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Silvio Inzucchi, MD: Dapagliflozin Reduces New-Onset Diabetes

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Silvio Inzucchi, MD, discusses the results of a prespecified exploratory analysis DAPA-HF examining the agent’s impact on new-onset diabetes.

What does this tell us about that google frozen and sglt2 inhibitors class as a whole and how useful is this agent for clinicians knowing all these additional effects outside of heart failure well first i would claim that i would give you a disclaimer that the the diabetes prevention abstract that we’re presenting this this week or next week was not the primary

Outcome of the trial so this is it wasn’t even a secondary was what we called an exploratory outcome basically we took the opportunity in damp hf which is a heart failure trial because we were checking hemoglobin a1cs and because we knew that we were going to get a lot of patients in dep hf who did not have diabetes we took this opportunity because they were going

To be randomized to placebo tapika flows and received abaca flows in had any specifically benefit in preventing those patients from developing diabetes so it wasn’t a diabetes prevention study per se but basically and like i said exploratory outcome so that has caveat in terms of how we powered the study and and we did not we did not pursue the diagnosis of new

Onset diabetes as aggressively as some of the legitimate diabetes prevention trials have done in other words we just had hemoglobin a1c we did not have fasting glucose we did not do oral glucose-tolerance test so there’s a lot of caveats about the trial having said that i agree that i think that the impact of dapa go frozen was substantial it’s interesting to note

That the most commonly is medication to prevent diabetes even though no medication is actually sanctioned by the us food and drug administration for diabetes prevention many clinicians particularly those in primary care who see lots of patients with pre-diabetes you know this this form of mild hyperglycemia that predicts the eventual development of diabetes many

Of those clinicians actually use metformin because it’s been out for decades it’s felt to be safe as long as you don’t use it in patients with renal failure and the data from the diabetes prevention program which is going back more than 10 years now significantly more than 10 years i think probably more than 15 years now suggested that metformin had a beneficial

Effect on preventing new onset diabetes of 31 percent so it’s interesting that the drug that is most commonly used for diabetes prevention has an effect that is very similar to what we what we found in deb hf so what we did was as mentioned just focused on those patients who did not have diabetes right the patients with diabetes constituted 45 percent of the patients

In def hf which i’ll remind you as they have breath studies so it’s heart failure with reduced ejection fraction and patients were randomized to dapa the flows in 10 milligrams or placebo and in focusing on the 55% of the patients who did not have diabetes at baseline we track them over time and the median duration of follow up in that hf because it was the the

Drug was so potent for preventing heart failure outcomes so the primary outcome just to remind you was cardiovascular mortality and worsening heart failure most of worsening heart failure was heart failure hospitalization and the drug had a huge effect on that outcome of 26% and because it was an event driven trial we achieve a certain number of of mortality and

Heart failure worsening pretty quickly so the median follow-up in this study was only about a year and a half not the typical time period you you’d prefer in a diabetes prevention trial because diabetes takes a while to develop and when you’re doing clinical trials you need a certain number of these events took to document statistical significance entering in your

Intervention having said that even though we only had about 18 months of follow-up we still were able to demonstrated this 32% risk reduction for new onset diabetes now many diabetes prevention investigations are criticized and the criticism is the following particularly when you’re using a drug that impacts glucose so if using a glucose lowering medication the

Following criticism is often levied which is hey you’re using a drug that lowers glucose so aren’t you just masking the development of diabetes right because it’s a it’s a disease it’s a disease that is diagnosed by glucose right or hemoglobin a1c or oral glucose tolerance testing so if you’re using an agent that lowers glucose or lowers a1c is the difference that

You see over time simply biochemical is it simply you’re masking the diabetes and and that has been that that that notion that that masking diabetes is all you’re doing with this with these medications has been what i mean to say is that the the folks that made that criticism about these trials they point to these withdrawal studies from these diabetes prevention

Investigations and these are where they take patients at the end of the trial withdraw study drug and then retest them after you know six weeks or three months and if you see that the patients who did not develop diabetes who were on the intervention write the medication then quickly develop diabetes over that period of time then that would suggest that the drug is

Just masking the underlying disease process now i might point out that i don’t necessarily agree with that because i think it is a biochemical disease and if you if you can mask it for like a lifetime i’m good with that you know because you’re you you were probably not going to develop a diabetes complication meaning a specific diabetes complication like diabetic

Retinopathy diabetic nephropathy diabetic neuropathy cardiovascular disease a separate because there are many different inputs into that right there there’s glucose and lipids and obesity and smoking and and and just reducing the glucose we don’t think necessarily prevents cardiovascular disease but something like diabetic eye disease if you don’t have diabetes

It’s kind of hard to get diabetic eye disease so i’m okay with masking if if the masking is safe and if it’s durable so i’ve always had a bit of an intellectual argument with those individuals who say that if you’re just masking diabetes it’s not as good as truly preventing diabetes as you might with weight loss where you’re really doing something fundamental you

Know having having said that the reason i bring this up is that in most of these diabetes prevention trials where you use a glucose lowering medication you actually do see small but significant decrease in hemoglobin a1c so in the studies that i can recall you know typically the hemoglobin a1c is the separation is at least point to if not 23 percent it’s interesting

That in dap at hf we did not find virtually any difference in the hemoglobin a1c the the the the hemoglobin a1c was about and we measured it at eight months because that’s where we measured a lot of our of our chemical parameters to give the drug enough time to exert an effect on the parameter although we did check a1c periodically during the study but for this

Analysis we use the eight eight month mark and and the difference is was about point zero five or zero point point zero four percent whether you’re talking about the mean or median so was it was less than 0.1 percent so it was really a trivial difference so despite that you still saw this diabetes prevention effect and i think this is maybe a manifestation of that

When you’re using a sglt2 inhibitors in patients who don’t have diabetes it doesn’t really affect their glucose levels all that much because hepatic glucose production the livers production of glucose probably compensates for any glucose losses so the body just tries to maintain the glucose level at his baseline level so that’s interesting right so this is you

Know maybe the first that maybe this is the first drug that we’ve used to decrease the development of new onset diabetes that maybe is not masking maybe is having a more fundamental effect on you know either insulin secretion or insulin sensitivity and i think it’s it’s it’s interesting and is a bit different from other diabetes prevention trials that have been looked at

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Silvio Inzucchi, MD: Dapagliflozin Reduces New-Onset Diabetes By HCPLive