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Circulation on the Run

Apr 29, 2019

Dr Carolyn Lam:                                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore.

Dr Greg Hundley:                             And I'm Greg Hundley, associate editor as well, at Circulation, and director of the Pauley Heart Center in Richmond, Virginia at VCU Health. Carolyn, this issue, we've got a super-exciting interaction to follow related to SGL2 inhibitors on 24-hour ambulatory blood pressure in African-Americans, something used to treat diabetes, and maybe a positive effect on blood pressure, but more to come on that. Now, Carolyn, you're also planning to discuss some results from another SGL2 study.

Dr Carolyn Lam:                                You bet. This time, I'm taking you to Japan for the results of the SACRA study which stands for SGLT2 Inhibitor and Angiotensin Receptor Blocker Combination Therapy in Patients with Diabetes and Uncontrolled Nocturnal Hypertension and this is from Dr Kario and colleagues from Tochigi in Japan. It's a multi-centered, double-blind parallel study of 132 non-obese older adults with type 2 diabetes and uncontrolled nocturnal hypertension, receiving stable antihypertensive therapy, including angiotensin receptor blockers, who were then randomized to 12 weeks' treatment with empagliflozin 10 milligrams once daily or placebo. Clinic blood pressure was performed at baseline in weeks four, eight and 12. Twenty-four hour ambulatory blood pressure monitoring was performed at baseline and week 12 and morning home blood pressure was determined for five days before each visit. The primary efficacy endpoint was changed from baseline in nighttime blood pressure.

Dr Greg Hundley:                             So, what did they find, Carolyn?

Dr Carolyn Lam:                                Well, empagliflozin significantly reduced nighttime systolic blood pressure versus the baseline. The reductions in daytime 24-hour morning, home, and clinic systolic blood pressure at 12 weeks with empagliflozin was also greater than placebo. Between group differences in body weight and glycosylated hemoglobin reductions were significant, but small and the changes in antihypertensive medication during the study also did not differ significantly between the groups.

Dr Greg Hundley:                             Very good. Well, I'm going to switch gears and talk also on the same theme of sugar and diabetes and evaluate the long-term consumption of sugar-sweetened and artificially-sweetened beverages and the risk of mortality in U.S. adults. This is a study by Vasanti Malik from the Harvard School of Public Health. Now, as you know, in epidemiologic studies, intake of sugar-sweetened beverages has been associated with weight gain, a higher risk of type 2 diabetes, coronary heart disease and stroke, but to date, few studies have examined the association between sugar-sweetened beverages and intake and mortality. All right, Carolyn, I'm going to give you a quiz now. Here's the first question.

Dr Carolyn Lam:                                What?

Dr Greg Hundley                               That's right, sugar-sweetened beverages are the single largest source of added sugar in the U.S. diet, true or false?

Dr Carolyn Lam:                                I'm going to guess true.

Dr Greg Hundley:                             Okay, so all those consumption of sugar-sweetened beverages in the United States has decreased in the past decade. National survey data show a slight rebound in consumption in recent years among adults in many age groups. With the average equivalent being, multiple choice, 2%, 6.5% or 10% of our total energy requirements?

Dr Carolyn Lam:                                Oh, my goodness. One of the higher ones. I'm just going to go in the middle, 6.5.

Dr Greg Hundley:                             Excellent, good choice, you're a good multiple-choice taker, 6.5%. So, among younger adults, sugar-sweetened beverages contributed. They're a little bit higher, 9.3% of the daily calories in men and 8.2% in women in the United States. Now, how about other parts of the world, particularly developing countries? The intake of sugar-sweetened beverages, is it dropping, is it flat or is it rising dramatically?

Dr Carolyn Lam:                                Sorry, Greg, but that one's too easy. It's definitely rising.

Dr Greg Hundley:                             Yup, you got that right.

Dr Carolyn Lam:                                I live in those other developing countries, so I've seen so.

Dr Greg Hundley:                             And it's really thought due to widespread urbanization and beverage marketing. So, now we've got an alternative, artificially-sweetened beverages. And they're often suggested as alternatives to sugar-sweetened beverages and intake levels have increased of these alternative sweeteners in the United States. So, next question. Are the artificially sweetened beverages a better alternative to sugar--sweetened beverages in regard to cardiovascular or all-cause mortality?

Dr Carolyn Lam:                                Yikes. Okay, so Greg I'm afraid to guess on this one because I have to admit I sometimes, with a sweet tooth, like to take these alternative beverages. I think you're going to be telling us.

