Expired activity
Please go to the PowerPak homepage and select a course.

Cardiovascular Outcome Trials (CVOTs): Practical Considerations for your Type 2 Diabetes Patients (Article)

INTRODUCTION

Patients with type 2 diabetes mellitus (T2DM) are at high risk for cardiovascular disease (CVD). The United States (U.S.) is slowly improving prevention strategies for T2DM, which has led to a lowering of the risk of CVD over the last 20 years.1 Unfortunately, according to data from the National Health and Nutrition Examination Survey, as of 2010, people with diabetes, most of whom have T2DM, have an estimated 6- to 8-fold higher risk of CVD outcomes than people without diabetes.1

Diabetes is a cardiometabolic disorder in which both microvascular and macrovascular complications contribute to morbidity and mortality.2 Hyperglycemia is the major risk factor for microvascular complications (i.e., retinopathy, nephropathy, and neuropathy), but more than a decade of poor glycemic control may be required to significantly contribute to macrovascular complications (e.g., myocardial infarction [MI], stroke).3,4 Classic cardiovascular (CV) risk factors such as hypertension, dyslipidemia, a procoagulant state, obesity, endothelial dysfunction, insulin resistance, and inflammation should be addressed in at-risk T2DM patients; if risk factors are aggressively managed, the risk of poor CVD outcomes can be reduced.

The Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes (Steno-2) study enrolled T2DM patients with microalbuminuria and treated them aggressively using either an algorithm for glycemic, blood pressure, and lipid control or standard of care. Within 4 years, the risk of retinopathy or nephropathy was significantly reduced and there was a 20% reduction in macrovascular outcomes in the aggressively treated group.5 The reported risk of death in the aggressively managed group decreased (p < 0.02) over 13 years of follow-up.5,6

There are 2 important considerations related to the Steno-2 study. First, the CV results of Steno-2 were unlikely influenced by short-term glycemic control. (This is also true for the cardiovascular outcome trials [CVOTs] that will be discussed in this module.) Evidence to prove this point is well documented in the Action in Diabetes and Vascular Disease (ADVANCE),7 Action to Control Cardiovascular Risk in Diabetes (ACCORD),8 and Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT)9 trials. All of these studies enrolled T2DM patients with an increased risk of CVD and randomized them to receive either standard of care or intensive glycemic control. Within 1 year of randomization, patients in the intensive treatment and standard of care groups of the ACCORD trial had achieved hemoglobin A1c (A1C) levels of 6.4% and 7.5%, respectively. Despite this difference, the ACCORD trial was stopped early, since a significantly increased risk of mortality was observed.8 Even with up to 5 years of follow-up, no reductions in CVD risk were reported in any of the 3 trials, despite excellent improvements in glycemic control.

Second, despite the CVD advantage of intensive risk factor management in the Steno-2 study, 24 deaths, non-fatal strokes, or MIs were recorded in the aggressively treated group.5,6 A residual CVD risk remained, despite intensive therapy, and a more effective prevention strategy may be needed to decrease this residual risk. Newer antihyperglycemic medications have the potential to decrease the residual risk of CVD, but well-controlled trials exploring the CVD effects have traditionally been lacking. This module will discuss the use of antihyperglycemics for the prevention of CVD in patients with T2DM, as well as briefly discuss potential mechanisms of protection and adverse effects related to the antihyperglycemic agents.

U.S. FOOD AND DRUG ADMINISTRATION AND OUTCOME TRIALS

Until the end of 2008, there was no mandate from the U.S. Food and Drug Administration (FDA) to conduct CVOTs for new antihyperglycemics seeking approval. This changed after several medications, including FDA-approved rosiglitazone10 and FDA approval-pending muraglitazar,11 encountered much controversy because of their potential CVD risks. In response, the FDA issued guidance that required CVOTs for all new antihyperglycemic medications that had not yet been approved. The requirement stated that all new antihyperglycemics should demonstrate glucose lowering and exclude clinically meaningful increases in major adverse CV events. When phase II/III trials are submitted to the FDA, the upper 95% confidence interval (CI) for the relative risk of major adverse cardiac events (MACE) should not exceed 1.8; if it exceeds this threshold, a CVOT will likely be required prior to marketing approval. If the upper 95% CI for the risk of MACE outcomes exceeds 1.3 at the completion of the CVOT, the medication will likely be at risk of restriction or removal from the market. Trials performed to assess CV safety must: 1) include patients with increased CVD risks, 2) be of adequate duration to detect adverse CVD effects, 3) include independent CV endpoint committees, and 4) submit a protocol to the FDA prior to beginning the trial that outlines planned statistical analyses and endpoints of interest.12

CVOTs conducted prior to FDA guidance

Clinicians have long been interested in whether antihyperglycemics may decrease the risk of CVD in patients with T2DM. CVOTs conducted prior to FDA guidance were primarily conducted to prove safety or CVD risk reduction; they were not required by or reviewed by the FDA.

Metformin

No well-controlled CVOTs have been conducted with metformin, though results of many observational trials have been published. In the United Kingdom Prospective Diabetes Study (UKPDS), metformin use in obese T2DM patients reduced total mortality, but this study was conducted before statins were widely available, before tight blood pressure control was recommended, and before the use of antiplatelet therapy was commonplace. Also, the risk of MI with metformin use did not diverge from the risk of MI with intensive therapy (with sulfonylureas and insulin) until 6 to 9 years of follow- up.13 In the Bypass Angiography Revascularization Investigation in Type 2 Diabetes (BARI-2D) trial, patients who underwent revascularization with coronary artery bypass graft had a lower incidence of major CV events if they were on insulin sensitizers (metformin and/or thiazolidinediones) than patients who received other treatments. However, this finding cannot be exclusively associated with metformin’s effects.14

Thiazolidinediones

All CVOTs for thiazolidinediones were completed prior to FDA guidance, and they have proved to be the most controversial trials for diabetes medications that have been conducted. In a meta-analysis, rosiglitazone was first reported to increase the risk of MI (odds ratio 1.43, 95% CI 1.03-1.98; p = 0.03) and increase the risk of CVD death (odds ratio 1.64, 95% CI 0.98-2.74; p = 0.06).10 On the basis of this and several other published meta-analyses that confirmed a higher risk of CVD, rosiglitazone use was restricted in the U.S. and the European Medicines Agency suspended use of the drug.

The Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial was completed to show that rosiglitazone did not, in fact, increase the risk of ischemic events. For patients with T2DM whose glycemic levels were uncontrolled on metformin and sulfonylurea therapy, rosiglitazone was added to therapy in an open-label design with a primary endpoint of neutrality on CVD or hospitalization. After 5.5 years of follow-up, non-inferiority criteria were met for the primary outcome (hazard ratio [HR] 0.99, 95% CI 0.85-1.16).15 Despite this result, the trial was widely criticized for being under-powered and the sponsor was even accused of altering data.16 After a separate, independent analysis of the data by scientists at Duke University, it was determined that the sponsor’s results were accurate, and, as of 2013, restrictions for rosiglitazone prescribing were removed. A black box warning remains on its labeling to advise of the increased risk of congestive heart failure, and “ischemic events” are now listed in the warnings in the package insert.17

In contrast to rosiglitazone, pioglitazone has never been shown to increase the risk of ischemic events. In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), pioglitazone 45 mg or placebo was administered to 5238 T2DM patients with diagnosed CVD; the trial included approximately 3 years of follow-up.18 The primary endpoint was a composite of atherosclerotic events, which was not significantly reduced (relative risk reduction 10%; p = 0.095), but a significant risk reduction (16%) in the second primary outcome of all-cause mortality, MI, or stroke was reported. The primary endpoint included peripheral revascularizations and amputations, which occurred slightly more often in the pioglitazone group.18 Pioglitazone, in patients who previously had a stroke, significantly reduced the risk of fatal or non-fatal stroke (HR 0.53, 95% CI 0.34-0.85; p = 0.0085).19

These results formed the basis for a second CVOT, Insulin Resistance Intervention after Ischemic Stroke (IRIS), which randomized non-diabetes patients with insulin resistance to either pioglitazone 45 mg daily or placebo after an ischemic stroke.20Though patients who had a diagnosis of diabetes were excluded, some of the patients in IRIS had A1C values at baseline of 6% or higher, which could have been used to diagnose them with T2DM, and the majority of patients met the criteria for a diagnosis of pre-diabetes. The study included approximately 5 years of follow-up. Pioglitazone significantly lowered the risk of ischemic stroke or MI (HR 0.76, 95% CI 0.62-0.93; p = 0.007). The relative risk reduction in stroke was 18%, but this did not reach statistical significance. On secondary analysis, pioglitazone did significantly decrease the relative risks of MI and acute coronary syndrome.21

Despite these positive outcomes, the use of pioglitazone needs to be weighed against potential negative adverse effects. The incidence of congestive heart failure, which was an exclusion criteria in the CVOTs, was not higher in patients who used pioglitazone in the IRIS trial but was substantially higher in patients who received pioglitazone in the PROactive trial compared to patients who received placebo. In addition, the IRIS trial confirmed that weight gain can be substantial with pioglitazone: approximately 50% of patients gained more than 10 lb and 11.4% gained more than 30 lb. Additionally, there were 3.7% more placebo-subtracted pioglitazone-related bone fractures, and peripheral edema was more frequent in patients receiving pioglitazone. Today, rosiglitazone is rarely used. Pioglitazone is the insulin sensitizer of choice and it lowers the risk of important atherosclerotic events. Still, its use must be balanced in each patient against the risks of heart failure, peripheral edema, weight gain, and fractures from falls.

Insulin therapy

It has been widely believed that insulin therapy may be associated with atherosclerosis and an increased risk of CVD.22 The caveat to this theory is that insulin tends to be used in patients with a longer duration of disease and, thus, a higher CVD risk. Two well-controlled CVOTs of insulin therapy have been conducted in T2DM: a study of insulin glargine was conducted prior to the 2008 FDA guidance and a study of insulin degludec was recently completed. In the Outcome Reduction with Initial Glargine Intervention (ORIGIN)23 trial, patients aged 50 years or older with evidence of CVD and with either pre-diabetes or early detected/established diabetes (i.e., drug naïve or receiving only 1 oral agent) were randomized to receive either 1 daily injection of insulin glargine titrated to achieve a fasting plasma glucose of less than 95 mg/dL or standard glycemic care (placebo). ORIGIN was a large trial that enrolled 12,537 patients; they were followed for a median of 6.2 years. The primary outcome of CVD death, non-fatal MI, or non-fatal stroke was not significantly different between the groups (HR 1.02, 95% CI 0.94-1.11; p = 0.63), and insulin glargine had a neutral effect on all measured CVD risks. The primary adverse effect observed with insulin glargine was hypoglycemia: rates of hypoglycemia were 3-fold higher in the insulin glargine group than in the placebo group, and the risk of severe hypoglycemia was also higher, with 1.00 events per 100 person-years in the insulin glargine group and 0.31 events per 100 person-years in the placebo group (p < 0.001). One death was attributed to hypoglycemia from insulin glargine. Adherence to therapy was fair, with 43% of patients not taking insulin glargine at any given time and nearly 20% permanently discontinuing therapy.23

