June 04, 2019 SGLT2 inhibitors in clinical practice

Erin Krusky: [00:00:01] OK. Welcome everyone to diabetes Canada's 2019 Spring webinar Series. This is the first webinar of a series of four webinars. My name is Erin Krusky and I will be your host today. We are delighted that you are able to join us today for the webinar to learn about SGLT 2 inhibitors in clinical practice. An evaluation will be available to fill out a couple of minutes after the webinar concludes today. Please return to this event page to complete the evaluation and view the event recording you will need to fill out the evaluation survey in order to receive a certification of completion for participating in the webinar today. We thank you in advance for your input. Throughout the presentation you will have the opportunity to type in the Q & A box. We ask that you use this box for any questions you may have along the way. And our presenter will be happy to answer at the end of the presentation. If we don't get to all the questions asked then we will post the answers from our speaker in the TimedRight Diabetes 365 forum. The presentation itself will be about thirty to forty five thirty to forty minutes in length with 10 to 15 minutes at the end for questions. It is important to note that this webinar will be recorded and posted on Diabetes Canada website at a later date. Now I would like to welcome our speaker Harpreet Bajaj. And thank him for joining us today. Before turning it over to Dr. Bajaj I'd like to give you a brief introduction. Dr. Bajaj started his endocrinology practice with LMC in Brampton in 2009. Dr. Bajaj is the director of the late phase research at LMC a research associate at Mount Sinai Hospital Toronto and an adjunct lecturer at McMaster University. He has co-authored publications in key medical journals in the field of diabetes, obesity and cardiovascular risk assessment. His major interest lie in translational research focused on real life practical approaches to improve standards of practice to reduce diabetes complications and cardiovascular risk factors. He volunteers in numerous community public health organizations as well as media programs with the intent of raising public awareness on diabetes prevention and treatment with a specific focus on the South Asian population in Canada. Dr. Bajaj serves Diabetes Canada as the co-chair of the communication and marketing portfolio within the professional section national executive as a national consultant editor for the Canadian Journal for diabetes and as an expert committee member for the 2018 clinical practice guidelines. He has recently been appointed as the vice chair of Diabetes Canada clinical practice guidelines for a three year term. So without further ado I present to you Harpreet Bajaj. 

Harpreet Bajaj: [00:03:08] Thank you Erin for that introduction. It's great to do this over the web wherever you are in Canada and it's great to talk to you. Communicate to you through this platform. As Erin mentioned this is the first of a series of webinars which will cover a gamut of topics in type 2 diabetes. And this is the first half of that series. As such it focuses on SGLT2 inhibitors in clinical practice. I'm going to be doing like an update on what we know of SGLT2 inhibitors now in the mid 2019. Here's my disclosures. So I have received speaking honouraium in the past from all these different companies many of them accredited and these are accreditation companies as well. Clinical trial participation. Some of the trials that we discuss I've participated in as a principal investigator and some of those trials. I don't have any personal research support or grants and don't do any consulting or advisory work for pharma. 

Harpreet Bajaj: [00:04:25] I don't hold any stocks. 

Harpreet Bajaj: [00:04:29] So this is an accredited program through Diabetes Canada and has received financial support from Diabetes Canada as well as in-kind support. I have received or I will receive an honorarium from Diabetes Canada's scientific group. Diabetes Canada has no products. In terms of mitigating potential bias the information that we talk about in this program will be based on evidence which is published and peer reviewed in high impact journals based on high grade of evidence randomized clinical trials is what we're basing this CME program on. 