Dr Greg Hundley:                             Well, we don't know. Most of the data in this area is from research and comes from associative analyses utilizing longitudinal cohorts and some studies suggest yes, some studies, no. For example, one in the elderly suggested artificially-sweetened beverages, but not sugar-sweetened beverages were associated with adverse events, but critiques indicated that finding may have related to reverse causation because the elderly patients were switching from sugar-sweetened to artificially-sweetened beverages. So, where are we now? Well this study, in our Journal, examined the associations between the consumption of sugar-sweetened beverages and artificially-sweetened beverages with the risk of total and cause-specific mortality among 37,716 men from the Health Professionals Follow-up Study between 1986 and 2014 and 80,647 women from the Nurse's Health Study from 1980 to 2014, who were free from chronic diseases.

Dr Carolyn Lam:                                Wow, that's a huge combined cohort. So, come on, what were the results?

Dr Greg Hundley:                             So, the researchers found after adjusting for major diet and lifestyle factors, consumption of sugar-sweetened beverages was associated with a higher risk of total mortality and cardiovascular mortality and cancer mortality and, thus, the results provide further support for the recommendations and policies to limit intake of sugar-sweetened beverages and to consume artificially-sweetened beverages in moderation did improve overall health. Now, what were the results from artificially-sweetened beverages? Well, they were associated with total and cardiovascular disease mortality in the highest intake category only. So, those consuming large amounts of those daily, but only in the cohort of women from the Nurse's Health Study, not from the men in the Health Professionals Follow-up Study. Artificially-sweetened beverages were not associated with cancer mortality in either cohort.

So, moving forward, the positive association between high intake of artificially-sweetened beverages and total and cardiovascular disease mortality observed among women requires more study and further confirmation and also, we might consider that even though artificially-sweetened beverages could be used to replace sugar-sweetened beverages among habitual sugar-sweetened beverage consumers, higher consumption of the artificially-sweetened beverages would probably be discouraged. Finally, policies and recommendations should continue to call for reductions and limits on sugar-sweetened beverages intake and also address alternative beverage offerings with an emphasis on our favorite, water.

Dr Carolyn Lam:                                Sweet, Greg! Or maybe not so sweet. Oh, goodness. All right, well my paper deals with related, but not related perhaps, but talking about ketone body, 3-hydroxybutyrate and the cardiovascular effects of treatment with this ketone body in chronic heart failure and this is from corresponding author, Dr Nielsen from Aarhus University Hospital in Denmark and his colleagues. Now, they performed a series of studies. In the first 16 chronic HFrEF patients were randomized in a crossover design to three hours' infusion of 3-hydroxybutyrate or placebo and monitored invasively with a Swan-Ganz catheter and studied with echocardiography and they found that infusion of 3-hydroxybutyrate increased cardiac output by two liters per minute or 40% with an absolute improvement in left ventricular ejection fraction of 8%, and the observed defects were accompanied by vasodilation with a resultant stable systemic and pulmonary blood pressure.

Now, in the second part of the study, they studied eight HFrEF patients examined at increasing infusion rates of 3-hydroxybutyrate and they found a dose response relationship with a significant increase in cardiac output. And, finally, they studied 10 HFrEF patients and 10 age-matched volunteers, randomized in a crossover design to a three hour infusion of 3-hydroxybutyrate or placebo and they looked this time at myocardial external energy efficiency and oxygen consumption using 11-carbon acetate PET and what they found was 3-hydroxybutyrate increased oxygen consumption without altering myocardial external energy efficiency. The response did not differ between HFrEF and age-matched volunteers.

Dr Greg Hundley:                             Wow, Carolyn, there was a lot of data in that study. So, what's your main take home?

Dr Carolyn Lam:                                In summary, 3-hydroxybutyrate, this ketone body, demonstrated dose-dependent beneficial cardiac and hemodynamic effects in patients with heart failure reduced ejection fraction without deteriorating mechano-energetic coupling and without causing any safety issues. And what's significant is that this opens the door to modulating circulating 3-hydroxybutyrate as a novel treatment option in patients with heart failure.

Dr Greg Hundley:                             Right, Carolyn, so I've got an interesting study from the world of basic science that's looking at the role of potassium channels as novel molecular targets and bradyarrhythmia’s and even, perhaps, in atrial fibrillation. This is from Yoshihiro Asano from Osaka University in Japan. So, the acetylcholine activated potassium channel is expressed in the sinus node, atrium, and atrioventricular node and contributes to heart rate slowing triggered by the parasympathetic nervous system. So the potassium, activated potassium channel is a heterotetramer of 2 inwardly rectifying potassium channel proteins encoded by two genes, KCNJ3 and KCNJ5, respectively.

Dr Carolyn Lam:                                Okay, so what did this study show?