A second insulin CVOT was completed after the FDA published its guidance. It compared therapy with insulin degludec to therapy with insulin glargine. A Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE; NCT01959529) was a multicenter, international, randomized, double-blind, active comparator-controlled trial designed as an event-driven study; it continued until 633 positively adjudicated primary events of CVD death, non-fatal MI, or non-fatal stroke were accrued. The sponsor has released information stating that insulin degludec is non-inferior to insulin glargine for the primary outcome of CVD, MI, or stroke, but the data are yet unpublished. The data are expected to be released at the American Diabetes Association Annual meeting in June 2017.24

Overall, according to the CVOTs, the 2 tested basal insulins appear to be neutral in terms of CV risks. However, the incidence of severe hypoglycemia may increase the risk of death for up to 1 year after occurrence.8 There are many other types of insulins available, including rapid-acting and inhaled insulins, which may never be tested in CVOTs, since they are older agents and received approval prior to the FDA guidance.

CVOTs conducted since FDA guidance

Several CVOTs have been conducted since the FDA guidance was published in 2008. Most of these have involved newer agents and classes of drugs. Many trials are still ongoing.

Dipeptidyl peptidase-4 inhibitors

There are currently 4 dipeptidyl peptidase-4 (DPP-4) inhibitors available in the U.S. CVOTs have been completed with 3 of them (Table 1).25-31 Saxagliptin, alogliptin, and sitagliptin were evaluated in 3 large trials: Saxaglipton and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI 53),25 Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE),26 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).27The fourth DPP-4 inhibitor, linagliptin, is currently being evaluated: the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes (CAROLINA; NCT01243424) compares linagliptin to glimepiride or placebo; this study is ongoing and the findings have not yet been published.

Table 1. Select Cardiovascular Outcome Trials in Type 2 Diabetes Mellitus
Study name Drug Trial identifier N Follow-up, years Primary outcome Primary result, HR (95% CI) Non-inferiority, p-value Superiority, p-value
SAVOR-TIMI 5325 Saxagliptin NCT01107886 16,492 2.1 CV death, non-fatal MI, or non-fatal stroke 1.00 (0.89-1.12) < 0.001 0.99
EXAMINE26 Alogliptin NCT00968708 5380 1.5 CV death, non-fatal MI, or non-fatal ischemic stroke 0.96 (≤ 1.16)* < 0.001 0.32
TECOS27 Sitagliptin NCT00790205 14,671 3 CV death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina 0.98 (0.88-1.09) < 0.001 0.65
EMPA-REG OUTCOME28 Empagliflozin NCT01131676 7020 3.1 CV death, non-fatal MI, or non-fatal stroke 0.86 (0.74-0.99) < 0.001 0.04
ELIXA29 Lixisenatide NCT01147250 6068 2.1 CV death, non-fatal MI, non-fatal stroke, or unstable angina 1.02 (0.89-1.17) < 0.001 0.81
LEADER30 Liraglutide NCT01179048 9340 3.8 CV death, non-fatal MI (including silent MI), or non-fatal stroke 0.87 (0.78-0.97) < 0.001 0.01
SUSTAIN-631 Semaglutide NCT01720446 3297 2.1 CV death, non-fatal MI (including silent MI), or non-fatal stroke 0.74 (0.58-0.95) < 0.001 0.02+
Abbreviations: CI = confidence interval; CV = cardiovascular; HR = hazard ratio; MI = myocardial infarction.
*Value represents the upper boundary of the 1-sided repeated confidence interval.
+SUSTAIN-6 was not prospectively powered to show superiority; this p-value is a post-hoc value and is not corrected for multiplicity.

SAVOR-TIMI 5325 enrolled 16,492 patients with T2DM and an A1C between 6.5% and 12.0%. Additional inclusion criteria were established CVD (cardiac, cerebrovascular, or peripheral vascular disease) in patients 40 years of age or older or multiple CVD risk factors in men older than 55 years and women older than 60 years. Patients were randomized to saxagliptin 5 mg or placebo, and the dose could be adjusted for renal disease.25 Follow-up lasted for a mean of 2.1 years to accrue the required number of events for the trial. The results indicated non-inferiority in the primary outcome of CVD death, MI, or stroke with saxagliptin compared placebo (HR 1.00, 95% CI 0.89-1.12; p = 0.99). Secondary analysis revealed that more patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (HR 1.27, 95% CI 1.07-1.51; p = 0.007), with most of the risk existing in the first 9 months of therapy. Identified risk factors for hospitalization for heart failure included a history of heart failure or renal impairment, but no definitive mechanism of action is known. A reanalysis of the data for only patients receiving saxagliptin reported a marginally higher risk of all- cause death (HR 1.18, 95% CI 0.99-1.39). There was no increase in the risk of pancreatitis or pancreatic cancer with saxagliptin.25

EXAMINE26 enrolled 5380 patients with T2DM and an A1C between 6.5% and 11.0%. Additional inclusion criteria were an acute coronary syndrome event (e.g., acute MI, unstable angina) within 15 to 90 days prior to enrollment and randomization. Patients were randomized to alogliptin 25 mg or placebo, and the dose could be adjusted for renal disease. EXAMINE enrolled high-risk CVD patients in order to accrue events at a relatively fast rate, and follow-up lasted for an average of 18 months to accrue the required number of events for the trial. The results indicated non-inferiority in the primary outcome of CVD death, non-fatal MI, or non-fatal ischemic stroke (HR 0.96, upper limit of 95% CI ≤ 1.16; p < 0.001 for non-inferiority; p-value was not significant for superiority). Secondary analysis revealed that, numerically, more patients receiving alogliptin experienced hospitalization for heart failure (106/2701, 3.9%) than patients randomized to placebo (89/2679, 3.3%). Additionally, in patients with no history of heart failure, a significantly increased risk of hospitalization for HR was reported with alogliptin (HR 1.76, 95% CI 1.07-2.90).32 An FDA reanalysis of data found that patients from the U.S. and Canada with a duration of diabetes of more than 10 years, with renal insufficiency, and without biguanide or insulin therapy had a higher risk of MACE outcomes but not total mortality.

