DPP4: BEYOND Glycemia
Mirhossein is my pleasure towards professor areas malak honor professor of medicine and consultant position a central manchester university teaching hospital and university of chester former president of neuro diabetes see there is robust a study group of the ased permissive mark will talk about the deep or inhibitors sponsored symposium but nobody’s have nothing
To do with the slides i’m going to present in fact i haven’t even spoken to anybody from novartis about so this is my my views my opinions of what we have at the moment he tells a therapist so the title is deep in foreign it is beyond glycemia so if we look at therapies in diabetes what is very clear is that in the world of hypertension from around 1950 onwards
We’ve had successively every five to ten years new therapies have come onto the market and new therapies have come onto the market to help patients in terms of controlling blood pressure however in the world of blood glucose control glycemia what we have is actually insulin which is actually started in the 1920s but then that’s all we had insulin we then had
Around the late 1950s often our ureas and the by granites but the bygone id that we had was fen forming which then of course was withdrawn because of lactic acidosis and then we had actually nothing happened for a long period of time and life as a diet ologist was very simple because all we had is a few drugs but then something happened around the mid-1990s that
Has accelerated the number of medications that we now currently have available to treat our patients with diabetes and i deliberately put xxx up there because i think there are many more new compounds that are gonna come one of those compounds is the dpp-4 inhibitors and we of course have the sto d2 inhibitors and the glp-1 receptor agonists which are currently
Available so what else is it that’s triggered this i guess need for newer therapies well one of them actually is this so this is a meta-analysis of trials that have been done to look at the effect of lowering glucose on cardiovascular outcomes what does it show well it shows you that the ukpds although not significant perhaps showed that improving blood sugar
In newly diagnosed type 2 diabetic patients might have a beneficial outcome but this was not significant however for other trials three of them showed no benefit for lowering glucose compared to a cord which actually showed that lowering glucose in our diabetic patients whether the therapies we had previously could potentially do more harm could increase the
Cardiovascular event rate so this has led to a search i think for newer therapies and the problem is this that if you look at a cord advance and vad t you can see that cardiovascular mortality and mortality was increased by 22% and 39% in advance no significant improvements and in v8 again actually a significant are not non significant but an increase by 25% so
You’re left with three major clinical trials which have asked the question can we by lowering glucose make our patients have less heart attacks and live longer and the conclusion of this studies is no so what is the problem well francis bacon many years ago in fact 500 years ago said that the remedy is worse than the disease sometimes so what was the remedy that was
Being used in these clinical trials well i could tell you at that time it was predominantly metformin so for now ureas thiazolidinediones and insulin they were really none of the newer drugs were on the market were being used at that time in those clinical trials which was the accord the advanced and the vatt trials and what’s very clear is that when you use these
Drugs they lower glucose but they don’t improve outcomes so there is something called an elephant in the room what is the elephant in the room the elephant in the room ladies and gentlemen is is an old english idiom where there is an obvious truth that is being ignored or goes unaddressed and it also applies to an obvious problem or risk no one wants to discuss
So as a physician i have these results but at the same time either facial imprinted lee hooni we need to lower glucose up so what do we do we carry on doing what we’re doing or we think of alternatives so who is this he was actually i think a very brave man because he took on big pharma and challenged what they were telling us did you know who this is says steve
Nissen cardiologist from the cleveland clinic and what he actually did is he was responsible for the loss of 12 billion dollars from two major companies and he did it by publishing two papers helena talked about clinical trials about the importance of clinical research well he published two papers one paper was in jama in 2005 where he showed that marie glitters
Are which was a thiazolidinedione combined a people are after a people gamma agonist actually caused excess cardiovascular events and because of that there was a loss of share value in the company by 2.4 percent and they lost 3 billion the other major fatality that steve listen was responsible for is rosiglitazone so he again showed that rosiglitazone could be
Causing car diva excess cardiovascular events and again gsk market share value fell to 0% and they lost nine billion dollars overnight so then we left so that so the tires all ddiamond story we know but what about sulfonylureas which we know we used in clinical practice in fact there are data published in this meta-analysis to show the following these are all the
Clinical cardiovascular outcome trials when sulfonylureas have been used and what you see is this 33 studies 1 million three hundred twenty-five thousand patients treated with either sulfonylurea or a comparator follow-up anything from no point four six to ten point four years what did they show actually they showed that the cardiovascular mortality was not
Decreased but was increased by 27% and yet we either ignore this or we don’t read about this and i think that’s important because if we’re going to improve the outcomes of our patients we need to look at this data so if you are treating people with sulfonylureas you are potentially increasing their cardiovascular outcomes by 27% so we have a problem with the current
Medications and of course metformin which i think actually is a perfectly safe drug and it’s a good drug has gi events but that does not it’s not kind of a problem because it doesn’t increase cardiovascular mass and we know in the uk pds in the overweight individuals it reduced cardiovascular events but the other therapies i think we really do have a problem with
And so in our pursuit of lowering glucose we need to think about what is it that we are dealing with so the elephant in the room to me in relation to these other therapies is two things one is the occurrence of hypoglycemia which we know occurs with sulfur nigeria’s which we know occurs with insulin and we know that in all three studies there was a three to two
Fold increase in cardiac hypoglycemic events the other aspect of these therapies is this an elliot jocelyn in 1927 this is only two or four years after the discovery of insulin said from an excess of fat diabetes begins and from an excess of fat diabetic patients die and yet in our clinical practice what do we do for our patients we improve their blood sugar but