Dr Greg Hundley:                             What it showed is a selective potassium acetylcholine channel blocker effectively inhibited a mutant potassium channel and up-regulated heart rate and bradyarrhythmias using a zebra fish model. And this is really interesting, Carolyn, because two conclusions are worth considering. First, future studies could determine the prevalence of bradyarrhythmias associated with dysfunctional mutation in this potassium channel. And, second, results raise the possibility that pharmacologic blockade of this channel might serve as a therapy for increasing heart rate and be especially beneficial for bradyarrhythmias in patients with gain of function mutations in the channel and, therefore, genetic testing for KCNJ3 and KCNJ5 in patients with bradyarrhythmias may provide a drug treatment option in lieu of an invasive surgical implantation of a pacemaker.

Dr Carolyn Lam:                                Fascinating! Thanks, Greg. What a great issue and now onto an even greater feature discussion.

Dr Greg Hundley:                             Welcome, everybody, to the second part of this interview. We've got a very exciting paper to discuss with you. Remember this is our backstage pass to Circulation and we've got today, Keith Ferdinand from Tulane University in Louisiana and our Associate Editor, our hypertensive expert, Dr Wanpen Vongpatanasin from the University of Texas Southwestern Medical School in Dallas. We're going to be discussing the anti-hyperglycemic and blood pressure effects of empagliflozin in African-Americans with type two diabetes and hypertension. Keith, we're going to start with you. What was your hypothesis for this study? Who's the study population? Review a little bit about your design and, importantly, what were your results?

Dr Keith Ferdinand:                         Well, my hypothesis was that one of the new classes of medications, the SGLT2 inhibitors, which have a mild diuretic effect and a mild natriuretic effect, may have benefits in self-described African-Americans in not only controlling glucose, but also controlling hypertension. These medicines are approved, of course, as medications for type 2 diabetes, but we had seen in some earlier trials that did not include self-defined African-Americans, that there may be a blood pressure effect. We know that diabetes is higher in blacks, almost twice that seen in the general population and, of course, hypertension and uncontrolled hypertension is disproportionate. So, here's a medication that may be even more beneficial in that population and we wanted to study it.

Dr Greg Hundley:                             And tell us a little bit about who was in the study and what was your design?

Dr Keith Ferdinand:                         The design was to be a placebo-controlled randomized trial using empagliflozin starting at 10 milligrams and force-titrating to 25 milligrams versus placebo on the background of conventional anti-hypertensive agents. Everyone was on one or more anti-hypertensive agents. We used the gold standard for blood pressure control with 24-hour ambulatory blood pressure and that was the means by which patients entered the study, although the primary endpoint was changed in hemoglobin A1c, we actually designed and powered the study to see if there would be a change in blood pressure. Additionally, we looked for changes in weight, losing calories with the effects of the SGLT2 inhibitors with glycosuria has translated in some preliminary trials to weight loss. So, this was a study looking at a population. Most of them had diabetes for approximately nine to 10 years, 59 years of age, definite hypertension, obesity, a high risk population, to see if a new class of medications would be beneficial.

Dr Greg Hundley:                             And what did you find?

Dr Keith Ferdinand:                         Fortunately, we did find an effect. It did lower the primary endpoint of a change in hemoglobin A1c, but remember it was powered also by blood pressure effect and fortunately, we did see that both with the ambulatory and clinic blood pressure, both at 12 weeks and 24 weeks. The clinic blood pressure was a trend, but the ambulatory blood pressure was positive at 12 weeks and both had a strong difference in terms of confidence intervals for blood pressure lowering. About five millimeters of mercury at 12 weeks and up eight millimeters of mercury at 24 weeks for the change in ambulatory blood pressure which, in a large population would translate into a significant blood pressure lowering, the hemoglobin A1c reduction was also significant. But, although that was the primary endpoint, my concern is as a cardiologist and cardiovascular specialist.

Dr Greg Hundley:                             And what dose did you select? Did you have to up-titrate this at all and, finally, were there any side effects?

Dr Keith Ferdinand:                         You know, with the SGLT2 inhibitors, you have an effect both in terms of glycosuria, some osmotic diuresis and some natriuresis, and with the loss of body weight. But the change in body weight really wasn't that much, about 1.2 kilos and the change in blood pressure was discordant with the change in body weight. So, we think that the effects in blood pressure may be from extended diuretic effect, but it may also be from effects on endothelial function that are outside those significantly related to diuresis, per se. Because you're urinating glucose, glycosuria, you would expect the potential for superficial infections, mycotic infections and that was seen. The rates were not prohibitive and not dissimilar to what's been seen in other studies. So, overall, the drug was well-tolerated. It did not have any significant adverse effects outside of a few mycotic infections, which are basically superficial fungal infections and that's been seen in other uses of the SGLT2 inhibitors, but nothing that I think would be unusually disturbing in this population.