Harpreet Bajaj: [00:05:16] If there's anything that is off label I'll mention it separately. So here is the learning objectives quite simple. So talk about what is the appropriate role for SGLT2 inhibitors in the multi-dimensional care of a patient with type 2 diabetes. Compare data on some currently available SGLT2 inhibitors from clinical trials. Well before I jump in to SGLT2 inhibitors focus I want to start broadly and maybe get a sense of where people are at. With a question and I've been told that people can see the question and answer this in a poll format on their device whatever device you're using as well. So let's see if we get some results. So the question is what is the most important, thee most important. So one single answer is correct is what I'm asking for. What is the most important goal of diabetes management? Is it an A1C target? It could be six point five or seven, a reduction of complications. Is it the resolution of symptoms? Is it to minimize hypoglycemia or is it durability of glycemic control? Let's see if we get any votes on this poll. Usually on such polls you get some background music but I guess we don't have any today here. And I'm not sure if this poll is live right now. OK we get some answers. A reduction of complications more than 50 percent of you agree. And I think that is the right answer. Everything else is important. Of course diabetes management includes everything else that is mentioned but reduction of complications is the answer that I was trying to get to. And that is the most important goal of diabetes management. And how do we get to that is by the A1C target, minimizing hypoglycemia. Trying to get the durability of glycemic control and using medications that we think reduce the risk of complications as well. So that's wonderful. Thank you. Let's go on and talk about the complications as such. So starting off with complications what complications are we talking about. So traditionally we have macro vascular complications or micro vascular complications. The macro vascular means the high or the big vessels in the body which are myocardial infarction, stroke, or peripheral artery disease. Micro vascular complications or the small vessel complications include retinopathy, nephropathy on neuropathy. But there are a lot of other complications that may not be easily classifiable as either macro vascular or micro vascular complications. For example fatty liver disease may be present in about 75 percent of people with type 2 diabetes but it's not. Neither macro vascular nor micro vascular. Similarly a large number of people with diabetes have depression or other mental health disorder as well. And those problems are not easily classified all in the same classification as well. And then there's heart failure which we know is a heart complication. But it can occur even without macro vascular complications not necessarily coronary artery disease. But even without that and it's often been called the frequent fatal and forgotten complication of diabetes. Why that? because heart failure is quite common actually in some of the studies more common than heart attacks or strokes. Also it is often fatal in people with diabetes and leads to significant morbidity and mortality and affects the quality of life of the patient. Also it's forgotten because you know we focus on the atherosclerosis or macro vascular disease risk but sometimes don't necessarily focus on the heart failure risk as well. Talking about goals of management and how this has evolved over time and how drug therapy has evolved over time. So I'm going to show you what I think how things evolved over the past maybe 20 - 25 years. So if you look at the era before 2000 that was the sulfonylureas and insulin era. And in that in that era the goal was to get the A1C as low as possible. A1C was a new new kid on the block at that time and we were trying to get the A1C as good as possible because UKPPS and DCCT trials in that era had shown benefit as we reduce A1C. Intensive glycemic control with sulfonylureas and insulin was what the focus was. And of course the bottom line always has been despite all the changes evolution has been unhealthy behavior interventions lifestyle modification also multifactorial risk factor modification. But here in the middle we are basically talking about just diabetes management it also includes of course blood pressure management, cholesterol management, giving anti-platlet agents in the right population etc.. So that was the first era. How about the middle era. So 2000 to 2014 this is when we got initially the Thiazolidinediones medications and then DPP 4 inhibitors. Now if you compared Thiazolidinediones to DPP4 inhibitors compared to Sulfonylureas and insulin one of the benefits has been that these medications have lower risk of hypoglycemia especially when you add to metformin. And also in this era around 2007 maybe 2008 we got an ACORD trial as well. The ACORD trial suggested that maybe intensive glycemic control or the lower the better A1C does not hold true as in that trial. When we tried to get to A1C target of less than 6 percent first of all that target was not achievable in the majority of the patients because of hypoglycemia. And it actually led to an increase of about 20 percent for all cause mortality as well. So then the goal kind of evolved over time and the goal for the last you know 2000 to 2014 so what 15 years has been the lower the better on an A1C but tried to avoid hypoglycemia. And then 2015 onwards we've started having started getting positive results on cardiovascular outcome trials where there's SGLT2 inhibitors and GLP-1 receptor agonists. So that's the 2015 onwards with these medications. Now of course GLP-1 receptor agonist, SGLT2 inhibitors reduce A1C, reduce glucose have lower risk of hypoglycemia they also help blood pressure cholesterol and some other parameters as well. But then what has changed and changed the goals as such in this era as such has been the cardiovascular and kidney disease outcomes that has come up with these new medications. So now the goal almost is that you want to reduce complications including the cardiovascular as well as chronic kidney disease complications with an individualized A1C target. 

Harpreet Bajaj: [00:13:40] An addition or to boot. 