We put them on drugs which causes what weight gain and if you look at the accord and the advance and the vad t study you don’t need to be a genius to work out why there were excessive cardiovascular events because if you look in the intensive arm of the accord study those who gained weight 30 percent almost gained more than ten kilograms in weight and you tell me
If you have a patient who’s already overweight and you give them medication to increase their way by 10 kilograms that this is not going to have an adverse event on cardiovascular outcomes of course it is so really we have to think long and hard before we put our people patients on therapies that will cause weight gain and the same for vad t actually they gained
Eight kilograms and we know that different medications have different impacts in terms of weight gain so so so for now ureas for example will you get a two to four kilogram weight gain magley tonight’s game waking tires or diesel weight gain insulin weight gain it’s only the dpp-4 inhibitors metformin and the glp-1 receptor agonist where you get weight loss which
Is what you want in your patients so what are these therapies that we are weight neutral oh i’ll give you weight loss well we have a choice you have the oral drugs dpp-4 inhibitors or you have the glp-1 agonists which are the injectables and of these we have a multiple kind of choices actually you have got buildig lipton sittig lipton saxagliptin linagliptin alig
Lipton all of the gliptins we know lower hba1c by around 0.5 to 1 percent but they also either either weight neutral or you do get some weight loss one to two kilograms so i think that’s a positive and of course on the other side you have the glp-1 receptor agonists where you get more hba1c reduction 1 to 2% but you also have greater weight loss 2 to 4 kilograms
So you have two therapies that potentially can lower glucose but also lower weight and of course the big dipper’s between dp for enabling the receptor agonist is actually one is it’s an oral the other one is an injectable but the cost as well and the availability so let’s compare the dpp-4 inhibitors with sulfur nitrous because people generally say well softener
Urea are better drugs for lowering glucose than anything else oral treatment wise but if you look at this analysis recent analysis what you see is this hba1c reduction actually in the first 12 weeks was better with sulphur nigeria’s competitive people for inhibitors but if you go out to one year and two years actually there is no difference in hba1c between you
Can see there between a sulfonylurea and deepen before so yes at 12 weeks no at 52 weeks and no at two years so long-term dp before and su are actually comparable but where you have an advantage is this weight loss you could see straightaway dpp-4 inhibitors you have much greater weight loss at 12 weeks at one year and at two years in the dpp-4 arm compared to the
Softener urea and high post actually again you have less high post in the dpp-4 arm compared to the s use so we have to start thinking of these drugs glp-1 or dp before and even the strt 2 inhibitors of something that will offer us more than just lowering glucose and we know that there are many potential benefits that can arise from these drugs and these include
Cardio protection and improvements in terms of inflammation body weight blood pressure there are clinical trials that have been published and of course we have the dpp-4 inhibitor trials there were three major trials which actually to me were a little bit disappointing because what we wanted to see is an improvement in outcomes but we didn’t see that but equally
We didn’t see more harm so i think as an oral therapy it certainly is better than what we have previously but it’s not an advantage to our patients whereas we know from the leader study and of course the sustain study that there is definitely a benefit to our patients with the injectables and of course the emperor egg and the other canvas studies which have shown
Improved outcomes so if we were to put the dpp-4 inhibitors on this chart then what i see you would get is something around here so you would see that there is not significant but there is is neutral in terms of outcomes so certainly is not worse as was found in accord but then there are concerns that we’ve had in terms of dpp-4 inhibitors and heart failure and
Fractures are these concerns something we should consider well for advice the most recent esc guidelines tell us the following in terms of type 2 diabetes mellitus and heart failure and you if you look at the therapies that are available so dpp-4 inhibitors for example sucks at liberty there is actually compared to placebo increase in heart failure hospitalization
But alig lipton and sittig lipton no effect the 8d glp-1 inhibitors no effect on heart failure hospitalization and in fact the sglt2 inhibitors you can see reduced heart failure hospitalization so overall these drugs seem to be safe in terms of heart failure hospitalization fracture risk again a large meta-analysis as shown when you compare dpp-4 inhibitors to
Other therapies actually no significant effect in terms of fractures for any of these therapies when you whether you compare them to percy bo or whether you compare them to other active terrorism this is true for the aces for all the deepen for inhibitors additional benefits that may arise from the user’s dpp-4 inhibitors include the following you can reduce the
Insulin dose actually in patients who were already on insulin there is also some work that suggests that it may be beneficial for what is called type 3 diabetes which is the association between dementia and type 2 diabetes and there is actually some little early data suggesting that it may have an impact on wound healing so in terms of dpp-4 inhibitors where
It’s very clear every single study that’s been done to date shows that if you have a type 2 patient on insulin and you add a dpp-4 inhibitor you will reduce the insulin dose and this varies from up to about 10 units of insulin so that is certainly an additional benefit and i think if weight gain is something that occurs with insulin you can limit that by putting
On a dpp-4 inhibitor in terms of increasing based therapies and neurocognitive function there’s actually a recent systematic review which suggested that there may be as a result of this was actually comparing metformin with well doug lipton and sittig lipton that there may be an improvement in terms of baseline cognitive function in the group that were on a dpp-4
Inhibitor after two years but we i think we need to see bigger longer-term studies to prove that this is really something that plays a role and finally there is actually from a theoretical point of view a role to be played of dpp-4 inhibitors in terms of wound healing because dipeptidyl peptidase-4 actually is expressed in wounds when they are healing so in fact
Dp4 inhibitors so you can see are expressed d before actually as a receptor is expressed on fibroblasts on myofiber plus and therefore it could potentially play a role in in terms of accelerating cutaneous healing even real fibrosis hepatic fibrosis and lung fibrosis so this is actually work in progress in terms of clinical trials that are being done to look at
Wound healing to look at glomerulus grossest and to look at hepatic fibrosis thank you
Transcribed from video
DPP4 inhibitors – Prof. Rayaz Malik – AASD By AASD Diabetes
