1. Introduction
Type 2 diabetes mellitus (T2DM) is associated with increased risk of cardiovascular (CV) disease but the clinical trials of intensive glucose control have generally not shown a significant reduction of CV events, at least in the short term. This may be because the benefits of improved glycemic control take a long time to influence the progression of atherosclerotic vascular disease but some of the treatments to reduce glucose may also have harmful effects on other CV risk factors, such as the increase in body weight with insulin and sulfonylurea (SU) treatments [Citation1].
Metformin is well established as the first-line oral hypoglycemic agent, based on the beneficial effects on CV events in the UKPDS in overweight patients with newly diagnosed T2DM as well as subsequent studies [Citation1]. Treatment with SU or insulin reduced microvascular complications but not macrovascular disease in UKPDS, and there are concerns from other studies that these treatments might increase CV risk [Citation1]. The trials of intensive glycemic control using multiple treatments with metformin, SU, insulin, and sometimes thiazolidinediones (TZDs) failed to show any CV benefit and there were frequent hypoglycemic events. In the recent Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial in people with T2DM, impaired fasting glucose (IFG), or impaired glucose tolerance (IGT) and increased CV risk, maintaining good glycemic control with insulin glargine for 6 years had a neutral effect on CV outcomes and reduced new onset diabetes but there was more hypoglycemia and a modest increase in body weight [Citation2].
The TZDs were thought to have benefits in addition to glucose lowering that might improve CV outcomes and treatment with pioglitazone reduced the composite CV end point in patients with T2DM and evidence of macrovascular disease in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study. The recently reported Insulin Resistance Intervention after Stroke (IRIS) trial in patients with insulin resistance but without T2DM and with a history of recent ischemic stroke or transient ischemic attack also showed a benefit with pioglitazone with reductions in the risk of stroke or myocardial infarction (MI) and the risk of developing diabetes [Citation3].
Initial studies with rosiglitazone looked promising with reductions in incident T2DM in patients with IFG and/or IGT in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study, better durability than metformin or glyburide in maintaining long-term glycemic control in T2DM in A Diabetes Outcome Progression Trial (ADOPT), and no increase in the risk of overall CV morbidity or mortality compared with standard glucose-lowering drugs in the initial analysis of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study. However, a meta-analysis of clinical studies with rosiglitazone treatment in patients with T2DM showed increased risk of MI and CV death [Citation4]. This resulted in the US Food and Drug Administration (FDA) issuing a warning on the use of rosiglitazone and a guidance for industry in defining preapproval and post-approval requirements for the demonstration of CV safety for all new drugs for T2DM in 2008. Other regulatory agencies developed similar requirements.
The CV outcome studies that have been conducted since then have generally adopted a non-inferiority design and included T2DM patients with high CV risk or established CV disease with the aim of showing absence of CV toxicity in the shortest possible time. The novel drugs have been compared to placebo in addition to standard care. Other antidiabetic therapy is adjusted in both groups in the study to attempt to achieve satisfactory glucose control, but most trials have shown better glucose control in the active treatment group. Such trials are unlikely to be effective in assessing the potential long-term benefits or possible risks of the new therapies and head-to-head trials of different therapies have largely been avoided. These trials have now been completed with several drugs from the three main classes of novel antihyperglycemics and others are currently in progress ().
Table 1. Major cardiovascular outcome studies with new antidiabetic drugs.
2. Dipeptidyl peptidase-4 inhibitors
The dipeptidyl peptidase-4 (DPP-4) inhibitors were predicted to have beneficial effects on the CV system through mechanisms that were dependent on activation of glucagon-like peptide-1 (GLP-1) and other actions that were independent of GLP-1 effects as the DPP-4 inhibitors also interact with many others substrates [Citation1]. It was therefore somewhat disappointing that the first outcome studies with the DPP-4 inhibitors saxagliptin [Citation5] and alogliptin [Citation6] showed non-inferiority but not superiority on the 3-point composite CV primary end point of CV death, MI, or ischemic stroke. Furthermore, the SAVOR-TIMI 53 study showed the unexpected finding of a higher rate of heart failure hospitalizations with saxagliptin. A subsequent analysis showed the risk of heart failure with saxagliptin in the SAVOR-TIMI 53 study was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease [Citation11]. A post hoc analysis of the EXAMINE trial with alogliptin, which enrolled high risk patients with T2DM and recent acute coronary syndromes (ACS), showed no increased risk of heart failure and this outcome did not differ according to history of heart failure or baseline concentrations of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-pro-BNP) [Citation12].
The TECOS study with sitagliptin showed no difference in the primary composite end point of CV death, MI, stroke, or hospitalization for unstable angina in the sitagliptin group relative to placebo and also no increase in heart failure-related outcomes with sitagliptin [Citation7].