Harpreet Bajaj: [00:13:46] So let's focus on the GLP-1 receptor agonists, SGLT2 inhibitors. What we are asking for from these medications is multifactorial effects. And I'll explain that in a minute. So glucose reduction is one of the things but then also blood pressure reduction, microalbuminuria reduction or renal protection, reduce inflammation weight and in many cases fatty liver disease and then lipid effects. But more importantly maybe cardiovascular protection and that's what the GLP-1 receptor agonists and SGLT2 inhibitors I think have brought to the table especially with a proven cardiovascular benefits as well as some of the renal protection studies that have been done or are ongoing as well. You'll find out what happens in the future. So basically this these two classes of drugs the GLP receptors agonists and SGLT2 inhibitors have changed how we think about managing diabetes and have brought the focus not just on glucose but also on everything else that we do in management of diabetes especially the focus on reducing complications in diabetes. 

Harpreet Bajaj: [00:15:04] I believe there's a webinar later on in this series that talks about specific goals of diabetes management so I'll leave it at that. I also believe later this month there is a webinar on GLP-1 receptor agonists separately so I'll leave that there as well and I'll move on just to SGLT2 inhibitors and talk about some of the cardiovascular outcome trials that we've had over the past few years since the 2015. What is the new era that we're talking about. So the first one that we got was the EPMA-REG outcome the first cardiovascular outcome trial which were all in diabetes. 

Harpreet Bajaj: [00:15:45] Actually the landmark because this is the first intervention trial with a diabetes agent that showed cardiovascular benefits which were quite significant and stark. 

Harpreet Bajaj: [00:16:00] So what we see is a reduction of all these end points. So MACE, MACE is Major acute coronary events and these are these include acute MI. These include stroke or peripheral vascular disease. So these events were significantly reduced as such. And this and this EMPA-REG outcome trial but also what was reduced was heart failure hospitalization which was significant quite significant as such as well the significance of the heart failure outcome was 35 percent and it is thought that SGLT2 inhibitors based on this outcome being reduced that maybe it's the volume or hemodynamic mechanism that is responsible for MACE reduction as well. 

Harpreet Bajaj: [00:16:56] So MACE you can think of as a macro vascular complication but heart failure as a not macro not necessarily a macro vascular complication but then hemodynamic reduction putting maybe less pressure on the heart and then hemodynamically helping the heart pump better and then possibly leading to some changes in the metabolism off the heart itself is what is thought to be the beneficial effect for the MACE in this trial. Then the combination in orange or CV at heart failure of hospitalization was also significantly reduced by 34 percent in this trial and not just a combination but CV deaths that individually was also reducing EMPA-REG outcome and that to this day it remains the only trial with a SGLT2 inhibitor that has shown a reduction in cardiovascular death as well as all cause mortality as well. 

Harpreet Bajaj: [00:17:55] And then the last bar on this graph is renal outcome renal outcome was quite a surprise in EMPA-REG outcome I don't believe most people, people who deal with research and clinically expected this stark reduction in renal outcome. In fact in the protocol renal outcome was not a pre specified outcome. And this was a post doc analysis that was done on the renal outcome which had significant reduction as well. The pre specified outcome was just including albuminuria in addition to two other renal outcomes that is shown here. But even without the albuminuria so doubling our serum creatinine accompanied by EGFR which is less than 45. Or the initiation of dialysis or death from renal disease was also reduced in this EMPA-REG outcome. So that was kind of a pleasant surprise in terms of SGLT2 inhibitors cardiovascular prevention as well as potential renal protection in this patient subgroup. The important question is what was the population in the EMPA-REG outcome trial. The population was completely 100 percent secondary prevention. What is mentioned on the left bottom corner there which is ECVD which is established cardiovascular disease. So that is what was reduced and that was that is what was the population in this EMPA-REG outcome in which we saw MACE reduction MACE reduction being again MI, stroke or cardiovascular death. A reduction in heart failure hospitalization as well as a reduction in renal outcomes as well. Some people or are not convinced and they said we need to see this in another trial and another trial came about just about two years later in the CANVAS program with Canaglifozin. So in this similar kind of benefit on all these outcomes was seen so MACE was reduced with a P-value which was significant with about the same magnitude about 14 percent relative risk reduction of MACE. Again MACE composite end point of MI, stroke and cardiovascular death. 

Harpreet Bajaj: [00:20:19] Heart failure hospitalization was reduced and the composite of CV death and heart failure hospitalization was reduced as well. The CV death itself was not reduce in this CANVAS program. 