TECOS27 enrolled 14,671 patients with T2DM and an A1C between 6.5% and 8.0%. Additional inclusion criteria were treatment with a stable dose of 1 or 2 oral antihyperglycemic agents or insulin, age of at least 50 years, and established heart disease (i.e., a history of coronary heart disease, ischemic cerebrovascular disease, or atherosclerotic peripheral artery disease). Patients were randomized to sitagliptin 100 mg or placebo, and the dose could be adjusted for renal disease. Patients were followed for an average of 3 years to accrue the required number of events for the trial. The results indicated non-inferiority in the primary outcome of CVD death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina (HR 0.98, 95% CI 0.88-1.09; p < 0.001 for non-inferiority; p = 0.65 for superiority). Unlike with saxagliptin and alogliptin, there was no increase in the number of patients who were hospitalized for heart failure with sitagliptin therapy (HR 1.00, 95% CI 0.83-1.20; p = 0.98).27

Overall, all 3 DPP-4 inhibitors studied to date have been neutral for CVD risk according to 3-point MACE composite outcomes. Both saxagliptin and alogliptin were associated with a higher risk of heart failure hospitalization, and their package inserts now have cautions about heart failure.33,34In addition, there was a trend toward higher all-cause mortality with saxagliptin and in subsets of patients receiving alogliptin.35The underlying mechanisms for the higher risks of these outcomes are poorly understood, but it is speculated that DPP-4 inhibitors block the degradation of other active peptides and some of these may be detrimental in certain circumstances, such as in the setting of fluid overload that is often seen with heart failure. Until these controversies are explained, sitagliptin may be the DPP-4 inhibitor of choice in patients with CVD and heart failure.

Sodium-glucose cotransporter-2 inhibitors

Trials with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have received much attention since the release of the first CVOT for this class: Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME)28 (Table 1). EMPA-REG OUTCOME enrolled 7020 patients with uncontrolled T2DM and CVD. Patients had antihyperglycemic therapy discontinued for at least 12 weeks prior to randomization and a baseline A1C of 7% to 9%. In addition, more than 99% of patients had documented CVD, such as a history of MI, at least 50% stenosis of 1 to 2 vessels on cardiac catheterization, unstable angina, history of stroke, or peripheral artery disease. Patients were randomized to either 10 mg or 25 mg daily of empagliflozin or placebo. The outcomes for both doses of empagliflozin were similar, so the data were combined to compare outcomes to the placebo group. Patients were followed for a mean of 2.6 years. The primary composite outcome of CVD death, non-fatal MI (not silent MI), or non-fatal stroke was reduced with empagliflozin compared to placebo (HR 0.86, 95% CI 0.74-0.99; p < 0.001 for non-inferiority; p = 0.04 for superiority). Significant relative risk reductions in CV mortality (38%), all-cause mortality (32%), and hospitalization for heart failure (35%) were observed with empagliflozin compared to placebo. The risk of MI (13%) was not significantly reduced, and the risk of non-fatal stroke (24%) increased but not significantly.28

The reduction in death without a reduction in MI or stroke suggests that the reductions in body weight and blood pressure cannot fully explain the reduction in CV death.36 Furthermore, separation of the Kaplan-Meier curves for CV mortality and hospitalization for heart failure was observed within the first 3 months of the trial. This indicates that the mechanisms of empagliflozin therapy had an early and profound effect on the risk of death or heart failure. Again, since MI was not significantly reduced, empagliflozin can be assumed to improve the survivability of such events. When post- hoc subsets of patients (analyzed according to effects of age, race, CVD, no CVD, etc.) were studied, all achieved benefit from empagliflozin, which is uncommon in clinical trials. On the basis of these findings, the FDA has approved empagliflozin “to reduce the risk of CV death in adult patients with T2DM and established CV disease.”37 Currently, no CVOT data has been published for any other SGLT-2 inhibitor; data from the Canagliflozin Cardiovascular Assessment Study (CANVAS) and the Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus (CANVAS-R) are expected to be released in June 2017 at the American Diabetes Association meeting; data from the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI 58) will likely be reported in 2018.

Glucagon-like peptide-1 receptor agonists

To date, 3 CVOTs of glucagon-like peptide-1 (GLP-1) receptor agonists have been completed (Table 1).29-31 The sponsor of a fourth CVOT has only published a press release. GLP-1 receptor agonists must be considered individually for CVOT outcomes, since each agent has a different molecular size, mechanism of prolongation, potency, and dosing regimen.

Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) was the first published GLP-1 receptor agonist CVOT.29Lixisenatide has a 4-fold higher affinity for the GLP-1 receptor than native GLP-1. The half-life of lixisenatide is 2 to 4 hours, yet it was studied with daily dosing (10 or 20 mcg daily; 85.5% of patients were taking the higher dose) in clinical trials. ELIXA enrolled 6068 T2DM patients who had experienced MI or unstable angina admission within 180 days of randomization. Patients were followed for a mean of 25 months, and the primary composite outcome was CV death, non-fatal MI or stroke, or hospitalization for unstable angina. Non-inferiority was reported for the primary outcome (HR 1.02, 95% CI 0.89-1.17; p < 0.001 for non-inferiority; p = 0.81 for superiority). Rates of death, non-fatal MI, non-fatal stroke, and unstable angina were non-inferior to placebo, and there was no trend toward significance in any of the outcomes. Overall, lixisenatide therapy had a neutral effect on CV outcomes.29

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) was the second published CVOT of a GLP-1 receptor agonist.30 LEADER was conducted with the daily-dosed liraglutide and enrolled 9340 patients with T2DM who were at high risk of CVD, which was defined as age of at least 50 years and at least 1 established CV condition (e.g., CVD, stroke, peripheral vascular disease, stage 3 or worse chronic kidney disease, New York Heart Association stage II or III heart failure) or age of at least 60 years with a CVD risk factor such as microalbuminuria, left ventricular hypertrophy, cardiac diastolic dysfunction, or an abnormal ankle-brachial index. More than 80% of patients had established CVD. Patients were eligible for inclusion in LEADER whether they were drug naïve or on antihyperglycemic or insulin therapy. They were randomized to liraglutide titrated to 1.8 mg daily or placebo injections and followed for an average of 3.8 years. The primary composite outcome of CV-related death, non-fatal MI (including silent MI), or non-fatal stroke was significantly reduced (HR 0.87, 95% CI 0.78-0.97; p < 0.001 for non- inferiority; p = 0.01 for superiority). Compared to placebo, liraglutide was also associated with significant reductions in CV death (HR 0.78, 95% CI 0.66-0.93; p = 0.007) and death from any cause (HR 0.85, 95% CI 0.74-0.97; p = 0.02). Liraglutide decreased the risk of MI (p = 0.046), and the risk of stroke trended downward but did not reach significance (p = 0.16). Risks for all atherosclerotic outcomes and hospitalization for heart failure trended downward, as well, but none of the factors was independently significant. On subset analysis, patients who had established CVD, were obese, or had an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 tended to receive the most benefits from treatment with liraglutide.30

The third CVOT evaluated semaglutide, a once-weekly GLP-1 receptor agonist that is not currently FDA approved. The structure of semaglutide differs from liraglutide by only a single amino acid and a linker/side chain that allows for stronger self-association and albumin binding, which prolongs the half-life to approximately 7 days. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) enrolled 3297 patients with T2DM.31 Inclusion criteria were identical to LEADER and included age of at least 50 years with CVD or CVD equivalent or age of at least 60 years with CV risk factors; at baseline, 83% of patients had documented CVD. Patients were randomized to receive either 0.5 mg or 1 mg weekly of semaglutide or matching placebo injection. The primary composite outcome was death from CV cause, non-fatal MI (including silent MI), or non-fatal stroke; patients were followed for a mean of 2.1 years. The primary endpoint was significantly reduced with semaglutide (HR 0.74, 95% CI 0.58-0.95; p < 0.001 for non-inferiority; p = 0.02 for superiority). SUSTAIN-6 was not powered to explore superiority, and superiority was assessed only in a post-hoc analysis. Neither CVD death nor all-cause death were significantly reduced, but the risks of non-fatal stroke (HR 0.61, 95% CI 0.38-0.99; p = 0.04) and revascularization procedures (HR 0.65, 95% CI 0.50-0.86; p = 0.003) were significantly reduced.31

A fourth CVOT has only been reported in a press release from the sponsor: the Exenatide Study of Cardiovascular Event Lowering (EXSCEL; NCT01144338) compared extended-release exenatide to placebo.38 EXSCEL enrolled and randomized 14,752 T2DM patients with a history of major clinical manifestations of CVD, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease. At baseline, approximately 70% of patients were classified as having CVD. Non-inferiority for exenatide was reported for the primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke. A full report of the results is expected to be released at the European Association for the Study of Diabetes meeting in 2017.38

IMPLICATIONS AND POTENTIAL MECHANISMS OF CURRENT CVOT DATA

The mechanism linked to the decreased CVD risks with SGLT-2 inhibitors is speculative, but it has been presented to be due, at least in part, to several factors. First, a glucodiuretic effect may be involved: as with diuretics, SGLT-2 inhibitors should help to lower the pre-load on the heart and eventually decrease systemic vascular resistance. Second, a reduction in uric acid levels may play a role: though abundant literature confirms that uric acid levels are related to vascular damage, several years of reduced levels may mitigate the damage. Third, reductions in weight and blood pressure have been shown to reduce CVD, but, other than stroke, short-term reductions in these parameters are unlikely to explain the effects of SGLT-2 inhibitors. Finally, ketones may represent a fourth mechanism of risk reduction: ketone formation with SGLT-2 inhibitors is associated with a metabolic change from reduced glucose levels and increased free fatty acid levels due, in part, to reduced plasma insulin and elevated plasma glucagon levels. The avid uptake of ketones as a fuel by the heart has been well explained in several reviews.39,40 This activity may explain early improvements in CVD and heart failure admissions observed with SGLT-2 inhibitors.

A logical and important question is whether the same positive CV effects can be obtained from all SGLT-2 inhibitors. A recently published abstract described evaluations of real-world data of SGLT-2 inhibitor use from the U.S. and Europe.41 In the cohort, approximately 53% of patients were taking dapagliflozin, 42% were taking canagliflozin, and the remainder were taking empagliflozin. A 51% reduction in all-cause mortality and a 39% reduction in hospitalization for congestive heart failure were reported.41

Liraglutide and semaglutide appear to lower 3-point composite MACE endpoints and trend toward lowering or significantly lower the risk of MI or stroke.30,31 This is in contrast to lixisenatide, which appears to be CV neutral.29 It is unclear why once-daily doses of lixisenatide and liraglutide showed such divergent results. However, the key differences between the trials may explain the different results. Though ELIXA was a large trial, LEADER enrolled nearly 3000 more patients. In addition, ELIXA enrolled patients who were post-MI or who had a hospital admission for unstable angina; this was a much different population than that enrolled in LEADER, which included a large number of patients with CVD risk factors. Speculatively, lixisenatide’s half-life is only 2 to 4 hours, and, though it has increased affinity for the GLP-1 receptor, the pharmacokinetics of lixisenatide may not allow adequate action at the GLP-1 receptor for 24 hours. Ultimately, this activity is insufficient to cause the necessary CV modifications that are needed to decrease CVD outcomes.

