line agents in type 2 diabetics with established atherosclerotic cardiovascular disease. Based on separate research journals from New England Journal of Medicine, Empagliflozin and Liraglutide underwent research in recording cardiovascular outcomes and mortality in type 2 diabetes. In the empagliflozin and liraglutide study, both groups had significantly lower rates of death from cardiovascular causes, and death from any cause compared to placebo. However, there was no significant difference in rates of myocardial infarction or stroke for either drug compared to placebo. However, rates of hospitalizations for heart failure were nonsignificantly lower in the liraglutide group, and significantly lower in the empagliflozin group. Both drugs prove to significantly lower the risk of death for type 2 diabetic with established atherosclerotic cardiovascular disease. No clear definitive 2nd agent exists to combine with Metformin for dual therapy. A clinician must consider a 2nd agent’s efficacy of A1C reduction, route of administration, effect on weight, cardiovascular effects, cost, renal considerations, FDA BBW, risk of hypoglycemia, and patient wishes.Introduction:Practicing medicine is an art. Just as an artist studies, uses, and works with a variety of artistic mediums, so must a clinician know the array of mediums for managing and treating diseases. Clinicians know there is no perfect way to treat chronic human illnesses. It takes years for clinicians to master their craft of medicine. For Diabetes Mellitus type 2, a multitude of medicines exist for controlling blood sugar.  Physician Assistants must choose their pharmaceutical tools carefully, with patient wishes in mind, in how they’ll paint a treatment plan for their individual patients. Diabetes and its management is important to discuss because it poses a significant health burden to the nation. 30.0 million people or 9.4% of the US population lives with diabetes.1 Approximately 1.5 million new cases of diabetes were diagnosed in 2015 in patients 18 years old or older.1 The CDC predicts by 2050 the incidence of diabetes could scope one in three adults by 2050.2,3 This is alarming because diabetes is currently the seventh leading cause of death.2 Will it be the leading cause of death by 2050? Type 2 diabetes is a risk factor for cardiovascular disease, and it’s also the leading cause of death in diabetics.4  It’s evident diabetics need protection against cardiovascular events, especially if they already have established cardiovascular disease. Usually Metformin is the first-line medication for type 2 diabetics. A plethora of add-on options could be considered, such as glucoagon-like-peptide-1 (GLP-1), sodium-glucose-cotransporter 2 (SGLT2) inhibitors, or dipeptidyl peptidase-4 (DPP4) inhibitors. The American Diabetes Association states patients with diabetes mellitus type 2 and established atherosclerotic cardiovascular disease, needs anti-hyperglycemic therapy starting with lifestyle management, Metformin, and then add-on an agent proven to reduce major adverse cardiovascular events and mortality (currently empagliflozin and liraglutide).5 Physician Assistants need to know how these two drugs effect cardiovascular events and mortality, because they can help lower the risk of those events and mortality for diabetic patients. No clear drug is a definite second line agent to combine with metformin for dual therapy. 2 Physician Assistants have to consider factors like A1C reduction, risks of hypoglycemia, cardiovascular effects, cost, effect on weight, renal considerations, and route of administration when selecting a add-on agent..2 The mechanism of action of glucoagon-like-peptide-1, liraglutide (VICTOZA) binds to GLP-1 receptors and stimulates insulin release, slows gastric emptying, and reduces postprandial glucagon4. Sodium-glucose-cotransporter 2 inhibitors, empagliflozin (JARDIANCE), block glucose reabsorption in proximal renal tubule’s, causing renal excretion of glucose and lowering blood glucose.4 This paper examines the risk of cardiovascular events and mortality in a type 2 diabetic with established atherosclerotic cardiovascular disease taking either GLP-1 or SGLT inhibitor in conjunction with metformin.Methods:In searching for information for antihyperglycemic agents and cardiovascular outcomes, I used The New England Journal of Medicine, Journal of the American Academy of Physician Assistants, and the American Diabetes Association website. Key words I used in searching included Sodium-glucose-cotransporter 2 inhibitors, glucoagon-like-peptide-1, major adverse cardiovascular events for SGLT2i and GLP1 agonists, second line agent for type two diabetic with established cardiovascular disease. A majority of information came from the original trial articles from The New England Journal of Medicine.  