Harpreet Bajaj: [00:20:32] The renal outcome was a pre specified outcome as a secondary outcome in this program and that was significantly reduced 40 percent as well. So all of this was kind of consistent with the EMPA-REG outcome and hence you know people especially us in diabetes. We got you know two large clinical trials which suggest benefit on cardiovascular events. Also a potential for a secondary benefit on renal outcomes as well. 

Harpreet Bajaj: [00:21:06] This population CANVAS was slightly different from the EMPA-REG outcome. As you can see at the bottom left of the screen so 66 percent I should say. 

Harpreet Bajaj: [00:21:19] Bottom right on the screen bottom left of you. So 66 percent of the population was secondary prevention or patients with established cardiovascular disease so those who had a MI, stroke or or peripheral vascular disease that baseline 34 percent or one third of those patients were with multiple risk factor or primary prevention. So these patients did not even have a history of MI, stroke or peripheral vascular disease. Now that was a smaller subset however and the majority of the patients were at secondary prevention. So that's great. How about more primary prevention. So we got a trial DECLARE trial just last year which was 60 percent primary prevention with multiple risk factors without established cardiovascular disease. And this was a 17000 patient study that went on for almost four years or so. And you know a lot. A large sample size with a large power to show difference if there was a difference as well. So there were two co- primary endpoints in DECLARE to me and DECLARE was with Emaglifozin versus placebo. So here I'm showing you both of those co-primary endpoints. So the MACE end point which we've seen was reduced in EMPA-REG outcome as well as in CANVAS did not meet statistically significant that was not significantly reduced. But what was reduced was a CV death heart failure hospitalization. In that CV death was not significantly reduced. So this composite of CV death hospitalization why we're seeing this this as significantly reduced is from reduction of heart failure hospitalization itself. Which is quite significant if we think about it. If we are reducing at least a heart failure hospitalization in this in this patient population that is a benefit that is there from SGLT2 inhibitors in this study. Now this hazard ratio was zero point eighty three where the p value of significance of zero point zero zero five for superiority. So this is what we got late last year and this adds to what we already knew from EMPA-REG outcome and CANVAS. And it actually expands some of this to the primary prevention. I'm not going to show you the primary prevention versus secondary prevention data separately but the rate reduction was lower and the primary prevention subgroup for heart failure hospitalization than was in the secondary prevention subgroup. Also in the secondary prevention sub group it appeared though not reaching statistical significance that MACE was trending towards an effect as well. Now in this clinically clinically when we think about benefit we always talk about number needing to treat in this paradigm as well in the secondary prevention trials so EMPA-REG outcome for example the number needed to treat was quite good it was around 30 to 40 for some of those end points or the three years time of EMPA-REG outcome. 

Harpreet Bajaj: [00:24:53] Whereas in DECLARE the CV death, heart failure, hospitalization. If you talk about just the primary prevention group it may be above 120 as a number needed to treat. 

Harpreet Bajaj: [00:25:08] Usually we think about a number needed to treat of 50 or so as being being a clinically significant number. So this was slightly over that limit. And that's also a question among clinicians and has led to some discussion around the around the impact of this benefit as well. So those are three cardiovascular outcome trials that we've had and the results from that in the DECLARE to me. They also looked at renal outcome as a secondary measure secondary outcome as well. And this is the renal composite endpoint from DECLARE to me which did suggest again a benefit on on the composite which was more than 40 percent reduction of EGFR, new dialysis, end-stage-renal disease or death from renal cardiovascular causes as well. 

Harpreet Bajaj: [00:26:07] And this was statistically significant as well. So that is a cardiovascular outcome trials. Of course the renal outcome. This was these were not kidney disease outcome trials. So these are kind of hypothesis generating then and we would need to see this in our kidney disease outcome trial to be convinced that this is indeed the case. 

Harpreet Bajaj: [00:26:31] But if you just talk about cardiovascular outcome trials how do we think of all of this together or what. What do these data mean for diabetes management. So if you think about patients with diabetes. 

Harpreet Bajaj: [00:26:47] Think of them as type secondary prevention which is the top triangle. 

Harpreet Bajaj: [00:26:53] And those are people who have coronary artery disease cardiovascular disease history or peripheral artery disease. So that's what PAD stands for. Or at the bottom. The primary prevention group which is with multiple risk factors diabetes of course is a risk factor but they may have other risk factors like blood pressure cholesterol maybe smoking maybe obesity other risk factors as well. 