Dr Greg Hundley:                             Outstanding. So, Wanpen, going to switch over to you and ask you to help us put this in the context of treating African-American men, women with hypertension. How do we think about using this new finding? How would we integrate it with other therapies that these individuals already might be taking?

Dr Wanpen Vongpatanasin:         Sure, so I think that this study is very intriguing and interesting that empagliflozin to me actually had more prominent benefit on lowering 24-hour blood pressure than the previous study that the true analysis showed the effects of 24-hour blood pressure is much less or almost half of four to five millimeters of mercury and that could be that this was not that significant in African-Americans and maybe this drug is particularly effective and, as you know, African-Americans tend to have more salt sensitive form of hypertension and I wonder if that could explain the results, but I think it's very encouraging because this drug class approved for treatment of diabetes and medication. African-American have higher blood pressures than other ethnic groups and having diabetes makes them prone to having more resistant hypertension. In this particular trial, almost 40% of the patients enrolled is already taking three or more antihypertensive medications, so adding this on top and having that benefit is as good as adding spironolactone, for example, and I didn't see from the manuscript, how many patients are taking spironolactone already, but I would be curious to see that, as well.

But I think that is something that physicians should think about and this drug is already FDA-approved for treating diabetes, so if you have a patient with difficult to control blood pressure and already needed something for diabetes, this could make a lot of sense to use it.

Dr Greg Hundley:                             Keith, do you have any thoughts on Wanpen's comment regarding the use of spironolactone in the study population?

Dr Keith Ferdinand:                         No, I don't have those specific data available at the time that we're speaking now, but that's certainly something that I will attempt to look at the database and get more information. But, I think Wanpen is absolutely right. If you look at some of the previous studies, for instance, EMPA-REG, the major outcomes trial that led to the indication of a decrease in cardiovascular death and heart failure, the blood pressure lowering wasn't that robust, maybe 4/2, but here we saw at week 24, 10 millimeters of mercury of blood pressure reduction and if you placebo subtract, which is what I mentioned in my first comments, you're talking about 8 to 8.5 millimeters of mercury reduction and that's a significant reduction, especially for ambulatory blood pressure measurement.

Dr Greg Hundley:                             Absolutely. So, I'm going to go with each of you separately, but taking this manuscript and this work that Keith, you've performed, we'll start with you. What do you think of the next steps in the research in this area, both from the perspective of using this family of agents in individuals with both diabetes and hypertension?

Dr Keith Ferdinand:                         What I would hope in the future is another outcome study is done with an SGLT2, any numbers of that class, that they particularly target enough African-Americans to see if this robust blood pressure reduction not only is found again, but also translates to decreased cardiovascular events. You know, NHLBI, for instance and ALLHAT, selectively over-represents African-Americans. They had 35% African-Americans in ALLHAT and the reason for that is you have a population that has a disproportionate degree of hypertension and a disproportionate degree of associated cardiovascular disease and renal disease, so you want to make sure that any medication that's been shown to be effective is effective in the higher risk population. So a future outcome study, regardless of whether they're renal-based or related to heart failure, I hope will target an increased population of blacks to see some of the robust reduction we have, translates in cardiovascular events.

My suspicion is that self-defined African-American versus a genetic factor, describes the phenotype of patients who tend to be more obese, have more salt sensitivity, perhaps subclinical kidney disease and will respond to a medication that has some diuretic natriuretic effects and effects with endothelial dysfunction and sympathetic discharge.

Dr Greg Hundley:                             Very good, well I heard sympathetic discharge. Wanpen, any comments there? That's your area.

Dr Wanpen Vongpatanasin:         I think that definitely needs to be studied. To my knowledge, there was only one small study that published that tried to measure sympathetic nerve activity directly, but unfortunately that study after a very short-term treatment for like four or five days, so I’m sure that there will be more studies to come and also hope that the future study will shed light on any particular markers with surrogate that will identify patients that will respond better, for example, PATHWAY-2 trials that were done to test the effects of spironolactone on resistant hypertension they found that the lower the reading, the more likely you can have better response to Aldactone and I wonder if this might apply to empagliflozin and be something else. I think the fact that the blood pressures continued to decline from the week 12 to week 24 is very, very interesting when the body weight effect doesn't necessarily go down much further. This really tells us there's something else beyond weight and perhaps glucose that would explain this.

Dr Greg Hundley:                             Very good. Well, I certainly want to thank you both for this outstanding discussion. Keith, we want to thank you for bringing this manuscript to Circulation and identifying this new application for this therapy in African-Americans. Wanpen, thank you also for your time and comments.

On behalf of Carolyn and myself, we really appreciate you listening. Have a great week and we look forward to seeing you next week.

Dr Carolyn Lam:                                This program is a copyright of American Heart Association 2019.