Melanie Sulistio, MD, Curtis Carothers, MD, Mandeep Mange, BS, Mike Lujan, BS, Rene Ofiveros, MD, and Robert Chilton, DO
PART 2: GLP 1 Agonist-based Therapies: How do they reduce cardiovascular risks in diabetic patients?
GLP-1 Agonist-based Therapies Reduce Cardiovascular Risk
Weight loss is critical to the management of diabetes. Before the advent of exenatide, no antidiabetic agents addressed the excessive weight gain that is the root cause of the diabetes epidemic. After 3 years of exenatide, patients lose an average of 5.3 kg, and approximately 50% of the patients treated with exenatide lose 5% of their initial weight. Meta-analyses suggest that a 5% weight loss (about 5 kg of weight loss) results in reductions of 4 mm Hg in systolic blood pressure, 5 to 8 mg/d1, of total and low-density lipoprotein (LDL) cholesterol, and about 18 mg/dL of triglycerides ….
In theory, solely reversing the weight gain spiral in patients with diabetes may translate to reduction in cardiovascular events. There are several randomized controlled trials of short-term duration (6 to 12 months) that have been published for both exenatide and liraglutide that can help us understand the impact of pharmacologic GLP-1 replacement on the known cardiovascular risk factors.
Effect on blood pressure
In contrast to the conflicting evidence in animal models of the effects of GLP-1 on sympathetic outflow, the clinical trial results consistently show improvement in blood pressure and no deleterious effects on heart rate. In a post hoc analysis from two head-to-head randomized controlled trials comparing exenatide and insulin (n = 1050 patients), Okerson et al.  reported a significantly greater reduction in systolic blood pressure with exenatide compared with insulin treatment (a decrease of 4.9 mm Hg in the exenatide-treated group compared with a decrease of 0.5 mm Hg in the insulin-treated group; P < 0.0001). This evidence is further supported by the Liraglutide Effects and Actions in Diabetes (LEAD) investigators  who studied another GLP-1 agonist. This study consisted of pooled data of the five randomized, placebo-controlled trials of liraglutide in addition to varying background therapy of antidiabetic agents over 52 weeks in 1041 patients. The authors reported a statistically significant reduction in both systolic (-2.7 mm Hg) and diastolic (-4.5 mm Hg) pressures with liraglutide versus placebo. The difference was seen within the first 2 weeks and could not be attributed to the degree of weight loss. Phase 3 trials with a once-weekly exenatide preparation show a similar significant improvement in blood pressure. On average, after 6 months of therapy, patients with type 2 diabetes assigned to the once-weekly preparation had a reduction in systolic blood pressure of 4.7 mm Hg (95% CI, -6.8 to -2.6) and a diastolic blood pressure reduction of -1.7 mm Hg (95% CI, -3.1 to -0.3) . The data with the DPP-IV inhibitors are more limited.
Because of the weight loss effect of exenatide, we would anticipate impacts on the lipid profile. In fact, in a subset of patients followed for 3.5 years while on exenatide, significant improvements were seen where triglycerides decreased 12% (P -= 0.0003), total cholesterol decreased 5% (P = 0.0007), LDL cholesterol decreased 6% (P < 0.0001), and high-density lipoprotein cholesterol increased 24% (P < 0.0001) . As expected, the greatest improvements were in those who lost the most weight. Caution should be exercised in interpreting these results because they represent a selected group of patients and because there are no control groups with which to compare the results. The overall impact remains to be determined in a properly controlled trial.
A growing body of evidence suggests that coronary heart disease may be associated with impaired postprandial lipid metabolism [24-26]. Postprandial lipoprotein abnormalities are more frequent in individuals with type 2 diabetes, which could explain in part the higher rate of cardiovascular diseases observed in diabetes patients. Postprandial hypertriglyceridemia is also a major determinant of oxidative stress and impaired endothelial function, which play an important role in atherosclerosis.
This illustration shows positive and negative aterial remodeling due to endothelial injury and inflammation progress where fibroatheromas grow and form the atherosclerotic plaque.