The EMPA-REG trial  observed 7020 patients over a 3.1 year period7. EMPA-REG was a randomized, double blinded, placebo-controlled trial. The effect of empagliflozin, 10mg or 25mg once daily, was assessed “compared to placebo on cardiovascular events in adults with type two diabetes at high cardiovascular” risk while receiving standards of care.7 The primary outcome was the total number of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.7 The secondary outcome was the primary outcome plus hospitalization for unstable angina.7 The trial also analyzed changes from baseline in hemoglobin level, systolic and diastolic blood pressure, weight, cholesterol, waist circumference, and heart rate.7 The trial continued until a primary outcome event had occurred in 691 patients.7 Inclusion criteria included body mass index of less than 45, at least 18 year of age, GFR more than 30, A1C of at least 7 and no more than 9 and “had received no glucose lowering agents for at least 12 weeks before randomization, or had received glucose lowering therapy for at least 12 weeks before randomization and had A1C of at least 7 and no more than10”, and all had cardiovascular disease.7  Follow up visits occurred  at week 2, month 3, every 12 weeks until end of trial and 30 days after the end of treatment.7 The LEADER trial observed 9340 patients over a mean of 3.8 years. LEADER was randomized, double blinded placebo-controlled trial to “assess the long-term effects of liraglutide, 1.8mg, on cardiovascular outcomes and other clinically important events”.8 The primary outcome was analyzed by time-to-event of the “first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stoke”.8 Inclusion criteria included age greater than 50 years old with at least one cardiovascular condition (coronary artery disease, stoke, peripheral vascular disease, chronic kidney disease stage 3 or more, and chronic heart failure grade 2 or 3), or age greater than 60 with at least one cardiovascular risk factor,  (microalbuminuria, proteinuria, hypertension, left ventricular hypertrophy, ankle-brachial index less than 0.9, or left ventricle dysfunction).8  Follow up visits were month 1,3,6,and every 6 months after.8 ResultsTable 1: Primary & Secondary Cardiovascular Outcomes in EMPA-REG trialThe EMPA-REG results were as follows: primary outcome occurred 10.5% in the empagliflozin group than in placebo 12.2%, which is significantly lower.7 The secondary outcome occurred in 12.8% in the empagliflozin group and 14.3 in placebo.7 Compared to placebo, empagliflozin had lower risk of death from any cause, cardiovascular cause, or hospitalization for heart failure.7 According to Tat, Empagliflozin has 32% reduction in death from any cause, and 38% composite reduction in death from cardiovascular causes, and heart failure or cardiovascular hospitalizations compared to placebo.2 Surprisingly there was no difference in incident of myocardial infarction or stroke between groups.7 4.8% of patients on empagliflozin compared to 5.4% on placebo had myocardial infarctions, and 3.5% to 3.0% respectively had strokes.7 A1C range improved 0.54 to 0.6 percent compared to placebo.7 Cardiovascular risk factors such as reduction in weight, waist circumference, uric acid level, and blood pressure all decreased slightly, but a increase in both LDL and HDL cholesterol occurred.7 Rate of genital infection increased in the empagliflozin group compared to placebo.7 The number to treat to prevent one death is 39 in a three year period.7 In the LEADER trial, primary outcome of 13.0% liraglutide to 14.9% placebo occurred.8  4.7% to 6.0% respectively had cardiovascular related death, and 8.2% to 9.6% respectively was the rate of death by any cause.8 Liraglutide had a 22% in relative risk reduction of cardiovascular death, and 15% relative rate of reduction of all-cause death.9 There was no significant difference in groups for frequency of nonfatal myocardial infarction and nonfatal stroke.8 The liraglutide group’s A1C improved by 0.4% on average, weight loss averaged 2.3kg, systolic blood pressure decreased by 1.2mm Hg, and diastolic increased by 0.6mm Hg.8 The most common adverse effect was gastrointestinal events.8 The black box warning for liraglutide is risk for thyroid C-Cell tumors.2 The number to treat to prevent one primary outcome event in three years is 66, and 98 for death of any cause.8 According to Busko, patients who received a SGLT2 inhibitor had 1% lower rate of death and a 0.8% lower rate of cardiovascular death than placebo.10 Busko also states patients who received a GLP1 agonist had 0.6% lower risk of death and 0.5% lower risk of cardiovascular death compared to placebo.10 Table 2: Primary & Secondary Outcomes in LEADER trialDiscussion:There is no exact second line pharmaceutical agent for diabetics with established cardiovascular disease. The American College of Endocrinology and American Association of Clinical Endocrinologists states lifestyle modifications including medical assisted weight loss is first line, then monotherapy with metformin when initial A1C less than 7.5%.2  The order of preference for alternative monotherapy are as follows: GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, alfa-glucosidase inhibitor, and sulfonylurea.2 If target A1C isn’t achieved in 3 months of monotherapy then a second agent is added.2 Order of preference includes: GLP-1  receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, thiazolidinedione, basal