Harpreet Bajaj: [00:27:19] And it is said that about maybe 50 in 10 to 15 percent of patients in a typical practice like a family practice or an endocrinology practice diabetes practice may have maybe people who fall into the secondary prevention subgroup whereas maybe 80 to 85 percent fall in the primary prevention subgroup as such. So then primary prevention EMPA-REG did not cover that primary prevention it was just a secondary prevention trial CANVAS had about a one third population in the primary prevention and then DECLARE to me had about two thirds of the population or about 10,000 patients in the primary prevention sub group as well. 

Harpreet Bajaj: [00:28:08] So if you're to take a look overall at what the data suggests from these three trials is that SGLT2 inhibitors May cover some of benefits as such so secondary prevention. There appears to be a benefit which is consistent in terms of MACE reduction. So these are thought to be again atherosclerotic events. And in this population MACE reduction was significant and EMPA-REG outcome as well as in CANVAS and trended towards significant and the DECLARE trial. In terms of primary prevention or people without a history of cardiovascular disease. In that and especially in the DECLARE there appears to be a reduction of heart failure hospitalization. It was seen in the DELARE trial and kind of suggested and in the CANVAS program as well. So that's what overall if you take a look all of these three cardiovascular outcome trials that is what is suggested. And in terms of renal disease also there's renal benefit from these cardiovascular outcome trials is suggested in either the secondary prevention or in the primary prevention sub group as well. 

Harpreet Bajaj: [00:29:28] So in secondary prevention there is a MACE reduction as well as heart failure reduction as well as renal disease reduction. Whereas in primary prevention MACE reduction does not appear to be there with SGLT2 inhibitors. However there appears to be a possibility of heart failure hospitalization or reduction as well as a possible suggestion as a secondary outcome of renal disease protection as well. So that's where we are at. 

Harpreet Bajaj: [00:29:56] For the three cardiovascular outcome trials and we recently just last month had the first kidney disease outcome trial called CREDENCE with a SGLT2 inhibitor, Canagliflozin as well. So I'm going to share some data from this recent publication. So CREDENCE study design is what you see on the slide here. The important things to note in the study design all of these are people with diabetes about 30 years of age A1C between 6.5 - 12 eGFR between 30 to 90 with a significant number for the UACR a urine albumin creatinine ratio. 

Harpreet Bajaj: [00:30:41] So in our in our mmols plan that that number equates to about 33 to about 300 for the mmol range on the urinary album creatinine ratio. 

Harpreet Bajaj: [00:30:57] So that is macroalbuminuria about 33 on our scale. 

Harpreet Bajaj: [00:31:02] So these people then entered this trial basically with diabetes kidney disease right. They had diabetes with a not at target A1C. as well as with eGFR which was between 30 to 90. So slight reduction at least or maybe a majority of them 60 percent were at least less than 16. As it turned out. And then the aluminium creatine ratio was significantly high and the worst protein urea stage 33 or higher as well. Also the last bullet point in the key inclusion criteria which is that all of these patients were were treated with a stable maximum tolerated dose of ACE inhibitor or an ARB as well. So that is kind of standard of care for people who have diabetes kidney disease. And it was mandated that all of these people have to be on what we do for standards of care as well. And then if we quickly go through the key exclusion criteria. They just make sense that if there were other kidney disease rather than diabetes kidney disease they were excluded people on dialysis or kidney transplant people who are using ACE inhibitor and an ARB or a renin inhibitor or a mineralcortico receptor antagonist were also excluded. 

Harpreet Bajaj: [00:32:27] Hypoglycemia was excluded if the level was more than 5.5. Also people who had recent cardiovascular events or class for heart failure were also excluded people who had type 1 diabetes or diabetes ketoacidosis history were also excluded. So that's what the CREDENCE study design was basically in the study what was done was Canaglifozin versus placebo. Now in this study just as in cardiovascular outcome trial that we've talked about as well. The placebo is not necessarily a placebo in the sense that standard of care is what is followed in the placebo group as well. So in any of these placebo controlled studies which are driven by complications of cardiovascular disease or chronic kidney disease the placebo group is free to add other medications non SGLT2 inhibitor medications in this case or maybe add insulin or change the dose of insulin or try to get maximum people to the target A1C as well. 

Harpreet Bajaj: [00:33:37] So that's the CREDENCE study design in a nutshell. And I'll just move forward to the results now. 