If established CVD, or risk factors for CVD, is present, clinicians face a difficult choice to use a neutral CV medication over medications that have proven CV protection. If available data for SGLT-2 inhibitors and GLP-1 receptor agonists are compared, it is clear that the beneficial CV effect of empagliflozin is primarily driven by a reduction in CV mortality, without a significant reduction in MI or stroke. Further, hospitalization for heart failure was markedly reduced by empagliflozin, but it was not significantly reduced with GLP-1 receptor agonist therapy. It is very likely that the mechanisms of decreasing death or heart failure with an SGLT-2 inhibitor are quite different from the mechanisms underlying the improvements observed with GLP-1 receptor agonists. Specifically, the Kaplan-Meier curves for the primary endpoints in GLP-1 receptor agonist CVOTs did not diverge until 12 to 16 months of follow-up; in CVOTs of empagliflozin, the curves diverged at 3 months. This is an unusual finding for a study of this type, and it indicates that, mechanistically, a change must happen extremely early in therapy with empagliflozin; but, with GLP-1 receptor agonists, there is a slow reduction in the burden of disease over time. GLP-1 receptor agonists appear to have a positive effect on endothelial dysfunction, which is present in almost all patients with T2DM. Data from human and animal studies clearly show that GLP-1 receptor agonists improve sodium balance, likely through secretion of atrial natriuretic peptide, decrease ischemic reperfusion damage, and lower weight and blood pressure.42 Together, these factors may contribute to the sum of the CVD reductions seen in LEADER and SUSTAIN-6.

Adverse effects in CVOTs

In addition to the outcomes and potential mechanisms of antihyperglycemic medications revealed by CVOTs, new information about adverse events has also been revealed. PROactive brought issues with pioglitazone18to the forefront of clinical discussions, but IRIS20 provided a more modern insight into the adverse effects of pioglitazone. IRIS reiterated that side effects related to fluid retention and weight are common with pioglitazone. The finding that more than half of the patients taking pioglitazone gained at least 10 lb and approximately 10% gained more than 30 lb reinforced that weight gain with pioglitazone is substantial and needs to be actively addressed and proactively managed in patients. Also, more patients receiving pioglitazone (17.9%) than placebo (12.1%) experienced severe edema. This is worrisome, since severe edema can indicate a higher risk for heart failure; as a serious adverse event (SAE), heart failure occurred numerically, but not statistically, more often with pioglitazone than with placebo. Other SAEs included a risk of bone fracture, which occurred in 5.1% of patients taking pioglitazone and 3.2% of those receiving placebo. This event has been well described in other pioglitazone studies, and it appears to be more likely to occur in postmenopausal women. No increase in the risk of bladder cancer was noted in the IRIS trial, but this SAE remains controversial.20

In the ORIGIN trial, weight gain and hypoglycemia were the primary side effects that were noted to occur more often with insulin glargine than with placebo.23 Severe hypoglycemia is worrisome, since it has been shown to be related to the risk of death, as well as other negative medical sequelae. Severe hypoglycemia was defined as the patient needing assistance and having a documented blood glucose of 36 mg/dL or lower. In all, 457 episodes of severe hypoglycemia occurred among patients receiving insulin glargine and 137 occurred with placebo. This is equivalent to rates of 1 episode with insulin glargine and 0.31 episodes with placebo per 100 person-years. The numbers of “confirmed” and “any” non-severe hypoglycemia events were also significantly higher with insulin glargine than with placebo (p < 0.001). Because of the risk of hypoglycemia, and its neutrality for CVD, basal insulin therapy in T2DM patients with CVD should be used only when necessary, such as when symptomatic hyperglycemia necessitates its use.

DPP-4 inhibitors are well tolerated, but the risk of hospitalization for heart failure is noteworthy, as previously discussed. Pancreatitis and pancreatic cancer continue to be associated with this drug class, though the actual risks are unclear. In TECOS,27 there were numerically more, but not statistically more, cases of pancreatitis with sitagliptin than with placebo, and no increase in pancreatic cancer was reported. In EXAMINE26 and SAVOR-TIMI 53,25 no increased risks of pancreatitis or pancreatic cancer were noted. Overall, the risk profile continues to show that DPP-4 inhibitors are relatively well tolerated and safe.

In the EMPA-REG OUTCOME28 trial, genital mycotic infections were the most common adverse event noted. Urosepsis was reported in 0.4% of patients taking empagliflozin compared to 0.1% taking placebo; neither the urinary tract infection rate nor the pyelonephritis rate was higher in the treatment group than in the placebo group. No increased risks of acute kidney injury or failure, volume depletion side effects, bone fractures, or diabetic ketoacidosis were noted in EMPA-REG OUTCOME. Still, continued caution is advisable with SGLT-2 inhibitors due to their effects on volume status and genitourinary infections.