Bunck et al.  investigated the effect of exenatide compared with insulin on postprandial lipids in 69 type 2 diabetes patients treated with metformin. After 1 year, the exenatide-treated patients had significantly lowered postprandial triglyceride excursions (-246 ± 60 mg x min/dL area under the curve change) compared with insulin glargine (-58 ± 63 mg x min/dL; P = 0.014), and a significant decrease in postprandial apolipoprotein 48, whereas there was no change in apolipoprotein A-I. The significant differences in postprandial lipemia existed despite no difference in overall glucose control between the two groups .
Effect on inflammatory markers
In addition to blood pressure and lipid changes, there are other important molecular and inflammatory markers that serve as risk factors for atherosclerosis. In a human in vitro cell system, Dear et al.  evaluated the effect of liraglutide on the expression of plasminogen activator inhibitor-1 (PAI-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. Initial exposure to 10 p.M of glucose over 48 hours significantly raised the markers. However, subsequent administration of liraglutide significantly reduced PAI-1 mRNA, VCAM-1, and ICAM-1 (there was no significant change E-selectin) . These markers are being evaluated in ongoing clinical trials with both exenatide and liraglutide. Elevated C-reactive protein is associated with increased cardiovascular disease. Patients treated with exenatide for 82 weeks had a significant decrease of 1.35 mgIL from a baseline of 3.21 mg/L. In the subgroup of individuals at high risk determined by a C-reactive protein level greater than 3 mg/L, exenatide-treated patients had a 50% decrease . It may come to bear that these changes in molecular physiology, prompted by GLP-1, could have an impact on the severe atherosclerosis associated with type 2 diabetes.
Effect on endothelial function
It is well accepted that patients with poor ability to vasodilate blood vessels (ie, poor endothelial function) have increased risk of cardiovascular disease. Nystrom et al.  studied the effects of continuous infusion of GLP-1 in healthy and type 2 diabetes patients with stable coronary disease in a randomized crossover trial. In patients with type 2 diabetes mellitus (n = 12), GLP-1 doubled the brachial artery diameter whereas no change was observed in the healthy control group (n 10) .
In an attempt to elucidate the effect of GLP-1 on the vasculature independent from other hormones influenced by GLP-1, such as insulin and glucagon, the authors developed a sophisticated design that included a euglycemic somatostatin pancreatic clamp where insulin, glucagon, and growth hormone were manually added. Forearm blood flow was measured by venous occlusion plethysmography with graded brachial artery infusions of acetylcholine and nitroprusside before and after intravenous infusion of GLP-1. As a variant, the healthy participants were randomized to placebo, gliinepiride, or glyburide (two sulfonylureas commonly used as anti-diabetic agents). As previously demonstrated, infusion of GLP-1 induced vasodilation; however, the combination with glyburide abolished GLP-1-induced acetylcholine-mediated vasodilation, whereas glimepiride did not change the improved endothelial function from GLP-1. This highlights the potential for drug-drug interaction to interfere with GLP-1-induced protective myocardial mechanisms. The biologic mechanisms for the difference between these two sulfonylureas are yet to be determined .
Experimental Evidence for Effects of GLP-1 on Cardiac Metabolism
Revisiting the basic principles of cardiac metabolism The heart consumes more energy than any other organ. Adenosine triphosphate (ATP) is the myocardial energy source that leads to contraction and calcium-related sarcoplasmic reticulum activity. Myocardial ATP is primarily produced by the mitochondria by oxidative phosphorylation. This has been documented by Mootha et al. , who studied animals at or near maximum workloads and found that the mitochondria produce 95% of myocardial ATP during nonischemic conditions, with nearly complete turnover of the ATP pool every 10 seconds. Thus, in a normal heart, the rate of ATP use is very closely associated to the rate of ATP hydrolysis (demand), such that ATP content (supply) remains constant even with large increases in cardiac output.
There are two main sources for cardiac energy production (ATPs): free fatty acids (FFAs) and glucose. Oxidation of FFAs constitutes the majority of ATP production, accounting for as much as 60% to 90% of energy under normal conditions. It makes sense that FFAs would be the preferred source of energy because fat has a higher energy value (9 calories per gram) than glucose (4 calories per gram). However, the healthy heart is adaptive to a multitude of conditions, such as a sudden change in workload, fuel availability, circulating hormones (such as insulin and catecholamines), or ischemia. In response to the changing environment, the heart can switch from one substrate to another to favor the most efficient pathway to ATP production . In the fasting state, FFA levels are high and therefore are used primarily during the fed state; high glucose levels trigger the body to recognize it as the major source of energy and switch fuel (Fig. 1) .