insulin, and sulfonylurea as the sixth choice.2 No head to head trial exists comparing cardiovascular events on Liraglutide or Empagliflozin. However, the results from the EMPA-REG and LEADER trials provide important statistics for diabetics with cardiovascular disease. Empagliflozin and Liraglutide both significantly lower the rate of cardiovascular death and all cause of death. The FDA has approved Liraglutide and Empagliflozin for the indication of reducing cardiac mortality in adults with type 2 diabetes and established cardiovascular disease.4 Empagliflozin seems to have a better reduction of morality than compared to the Liraglutide. However, different patient populations can benefit from one drug compared to the other. For example, Empagliflozin is better for a diabetic with heart failure, and sustained kidney function better than stage 4. Liraglutide is better for patients with deteriorating kidney function, or who’d rather inject themselves than take a pill.  Empagliflozin has potential benefits for reducing risk of hospitalization for heart failure and nephropathy.4 Liraglutide offers benefits to reduce nephropathy too.4 This paper simply focused on two therapy agents while the approach to treating diabetic is multidimensional. Hemoglobin A1C, weight loss, blood pressure, administration route, cost, potential side effects, and patient preference are a few examples of the variables needing consideration to individualize treatment.  Even the American Diabetes Association states “aggressive management of cardiovascular risk factors like blood pressure, lipid therapy, antiplatelet treatment and smoking cessation” is likely to have greater benefits than strict glycemic control.6 Empgliflozin improved A1C and blood pressure, and is cheaper compared to Liraglutide. Liraglutide improved weight loss better than empagliflozin and is FDA approved for weight loss5. Interestingly, neither drug reduced the rate for non-fatal myocardial infarction or non-fatal stroke. Further trials are needed to discover why the rate of non-fatal myocardial infects and stroke did not improve. More data needs to evaluate cardiovascular mortality and morbidity in patients with low cardiovascular risk. In the eyes of the consumer, taking these drugs won’t decrease the risk of them having the heart attack or stroke, it only decreases the chance of dying from a cardiovascular event. Due to the mechanism of action of SLGT2i, the hemodynamic changes to blood volume and sugar excretion may be a leading cause of the observed benefits.  Perhaps the GLP-1 mechanism slowing gastric emptying and reducing postprandial glucagon is why greater weight loss occurred. Medical clinicians need to build a patient-centered approach to guide the choice of pharmaceutical agents. Further research needs to be conducted to know if the findings from EMPA-REG and LEADER can translate to other drugs in their respective class of medications?  Can other GLP-1 agonists have similar cardiovascular protection since Liraglutide proved it’s benefit? Can all SGLT2 inhibitors reduce the rate of hospitalizations for heart failure patients? In contrast, can the adverse effects of each drug be slapped on all other drugs within the respective classes of drugs? If all SGLT2 inhibitors increase the risk of genital infections, and have similar adverse effect profiles, can one SGLT2 inhibitor black box warning be generalized to all SGLT2 inhibitors?  Further research needs to investigate the amputation rate and safety of Empagliflozin, and other drugs of the SGLT2 inhibitors.  These results are successful landmarks to a bright future of preventing mortality while applying standards of care. In conclusion, either one of these drugs should be second line for a type 2 diabetics with established cardiovascular disease. Patients and their physician assistant have the resources of information to make informed decisionsBibliography:Center for Disease Control and Prevention. National Diabetes Statistics Report, 2017. www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed September 29, 2018.Tat V, Forest C. The role of SGLT2 inhibitors in managing type 2 diabetes.JAAPA.2018; 131(6): 35-40.Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popil Health Metr. 2010; 8:29.Covino J, Hoffman J. What are the cardiovascular effects of the newer classes of drugs for type 2 diabetes? JAAPA; 31 (3): 12-14.Riddle MC, Makris G, Blonde L, et al. American Diabetes Association. Standards of Medical Care in Diabetes -2018. Diabetes Care. 2018; 41:  51 – 100.Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012; 35 (6): 1364 – 1379.Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular outcomes, and mortality in itype 2 diabetes. N Engl J Med 2015;373:2117-28.Marso SP, Faniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375 (4): 311-322Novo Nordisk. Victoza liraglutide injection. Prescribing information V10.1. 2017. 1-11.Busko, M. Two New Drug Classes Tied to Better Survival in Type 2 Diabetes – Medscape – Apr 18, 2018. https://www.medscape.com/viewarticle/895331?src=WNL_infoc_180819_MSCPEDIT_TEMP2&uac=282512MN&impID=1714694&faf=1#vp_2