GLP-1 receptor agonists are well known to cause gastrointestinal (GI) side effects such as nausea, vomiting, and diarrhea. In ELIXA,29 GI side effects were the main reason for discontinuation of lixisenatide. No increased risks of pancreatitis or pancreatic cancer were noted. LEADER30 also reported GI intolerance as the main adverse event leading to discontinuation of liraglutide. In this study, pancreatic cancer trended toward a higher risk with liraglutide (n = 13) than with placebo (n = 5), though after further adjudication of deaths, 4 more pancreatic cancer deaths were added to the placebo group for a total of 9 cases. Medullary thyroid carcinoma was noted in only 1 patient who was taking placebo. Acute pancreatitis did not occur more often with liraglutide, but mild elevations in amylase and lipase levels were noted with therapy. Also, the incidence of acute gallstone disease was higher in the liraglutide group than in the placebo group (n = 145 vs n = 90), which leads to a better understanding of why some mid-epigastric pain that occurs with GLP-1 receptor agonists is not due to pancreatitis. SUSTAIN-631 also reported more GI issues with the 0.5-mg and 1- mg doses of semaglutide than with placebo. No increased risks of pancreatic cancer, cholelithiasis, or cholecystitis were observed. There were also no increases in pancreatitis or pancreatic cancer, though slight increases in amylase and lipase levels were noted after starting therapy.

Microvascular complications

Empagliflozin demonstrated extremely positive results in an analysis for renal outcomes over a follow-up of 3.2 years. The risk of doubling of serum creatinine (SCr) accompanied by an eGFR of less than or equal to 45 mL/min/1.73 m2, the need for renal replacement therapy, or renal disease-related death was reduced by 46% (p < 0.001).43This improvement is similar to what most antihypertensive medications must achieve to be considered for a renoprotective indication. Liraglutide reported an approximate 20% reduction in the risk of poor renal outcomes regardless of baseline eGFR. LEADER30 reported a 26% reduction in persistent macroalbuminuria with liraglutide, and SUSTAIN-631 reported a 36% reduction in the risk of persistent macroalbuminuria, persistent doubling of the SCr accompanied by an eGFR of less than or equal to 45 mL/min/1.73 m2, or the need for continuous renal-replacement therapy with semaglutide. However, in patients who already had retinopathy, semaglutide was associated with an increased risk of severe retinal complications, such as vitreous hemorrhage, diabetes-related blindness, and the need for an intravitreal medication or photocoagulation (HR 1.76, 95% CI 1.11-2.78; p = 0.02).31 In the past, rapid improvement in glycemic control has been shown to be detrimental to advanced retinopathy, and other trials did not include patients with such severe retinopathy; further investigation into whether this is a significant issue or not is imperative, since these outcomes confer an increased risk of blindness. It is notable that, in LEADER, the use of liraglutide was not associated with any increase in retinal complications.30

PATIENT-SPECIFIC THERAPY BASED ON CVOT RESULTS

It is wise to consider how each of the antihyperglycemic medications could be used in different clinical situations, but it is not possible to address all patient scenarios that may be encountered. General patient-specific considerations for reducing CVD risks are presented in Table 2.18-21,25-31 Empagliflozin clearly decreases all-cause mortality in patients with T2DM and established CVD. It is, therefore, reasonable to consider empagliflozin as required therapy if a patient is a candidate for an SGLT-2 inhibitor and has CVD. Further, since empagliflozin significantly decreased hospitalizations for heart failure, it should be considered as ideal therapy for any T2DM patient with or at high risk for heart failure. Empagliflozin also significantly reduced progression of nephropathy, and, though not indicated, should be considered as additional therapy after adequate renin-angiotensin blockade and blood pressure control. It is still unclear if these benefits are specific to empagliflozin or are class effects of all SGLT-2 inhibitors.

Table 2. Patient-specific Effects of Antihyperglycemic Therapy on CVD Risks18-21,25-31
Drug class CVD risk
Mortality Myocardial infarction Stroke Heart failure Microvascular
DPP-4 inhibitors Neutral Neutral Neutral Neutral: sitaglitpin

May increase:
saxagliptin, alogliptin		 NR
SGLT-2 inhibitors
(empagliflozin only)		 Reduction Neutral Neutral Reduction Nephropathy
Reduction
Thiazolidinediones
(pioglitazone only)		 Neutral Neutral/reduction+ Neutral/reduction+ Increase NR
GLP-1 receptor
agonists		 Reduction: liraglutide

Neutral:
lixisenatide, semaglutide		 Reduction:
liraglutide

Neutral/reduction+:
semaglutide Neutral: lixisenatide		 Reduction:
semaglutide

Neutral/reduction+:
liraglutide Neutral: lixisenatide		 Neutral Renal outcomes
 Reduction: liraglutide,
semaglutide
Neutral: lixisenatide

Eye outcomes
Increase: semaglutide
Abbreviations: CVD = cardiovascular disease; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; NR = not reported; SGLT-2 = sodium-glucose cotransporter-2.
+IRIS, PROactive, and LEADER reported numerically fewer myocardial infarctions and strokes, but these differences did not reach independent significance.

Each GLP-1 receptor agonist should be considered separately, since each acts in a slightly different way due to the respective formulations and, as a result, offers drug-specific benefits and advantages. As a result of LEADER,30 liraglutide stands out within this class due to a reported reduction in all-cause mortality and a downward trend in the risks of MI and stroke. LEADER also reported that liraglutide significantly decreased the need for revascularization procedures. Semaglutide,31 though not currently available, would be a logical second choice if a weekly preparation was necessary for patients with CVD, since it reduced the risks of MI and renal disease; however, caution should be exercised in patients with advanced eye disease until more is known about the risks and benefits of this drug. For renal protection throughout the life of a T2DM patient, liraglutide or semaglutide would be excellent choices. (Though, a second, well- designed study showing similar positive renal outcomes would be optimal to confirm this choice.)

