CardioSource WorldNews - Page 44

That’s all pretty broadly known among the cardiovascular community. But in the last couple years, some confusion has set in. It stands to reason that tight glucose control should reduce risk and including glycemic measures in algorithms used to calculate risk of CVD might improve their predictive ability. Indeed, guidelines on risk assessment conclude that measurement of glycoslated hemoglobin or HbA1c levels may be reasonable in asymptomatic adults without a diagnosis of diabetes. Makes sense…until you look at the data. It turns out that HbA1c is not associated with clinically meaningful improvement in assessment of CVD risk. That was a big surprise when the results were first reported of an analysis of data from almost 300,000 people without known diabetes and CVD at baseline indicates.7 There seems to be a glucose paradox: while fasting blood sugar and HbA1c predict future macro- and microvascular events, tight glucose control definitely reduces microvascular events but does not impact macrovascular effects. That’s quite different from blood pressure control and the use of statins for lipid lowering, both of which reduce macrovascular events. So, does a place for tight glucose control exist? Probably. Dr. Creager and colleagues note that, despite this paradox, diabetes is most certainly a risk multiplier in atherosclerosis. It increases both the risk of developing atherosclerosis and the incidence of complications of atherosclerosis, and is associated with poorer outcomes from these events. They added that health care professionals enjoy the benefit of a wide variety of clinical trial data supporting specific treatments and targets for patients with diabetes. These include: • Lipid-lowering therapy with statins, medication for blood pressure control, and antiplatelet therapy in patients with increased cardiovascular risk scores. • Hyperglycemia should be treated to a target glycosylated hemoglobin of 7%, with therapy that includes an agent that improves insulin sensitivity, such as metformin. • Optimal medical treatment, including risk factor modification, antiplatelet therapy, and antianginal medications re- 42 CardioSource WorldNews mains the preferred approach for most patients wit h diabetes and stable CAD. What about aggressive glucoselowering therapy? When you parse the data, this approach continues to demonstrate benefits in some individuals. At ACC.15, Dr. Creager said aggressive glucose lowering is particularly warranted in younger, leaner patients with a shorter duration of T2DM, lower baseline HbA1c levels, and without evident CAD. While tight glycemic control improves macrovascular events, caution is warranted in older patients and those with established CVD or multiple comorbidities. He also emphasized that aggressive early treatment of T2DM may impact CV events due to a legacy, or memory, effect which may take many years to become evident. “A Heart Med Masquerading as a Diabetes Med” At a scientific meeting, a presenter will commonly enjoy polite applause upon reaching the end of his or her presentation. But it’s not often the findings of a new trial are met with a gasp followed immediately by a standing ovation. When it happens, it’s a good guess the findings might be “game changing.” Enter the EMPA-REG OUTCOME trial. “It’s the first rigorously designed, positive clinical outcomes trial using any clinical outcome endpoint in the field of diabetes, type 1 or type 2,” said Darren K. McGuire, MD, MHSc, in an interview with CardioSource WorldNews. “It is absolutely a game-changing result.” Dr. McGuire is the Dallas Heart Ball Chair for Research on Heart Disease in Women at UT-Southwestern Medical Center in Dallas, and an expert in large-scale clinical trial design and execution. He is the coeditor of Diabetes in Cardiovascular Disease: A Companion to Braunwald’s Heart Disease (1st edition, 2015) and disclosed that he consults with several pharmaceutical companies on their diabetes programs. With nearly 1 in 10 U.S. adults suffering from type 2 diabetes, it’s no wonder the EMPA-REG OUTCOME trial results engendered excitement from diabetologists. The results were initially presented at the 2105 European Association for the Study “[The EMPA-REG OUTCOME trial is] the first rigorously designed, positive clinical outcomes trial using any clinical outcome endpoint in the field of diabetes, type 1 or type 2. It is absolutely a game-changing result.” —Darren K. McGuire, MD, MHSc of Diabetes meeting in September with the main findings presented for a cardio-centric audience at the 2015 AHA Scientific Sessions 2 months later in Orlando.8 The trial enrolled patients with T2DM and established CVD at high risk for CV events and assigned to either empagliflozin 10 or 25 mg (Jardiance, Boehringer Ingelheim) or placebo. A total of 7,020 patients from 42 countries and 590 sites participated. Here’s why cardiologists should be interested in this drug: over a median of 3.1 years, empagliflozin (pooled data from the doses studied) was superior to placebo for the primary composite outcome of CV death, nonfatal MI, or nonfatal stroke (10.5% vs. 12.1%; hazard ratio [HR]: 0.86; p = 0.04), with the difference driven primarily by a 38% relative risk reduction (RRR) in CV death (p < 0.0001). No significant differences were seen in nonfatal MI or nonfatal stroke. Empagliflozin also reduced the composite of heart failure (HF) hospitalization and CV death (HR: 0.66; p < 0.001), with similar benefit seen with both doses. All-cause hospitalization was reduced by 11% with empagliflozin (HR: 0.89; p < 0.05). Further investigation of HF outcomes in EMPA-REG were published in January 2016 and showed that the drug improved HF outcomes both in those patients with and without baseline HF.9 “We now have a drug that’s labeled as a drug for diabetes that actually prevents hospitalization for heart failure and cardiovascular and all-cause mortality, but none of us believe (that) has anything to do with blood glucose control, so it’s kind of difficult to call this a diabetes drug,” said Dr. McGuire. “It looks more like it’s a cardiovascular drug that has a side effect of lowering blood glucose.”  It Works, Use it! As for Dr. McGuire, he started prescribing empagliflozin to his T2DM patients the day after he saw the EMPA-REG findings. “Despite my diabetes interest, I have never managed blood glucose as a clinician, but after EMAP-REG OUTCOME, it is the first time in my career where I have a drug that lowers blood glucose and has cardiovascular risk benefit so I use it not for the glucose benefit but for the cardiovascular risk benefit.” He lets his patients’ primary care physicians know he has prescribed an SLGT2 inhibitor, but doesn’t delay starting the medication. “It’s a simple prescription, there is no dose titration and very little risk of hypoglycemia. The two doses in the trial looked identical, so I use 10 mg daily and don’t think there is any use for 25 mg.” His bigger concern is affordability, since empagliflozin costs about $300 monthly. “Some physicians are still going to wait and my question is what are you waiting for? Do you think there’s going to be another trial? No way, we’ve got a winner here. The trial was robust and well conducted; the results were significant and heart failure and CV death signals were extremely robust.” Most of the glucose filtered by the kidneys is reclaimed in the proximal tubules and sodium glucose cotransporter-2 (SGLT2) is responsible for about 90% of this reabsorption. A selective inhibitor of SGLT2, empagliflozin reduces this reabsorption and increases urinary glucose excretion. It is this “glucosuria” that is responsible for the most common known issue of SGLT2 inhibitors: genital infections. Other than glucosuria and an increased risk of subsequent genital infection, particularly in women, the March 2016