Whether the increased risk of heart failure seen with saxagliptin in the SAVOR-TIMI 53 study is a true adverse effect of this drug, which is not shared by alogliptin and sitagliptin, or whether this was a chance finding or something related to differences in the patients included in the studies remains uncertain. There are ongoing CV outcome trials with another DPP-4 inhibitor linagliptin including the CAROLINA study which is the only trial to directly compare a new antidiabetic drug with an established agent, glimepiride.
3. Glucagon-like peptide-1 agonists
After the three studies with DPP-4 inhibitors, the next CV outcome study to be completed with a new antidiabetic drug was the ELIXA study with the GLP-1 agonist lixisenatide, at doses titrated up to 20 μg once daily in high-risk T2DM patients with recent ACS [Citation8]. This showed non-inferiority but not superiority of lixisenatide compared to placebo and there was no signal of any serious adverse events with lixisenatide. Gastrointestinal events leading to discontinuation of treatment were more common with lixisenatide (4.9%) than with placebo (1.2%). Compared with the placebo-treated group, the lixisenatide-treated group had greater average reductions in HbA1c of 0.27%, reductions of body weight of 0.7 kg, reductions in systolic blood pressure (SBP) of 0.8 mmHg, but an increase in heart rate of 0.4 beats/minute. Lixisenatide has a short half-life (3–4 h) and duration of action and when given once daily the effects on HbA1c, body weight and SBP are less than with the longer acting GLP-1 agonists [Citation13]. This may have contributed to the neutral outcome in the ELIXA study.
In the very recent LEADER trial with liraglutide 1.8 mg (or the maximum tolerated dose) once daily compared to placebo, there was a 13% reduction (P = 0.01) in the primary composite outcome of death from CV causes and nonfatal MI or stroke, 22% reduction (P = 0.007) in CV mortality and 22% reduction (P = 0.003) in nephropathy events in the liraglutide group [Citation9]. Subgroup analysis suggested a greater benefit of liraglutide in patients with reduced estimated glomerular filtration rate (eGFR, <60 mL/minute/1.73 m2) and possibly in patients with established CV disease at baseline. The mean differences between the liraglutide group and the placebo group throughout the trial were a reduction in HbA1c of 0.40%, reduction of body weight of 2.3 kg, reduction in SBP of 1.2 mmHg, reduction in diastolic blood pressure (DBP) of 0.6 mmHg, and increase in heart rate of 3.0 beats/minute.
There were no major safety concerns although there was a nonsignificant increase of total benign or malignant neoplasms and of pancreatic cancer seen with liraglutide as compared with placebo. There was a nonsignificantly lower incidence of acute pancreatitis with liraglutide. There were significant increases in amylase and lipase throughout the study in the liraglutide-treated group but the implications of this are uncertain. Gastrointestinal events led to more permanent discontinuations with liraglutide than with placebo.
CV outcome studies are being conducted with four other GLP-1 agonists and the SUSTAIN 6 study with semaglutide has been completed and a preliminary announcement indicated it shows a positive result.
4. Sodium-glucose cotransporter 2 inhibitors
The EMPA-REG OUTCOME study was the first trial to show a significant CV outcome benefit with a novel antidiabetic drug, the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin [Citation10]. The 14% reduction (P = 0.04) in the 3-point composite primary outcome was largely due to reductions in CV death by 38% and all-cause mortality was reduced by 32%. The effects were similar with the two doses of 10-mg or 25-mg empagliflozin once daily. There were nonsignificant increases in the hazard ratios for strokes and silent MI. Hospitalization for heart failure was reduced by 34% (P < 0.001) and there was a consistent benefit in patients with and without baseline heart failure [Citation14].
Most of the major CV risk factors including HbA1c, body weight, waist circumference, SBP, DBP, HDL-cholesterol (HDL-C), and uric acid levels were improved to varying degrees during the course of the study in the empagliflozin-treated groups compared to the placebo group but there was a small and potentially dose-dependent increase in LDL-cholesterol (LDL-C) with empagliflozin throughout most of the study. Most treatments that improve glycemic control will tend to decrease triglycerides and increase HDL-C, but the SGLT2 inhibitors appear to be unusual in causing a small increase in LDL-C, which could potentially increase CV risk. The SGLT2 inhibitors consistently reduce serum uric acid but uric acid has not been shown to be an independent risk factor for coronary artery disease.
The time to benefit in the EMPA-REG OUTCOME study appeared much earlier than in the LEADER trial and benefits were seen in different components of the composite primary outcome in the two studies. Both empagliflozin and liraglutide reduced body weight and blood pressure and these are likely to contribute to long-term benefits. SGLT2 inhibitors have additional diuretic and natriuretic effects and it seems likely that the hemodynamic effects from decreased extracellular volume influenced the reduction in CV mortality and heart failure hospitalization with empagliflozin. The early benefits on CV mortality and heart failure hospitalization may also be explained by a shift in myocardial and renal metabolism from the use of fat and carbohydrate to the more energy-efficient ketone bodies [Citation15].