Harpreet Bajaj: [00:33:43] So this is the primary outcome of this trial which is end stage kidney disease doubling our serum creatinine or renal or CV death. Is what is shown here. And this was highly significant where the hazard ratio was zero point seven. A P-value that has many zeros in there and you can see there were enough participants who met this endpoint as well. And that's why because of this highly significant result this trial was halted prematurely at about two and a half years off of the trial period. Further outcomes have been looked at and this may be an important outcome for some of us. Which is how many people are we talking about that can be prevented from dialysis or kidney transplant or renal death. So this is an outcome where you say this is basically end stage renal disease right. So this is a clinically important endpoint and the results on this. The hazard ratio is zero point seven with a confidence interval upper bound being less than one still so it is still statistically significant. So people who have end stage renal disease there is a reduction with canagliflozine versus placebo in this trial. 

Harpreet Bajaj: [00:35:05] And this is the eGFR part of it. So eGFR how it changed over time in the CREDENCE trial. So initially there was a reduction of about three point seven on the eGFR scale for people with canagliflozin versus only about zero point five for placebo. And we know that this is the case over time in many trials. We've seen this with any SGLT2 inhibitor that there is a slight reduction of eGFR initially and that is thought to be a reduction of the intraglomerular pressure or circulation that leads to that. And this has also been seen and documented an ACE inhibitor ARB trials as well. 

Harpreet Bajaj: [00:35:49] Well what we are worried about or what we actually care about is what happens long term and so long term what happened in this CREDENCE trial was that there was a less slippery slope or the slope was less kind of acute in people who were given Canaglifozin versus the standard of care or placebo and the slope was one one point eight five in the canaglifozin arm versus almost 5 or 4.59 in the placebo arm. So there was a reduction or the difference was about two point seven per year change with benefit shown on Canaglifozin. So what does this mean over time. 

Harpreet Bajaj: [00:36:38] So if you think about people who are starting in this trial with a mean eGFR of 56 of about 55-56 and let's say 10 is what the end stage renal disease cutoff is the let's say the placebo arm is reducing at about five per year. Round it up. And that means from fifty-five to ten it'll take about eleven years for them to reach that end stage renal disease cutoff of ten on eGFR. Whereas if you look at the Canaglifozin arm. 

Harpreet Bajaj: [00:37:18] So starting at fifty five it's let's say two per year reduction two eGFR reductions per year. Then it'll take about double about from fifty-five to ten it'll take about twenty-two and a half years or twenty three years to reach that eGFR cutoff of ten. So what are the differences between placebo and canaglifozin ARM is about eleven to twelve years more with a with not end-stage renal disease eGFR. So basically dialysis is being pushed about eleven twelve years as what is suggested now of course this is all speculation and this trial did not go on for eleven or twelve years or twenty two years. It was just a two and a half years and and whether that turned out to be true in real life practice is still to be seen. Also I should mention that Caneglifozin does not have a label for kidney disease protection at this point as such. But this is data that is published in The New England Journal of Medicine and that's why I'm sharing it. 

Harpreet Bajaj: [00:38:31] All right. 

Harpreet Bajaj: [00:38:32] That's basically the complication reduction that we saw from these these cardiovascular outcome trials as well as the chronic kidney disease trial that have been published until now. How about the risks or side effects of SGLT2 inhibitors and what do we need to know about it. 

Harpreet Bajaj: [00:38:50] So some of you may know that these drugs the common side effect which can be up to 10 percent in women and maybe up to 3 percent 2 to 3 percent in men who are given SGLT2 inhibitors may develop genital yeast infections. And these are usually one time as you usually easily treated with topical anti-fungal treatments. 

Harpreet Bajaj: [00:39:17] Less common side effects include the urinary tract infections some hypotension or osmotic diuresis or volume related side effects. Also amputation and we'll we'll take a look at amputation data from CREDENCE with Canaglifozin as well in a minute amputations were increased with Canagliflzin and in CANVAS and I'll show you the data in a minute. Also in CANVAS there was an increase in fractures from Canaglifozin and the canvas program as well. Also mild increase in LDL but then again you know if cardiovascular reduction is their LDL increase should not matter. Rare side effect and maybe this is important to note is a diabetic ketoacidosis. This is a euglycemic diabetic ketoacidosis means that glucose control is within or close to target maybe 6 7 8. And then there is still acidosis and this is thought to be related to those people who are on insulin or are insulin deficient and need insulin and has been related to either sickness or surgery other problems sometimes a keto diet or low carbohydrate diet as well as alcohol, alcohol chronic alcohol consumption as well. 