Figure 1. A diagram of cardiac metabolism, which is key to understanding myocardial energy. ATP adenosine triphosphate: FFA — free fatty acid. (Adapted from Kelley et al. 155).
Ischemia causes a metabolic shift toward increased glucose oxidation and reduction of fatty acid oxidation. When the supply of oxygen is compromised, there is a rapid shift to glucose as the substrate for oxidation. The shift favors the most efficient pathway to ATP production because carbohydrates use much less oxygen than fatty acids to generate ATP .
As the external conditions dictate substrate utilization, substrate selection also impacts the performance of the heart. Growing evidence supports that heart contractility is greater when oxidizing glucose than FFA .
GLP-1 Increases Myocardial Glucose Uptake
Metabolism of the heart during ischemia underpins many of the abnormalities seen during the acute myocardial setting. The early rationale for the glucose-insulin-potassium infusions as metabolic adjuvant in acute myocardial infarction was to enhance myocardial glucose uptake to favor glucose oxidation and increase ATP production. Unfortunately, because of the complexity of the regimen (including nursing personnel time), the increased risk of hypoglycemia, and the volume overload in patients at risk with low ejection fraction, the risk outweighed the benefit. However, GLP-1 strategy may harness the benefit of the insulin without the unwanted adverse effects of hypoglycemia, complexity, and volume overload from the triple infusions.
Shannon and colleagues [36-38] conducted most of the preclinical studies reporting a beneficial effect of GLP-1 on left ventricular contractility. Data from animal studies suggest that GLP-1 1) improves myocardial insulin sensitivity and glucose uptake; 2) increases stroke volume and cardiac output; 3) decreases left ventricular end-diastolic volume, heart rate, and systemic vascular resistance; and 4) prolongs survival after chronic administration [36-38].
Nikolaidis et al.  investigated the effect of a 72-hour infusion of GLP-1 in high-risk patients (n = 10) with acute myocardial infarction and reduced systolic function (ejection fraction < 40%) undergoing percutaneous coronary intervention compared with an untreated control group. Both groups received standard post–myocardial infarction therapy after primary angioplasty, including aspirin, clopidogrel, heparin, glycoprotein inhibitors, 13-blockers, angiotensin-converting enzyme inhibitors, and statins. There was no change in left ventricular ejection fraction (LVEF, 28% to 29%) in the control group, whereas the GLP-1–treated patients had a significant improvement (29% to 39%; P < 0.01). The improvement was observed in both diabetic and non-diabetic patients. In addition, regional wall motion score significantly decreased (-21%; P < 0.001) in the GLP1-treated patients, indicating better contractility. Overall, there was a significant improvement in the global LVEF after acute myocardial infarction with GLP-1, which is one of the most important markers of survival in cardiac patients. The positive inotropic effects of GLP-1 were demonstrated in a small group of patients with chronic heart failure (New York Heart Association III and IV), increasing LVEF from 21% to 27% over S weeks of therapy [391. Perioperative treatment with GLP-1 during coronary bypass surgery (12 hours before the operation followed by 48 hours after the operation) resulted in significant improvement in glycemic control with reduced requirements for inotropic and vasoactive agents .
Whether, GLP-1 has a direct cellular effect on the myocardium or whether all of its beneficial effects are related to the observed increased myocardial glucose uptake remains to be determined. These preliminary data suggest that this new class may offer benefit beyond glucose control for patients presenting on the cardiology floor.