The FDA seeks at least neutrality in CVD risks for antihyperglycemics. Insulin glargine and the DPP-4 inhibitors meet these criteria. Though, sitagliptin should be favored in heart failure patients; saxagliptin (due to unexplained heart failure) and alogliptin (in patients with no history of heart failure) reported negative results and, therefore, these agents should only be used on an as-needed basis in patients with CVD. IRIS reported a significant reduction in spontaneous ischemic MIs with pioglitazone in patients who previously experienced a stroke or transient ischemic attack, especially if the MIs were considered “large” according to serum troponin levels. Pioglitazone for MI reduction/prevention should be considered for macrovascular risk reduction.21

CONCLUSION

In 2008, the FDA began mandating CVOTs to ensure the safety of antihyperglycemic medications. Though not all classes or agents have published results, the results that are available provide deeper understandings of several of the drug classes and the related CVD benefits. These are important principles to consider, since a T2DM patient with CVD whose other risk factors are well-controlled often has limited choices for further treatment. Identification of diabetes medications that are efficacious in decreasing residual risk or, at a minimum, showing neutrality can be useful for many patients with T2DM. To date, only 1 trial evaluating SGLT-2 inhibitors has been published; though it reported a decreased risk of death, not all T2DM patients with CVD are appropriate candidates for therapy with empagliflozin. In addition, liraglutide demonstrated very positive results, with a CVOT reporting a reduction in all-cause mortality and positive renal outcomes. Still, this may not be a class effect and each GLP-1 receptor agonist must be independently studied for its CVD benefits. SGLT-2 inhibitors and select GLP-1 receptor agonists should generally be considered ahead of DPP-4 inhibitors, metformin, and newer basal insulins for improving renal outcomes and reducing mortality. Understanding and recommending appropriate medications for T2DM patients at risk of CVD outcomes should comprehensively consider patient-specific morbidity and mortality risks.

REFERENCES

  1. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514-1523.
  2. Triplitt CL, Repas T, Alvarez C. Diabetes. “Diabetes Mellitus.” In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. New York: McGraw-Hill Education; 2017.
  3. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.
  4. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653.
  5. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383-393.
  6. Gaede P, Lund-Anderson H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580-591.
  7. ADVANCE Collaborative Group; Patel A, MacMahaon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
  8. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
  9. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139.
  10. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Eng J Med. 2007;356(24):2457-2471.
  11. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294(20):2581-2586.
  12. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research. Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071627.pdf. Published December 2008. Accessed May 13, 2017.
  13. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854-865.
  14. BARI-2D Study Group; Frye RL, August P, Brooks MM, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360(24):2503-2515.
  15. Home P, Pocock SJ, Beck-Nielsen H, et al; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open- label trial. Lancet. 2009;373(9681):2125-2135.
  16. Nissen SE. The rise and fall of rosiglitazone. Eur Heart J. 2010;31(7):773-776.
  17. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2016.
  18. Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289.
  19. Wilcox R, Bousser MG, Betteridge DJ, et al; PROactive Investigators. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events 04). Stroke. 2007;38(3):865-873.
  20. Kernan WN, Viscoli CM, Furie KL, et al; IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321-1331.
  21. Young LH, Viscoli CM, Curtis JP, et al; IRIS Investigators. Cardiac outcomes after ischemic stroke or transient ischemic attack: effects of pioglitazone in patients with insulin resistance without diabetes. Circulation. 2017;135(20):1882-1893.
  22. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287.
  23. ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328.
  24. Tresiba® demonstrates a safe cardiovascular profile and reduces the risk of severe hypoglycaemia compared to insulin glargine U100 in the DEVOTE trial [press release]. Bagsvaerd, Denmark: Novo Nordisk; November 29, 2016. https://www.novonordisk.com/bin/getPDF.2060124.pdf. Accessed May 14, 2017.
  25. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
  26. White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335.
  27. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242.
  28. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
  29. Pfeffer MA, Claggett B, Diaz R, et al; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257.
  30. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
  31. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
  32. Standl E, Schnell O. DPP-4 inhibitors and risk of heart failure EXAMINEd. Lancet. 2015;385(9982):2022-2024.
  33. Onglyza [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2017.
  34. Nesina [package insert]. Deerfield, IL: Takeda Pharmaceuticals America; 2016.
  35. SAVOR: Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus; sNDAs for Onglyza (22-350/S-014) and Kombiglyze XR (200-678/S-013); Briefing Document for Endocrinologic and Metabolic Drugs Advisory Committee Meeting [advisory committee briefing document]. AstraZeneca; March 11, 2015. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologicand MetabolicDrugsAdvisoryCommittee/UCM442061.pdf. Accessed May 14, 2017.
  36. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care. 2016;39(5):717-725.
  37. Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2016.
  38. BYDUREON EXSCEL trial meets primary safety objective in type-2 diabetes patients at wide range of cardiovascular risk [press release]. AstraZeneca; May 23, 2017. https://www.astrazeneca-us.com/media/press- releases/2017/bydureon-exscel-trial-meets-primary-safety-objective-in-type-2-diabetes-patients-at-wide-range- of-cardiovascular-risk-05232017.html. Accessed May 27, 2017.
  39. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108-1114.
  40. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115-1122.
  41. Kosiborod M, Cavender M, Norhammar A. Lower rates of hospitalization for heart failure and all-cause death in new users of SGLT2 inhibitors: the CVD-REAL study [abstract]. Presented at the 66th Scientific Session of the American College of Cardiology; March 17-19, 2017; Washington, DC. Abstract 415-14.
  42. Chilton RJ. Potential cardiovascular effects of the glucagon-like peptide-1 receptor agonists. J Diabetes Metab. 2015;6:483.
  43. Wanner C, Inzucchi S, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334.

Back to Top