[00:40:41] So those are some of the things to keep in mind. It's a rare complication but those are the people who are at risk and appropriate precautions should be taken. In terms of amputations so this is data from the three cardiovascular outcome trials on amputations that have been published so EMPA-REG outcome and DECLARE as you can see in this forest plot there was no increase in amputation whereas in CANVAS that's only trial program that suggested an increase in amputation on the forest plot. 

Harpreet Bajaj: [00:41:11] You can see the hazard ratio 1.97 which was statistically significant. However in the CREDENCE program the participants the number of participants who got amputation lower extremity was similar and placebo vs.Canaglifozin without there being any any statistical difference between Canaglifozin versus placebo as such as you can see and thus CREDENCE program. So we have the same drug Canagliflozin and CANVAS program there was an increase here there is no increase at least. And still under discussion and debate as to why this discrepancy is there and what is true and what is not true. We don't know. I'll just finish off quickly with how this applies or maybe I'll just finish off with Diabetes Canada guidelines and say how we are treating right now people with diabetes. With two quick cases. 

Harpreet Bajaj: [00:42:11] So first cases primary is secondary prevention so people like Oscar who have NSTEMI in 2015 a bypass graft in 2015 type 2 diabetes for 10 year hypertension, dyslipidemia. So Oscar is a 66 year old male with abdominal obesity BMI of thirty one point five. You can see the parameters there. Where A1C is seven point eight LDL of two point three blood pressure 138. So all those parameters need to be controlled as we know ABCDE is what Diabetes Canada guidelines recommend to try to reduce in this case a secondary prevention objective. 

Harpreet Bajaj: [00:42:55] Also in this case we are given grade 2 diastolic dysfunction with a reduced eGFR and no albuminuria as well. 

Harpreet Bajaj: [00:43:03] So this patient is on metformin, sitagliptin,atorvastating,ramipril and hydrochlorothiazide. This is a person with secondary prevention and diabetes and what the guidelines suggest in this case is at least the 2018 guidelines that were that were released in April last year suggested that in such a patient who has a history of cardiovascular disease. So we go to yes which is an orange are our choice of therapy should be Canagliflozin, Empaglifozin or Liraglutide. If no. So let's talk about a patient who has no cardiovascular disease so Florence is such a fictitious patient. Fifty four year old female, overweight, type 2 diabetes for 7 years hypertension, dyslipdiemia and gout and no cardiovascular disease history but with smoking let's say that her BMI is twenty nine point five, A1C is eight, LDL is one point eight, blood pressure 134 so slightly high still. She does have some shortness of breath symptoms on exertion so Class 2 NYHA, heart failure symptoms if you will and then an EGFR that is 78 with no micralbuminuria. Her medication is just metformin,atorvastatin, ezetimibe, losartan and 

Harpreet Bajaj: [00:44:31] allopurinol for her gout. So we are talking about what to do after metformin her A1C is 8 percent so not a target. And this is a case of primary prevention. Again what I'm going to discuss is going to be based on last guidelines so Diabetes Canada of 2018 guidelines because we do not have any any data on complication reduction in this primary prevention. 

Harpreet Bajaj: [00:45:04] What the guidelines have recommended in a patient like Florence who does not have clinical cardiovascular disease is to talk about drug therapies or classes of drugs that need to be prioritized because of lack of hypoglycemia and weight gain. So what is recommended is either to choose Incretin agents, DPP inhibitors or GLP receptor agonists or an SGLT2 inhibitor as a second line option in this case. So either of those are are suggested. So that's how the guidelines have been in the past and we'll see how this evolves with the evolving data that we've discussed in this last 30 to 40 minutes as such. So I'll just conclude and say that what we started off with is that we know that diabetes impacts multiple organs microvascular complications macrovascular complications and you all agreed or a majority of you agreed that prevention of complications is the paramount goal of therapy. 

Harpreet Bajaj: [00:46:16] We discussed some of the cardiovascular as well as renal outcome studies specifically the EMPA-REG outcome and CANVAS which showed a MACE reduction especially in the secondary prevention population. 