CV outcome studies are being conducted with three other SGLT2 inhibitors and with canagliflozin there are two additional studies to examine renal endpoints in T2DM patients (CANVAS-R: A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus) and renal and CV outcomes in participants with diabetic nephropathy (CREDENCE: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy).
5. Conclusion
The CV outcome trials completed with the three DPP-4 inhibitors were on balance neutral, apart from the possible increased risk of hospitalization for heart failure with saxagliptin. The ELIXA trial with lixisenatide also showed a neutral outcome but the trials with liraglutide and empagliflozin showed reductions in the composite primary end points with these two drugs and a different pattern of benefits for secondary outcomes. Whether these benefits are related to the specific drugs or whether they represent class effects remains uncertain. It seems likely that different patients may benefit from one drug more than another but this will require further studies and analyses to ascertain.
6. Expert opinion
The CV outcome trials with novel antihyperglycemic agents have generated a large amount of data resulting in some insights but also many unanswered questions. The trials were designed to demonstrate CV safety and it came as some surprise to see the superiority of a new drug, particularly in the EMPA-REG OUTCOME study. It is not certain why empagliflozin showed such an advantage in that study, but the rapid onset of benefit and reduction of heart failure hospitalization would suggest it was related to a diuretic effect or a shift in fuel energetics. The nonsignificant increase in risk for strokes and silent MIs is of some concern. Although many of the risk factors for stroke, such as blood pressure, were improved, there were small increases in hematocrit and LDL-C which could increase stroke risk.
In the LEADER trial, liraglutide improved most CV risk factors, except for heart rate, and this could explain the longer-term benefits on CV events from a reduction in the progression of atherosclerotic vascular disease (). The magnitude of changes in the CV risk factors was generally greater in the LEADER trial than in the ELIXA trial and the ELIXA trial enrolled a different patient group and had shorter follow-up time than the LEADER trial which may all have contributed to the neutral outcome with lixisenatide. It remains uncertain whether there are real differences between the two drugs apart from the duration of action or whether the benefit seen with liraglutide is a class effect.
Figure 1. Cardiovascular benefits and cardiovascular risks with the new classes of glucose-lowering drugs.
Abbreviations:DPP-4: dipeptidyl peptidase-4, GLP-1: glucagon-like peptide-1, SGLT-2: Sodium-glucose cotransporter-2BP: blood pressure; Hct: hematocrit; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; TG: triglycerides↔: neutral effect; ?: significance of the change is uncertain.
These intriguing findings might suggest that different groups of patients may benefit more from one drug than another and perhaps the combination of an SGLT2 inhibitor and a GLP-1 agonist would have even greater benefits in both the short term and long term. There were no measures of cardiac function or biomarkers, such as BNP, at baseline in the EMPA-REG OUTCOME study, but if these were available evidence of left ventricular dysfunction might favor the use of an SGLT2 inhibitor and the avoidance of a TZD or possibly saxagliptin.
The DPP-4 inhibitors are well tolerated with no obvious serious adverse effects and their CV safety has been confirmed, apart from the potential concern regarding heart failure with saxagliptin. However, they have not shown CV benefits as yet so there is likely to be a preference for using SGLT2 inhibitors or GLP-1 agonists at an earlier stage in the management of T2DM in the future. The choice may also depend on the tolerability, cost, and convenience of the drugs. The SGLT2 inhibitors are generally well tolerated but do have the side effects of increased genital mycotic infections, urinary tract infections, and volume depletion and the rare occurrence of ketoacidosis, and with some of the drugs a possible risk of bone fractures and acute kidney injury. The currently available GLP-1 agonists require subcutaneous injection and frequently cause gastrointestinal side effects [Citation13]. It may be fortuitous that liraglutide showed an advantage in patients with renal impairment [Citation9] as the SGLT2 inhibitors are contraindicated in patients with renal impairment of greater than moderate degree.
Positive indications and contraindications are emerging with these new classes of antidiabetic drugs, which by themselves are all unlikely to cause hypoglycemia. Empagliflozin and liraglutide have shown CV benefits but these drugs may not be suitable for all patients and we would suggest a note of caution before changing clinical practice to use these drugs in all T2DM patients at high CV risk. It will be important to look at further analyses from completed studies and the results from the other CV outcome studies that are in progress before making definitive changes in management strategies for patients with T2DM.
Declaration of interest
B Tomlinson has received research funding from Amgen, AstraZeneca, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer and Roche. B Tomlinson has served as a consultant/advisor/speaker for Amgen, AstraZeneca, Merck Serono and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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