Effects of GLP-1 on Ischemic Preconditioning and Postconditioning
Saving myocardium during acute injury is paramount in cardiology. The residual left ventricular systolic function after injury is crucial in determining the prognosis. Ischeniic preconditioning is a process by which transitory ischemia and subsequent reperfusion before acute myocardial infarction reduce infarct size 001. For example, preinfarction angina improves clinical outcome after myocardial infarction . The current understanding of the protective mechanisms of ischemic preconditioning suggests that a series of intracellular signals involving phosphatidylinositol 3-kinaselAKT and extracellular signal-regulated kinase-1 and -2 ultimately result in the opening of the ATP-dependent mitochondrial potassium channel . Sulfonylureas’ mechanism of action is to close the ATP-dependent potassium channel in the pancreatic cells in order to increase intracellular calcium levels and stimulate insulin secretion. Sulfonylureas also block the ATP-dependent potassium channel in cardiac cells and coronary vessels and prevent coronary vasodilatation during ischemia . Sulfonylureas’ negative effect during ischemia may explain their less than favorable cardiovascular profile in patients with coronary heart disease [44,45].
Apoptosis is another important mechanism resulting in cardiomyocyte loss during ischemia and reperfusion. 13-blockers, angiotensin-converting enzyme, and the angiotensin II type 1 antagonist have all shown mortality benefit in patients with myocardial infarction, and part of the mechanism of action may be explained by their ability to reduce apoptosis [33,46,47]. Similarly, exenatide activates prosurvival kinase (phosphoinositide 3-kinase), leading to a reduction in [3 cell apoptosis in mice that were treated with streptozotocin. This indicates that GLP-1 receptor stimulation could provide protection from apoptosis. It is suggested that the increase in circulating adenosine monophosphate levels, which are known to enhance survival, may play an important role in cellular apoptosis along with phosphatidylinositol 3 kinase, which further activates AKT, a prosurvival factor that inactivates many proapoptotic proteins (caspase-9 and BAD) [48-51].
GLP-1 combined with a DPP-IV inhibitor (vildagliptin was added to provide a longer duration of action to GLP-1) administered before ischemia in a rodent model of ischemia/ reperfusion resulted in a significant decrease in infarct size compared with control and DPP-IV inhibitor alone (26.7% ± 2.7% vs 58.7% ± 4.1% in control and 52.6% ± 4.7% in the DPP-IV inhibitor group; P < 0.0001) [15).
Dokken et al.  evaluated the impact of GLP-1 on myocardial infarct size when administered during the reperfusion period after cardiac ischemia. Following thoracotomy with occlusion of the left anterior descending coronary artery in age-matched rats, those receiving GLP-1 (a .5) experienced a decrease in infarct size (17% vs 74% of left ventricle; P < 0.05) compared with the control group (n = 4). In an isolated rat heart preparation, exenatide administered during reperfusion showed a 2.3-fold decrease in infarct size. The effect was abolished by the administration of a GLP-1 receptor antagonist, indicating that the beneficial effects are driven by the GLP-1 receptors . In the same ischemia-reperfusion injury of the heart model, Sonne et al.  also investigated the effect of exenatide and GLP-1(9-36) on myocardial performance after reperfusion. Both exenatide and GLP-1(9-36) exerted significant improvement in left ventricle performance measured by left ventricular developed pressure and rate-pressure product. Interestingly, these effects were only partially diminished by a GLP-1 receptor antagonist, suggesting involvement of other receptors. Liraglutide was also reported to significantly decrease infarct size in an ischemia-reperfusion injury murine heart preparation .
Ban et al.  propose two pathways to explain the cardioprotective effects of GLP-1. One pathway is mediated by the GLP-1 receptor and involves positive inotropic effects, glucose uptake, ischemic preconditioning, and mild vasodilatory effects. The second pathway is independent of the GLP-1 receptor and is attributed to the metabolite GLP-1(9-36). The metabolite, in their experiment, improved postischemic recovery of cardiac function and vasodilatation but lacked inotropic action .
The GLP-1 agonist-based therapies such as exenatide and liraglutide not only offer blood glucose control in patients with type 2 diabetes, but are also able to improve markers of cardiovascular disease such as hypertension, dyslipidemia, inflammatory markers, and, most importantly, reverse the spiral of weight gain. The potential for their ability to offer cardioprotective effects is independent of their effect on glucose control and may translate to improved cardiovascular outcomes in patients with type 2 diabetes. Whether the beneficial effects on cardiac metabolics and the protective effect during myocardial infarction will be replicated in humans remains to be systematically studied.
We are deeply indebted to Elaine Chiquette for her prompt and outstanding review of this manuscript.
Disclosures: No potential conflicts of interest relevant to this article were reported.
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