Harpreet Bajaj: [00:46:30] DECLARE to me then did not show MACE reduction because it had a large primary preventions sub-group but it broadens that evidence and heart failure hospitalization. So HHF is the hospitalization heart failure and DECLARE to me in terms of primary prevention was reduced and then CREDNCE now expands this to people with DKD or diabetic kidney disease population as well and confirms the kind of secondary or exploratory results off of previous cardiovascular outcome trials and confirms that kidney protection in this in this trial. So of course the data is evolving and and so should the clinical practice as well as guidelines over time. Over time one thing that has remained constant kind of is the diabetes management must remain individualized with multifactorial interventions and healthy behavior interventions as the bottom line as well. So I'll just end there and see if if we have any questions that I can address. 

Erin Krusky: [00:47:42] Thank you Dr Bajaj for that excellent presentation. We do have some questions. So I'd just like to take a moment before we do the Q and A to thank our generous sponsor Jansen for supporting this webinar. So our first question is when treating diabetes retinopathy patients. What is the threshold to discontinue SGLT2 inhibitors with GFR 

Harpreet Bajaj: [00:48:12] When treating retinopathy not nephropathy? 

Harpreet Bajaj: [00:48:18] That's right I see the question. So while treating diabetic nephropathy what is the threshold to discontinue SGLT2 inhibitors and that's a great question because you know that that's what this is getting at. Right now label what labels currently are in Canada. So initiation should be above 60 eGFR but an Empaglifozin label they can be continued down to an eGFR of 30 as the cutoff as a threshold to discontinue Empagliflozin. Whereas for Dapagliflozin and for Canagliflozin 100 milligram dose that lower cutoff is 45 on the eGFR. So Canaglifozin 300 milligram is not recommended less than 60 but 100 milligram can be continued down to 45 eGFR and Empagliflozin at any of those doses can be continued down to 45 whereas Empaglifozin either of those doses 10 or 25 milligrams can be continued to an eGFR of 30. Is the answer. 

Erin Krusky: [00:49:30] Thank you Dr Bajaj. So another question that we have is for patients with established cardiovascular disease would you recommend. Empaglifozin? 

Harpreet Bajaj: [00:49:42] Yeah. So one of the options that is recommended in Diabetes Canada guidelines is Empaglifozin. Other options to consider are Canagliflozin and Liraglutide. 

Harpreet Bajaj: [00:49:52] And this was based on trials that were done in the specific populations we talked about EMPA-REG outcome and CANVAS also Liraglutide with its LEADER trial and you can join the webinar later this month on GLP-1 receptor agonists that also showed significant cardiovascular benefit in that specific population of established cardiovascular disease. So those are three options that are recommended in the Diabetes Canada guideline last time. 

Erin Krusky: [00:50:22] That's great thank you Dr Bajaj. We have another question, from your perspective are the various effects of SGLT2s on renal and cardiovascular in terms of class effect? 

Harpreet Bajaj: [00:50:37] That's a fair question as well and an interesting one. 

Harpreet Bajaj: [00:50:44] And you know most of these trials were done with one drug versus placebo. So we've not seen head to head data but that's what it appears to be right. They're mostly consistent there are some small differences here or there. Their population level differences of course. And I think SGLT2 inhibitors is a class that has shown consistent effects from trial to trial more so than a GLP1 receptor agaonist cardiovascular outcome trials for example in that class GLP1 receptor agaonists there are some drugs some trials that have shown cardiovascular protection but as many others that have not shown that benefit as well. So it's a more of a question in that GP1 receptor agonists class but in SGLT2 inhibitors for the majority how I perceive it anyway is that it appears to be a class effect. Now in the kidney disease and the only trial that we've now had a result for the CREDENCE trial there are there is ongoing trial with Dapaglifozin called DAPA-CKD which may report by next year or so and then there is a trial with Empaglifozin that is about to start it was not started yet as well in the future. So we'll see if this class effect exists in diabetes kidney disease protection or not. 

Erin Krusky: [00:52:13] Thank you Dr. Bajaj. We have many more questions but I think what we will do is we'll post the answers on TimeRight. The 365 forum. So for anyone who asked a question and didn't get the answer answered live today we'll post the answer on that forum. 

[00:52:33] So check there. And that concludes our webinar for today. I'd like to sincerely thank Dr. Bajaj for speaking on behalf of Diabetes Canada. It has been a great learning experience