Thread by @cardiomet_CE

The @GoggleDocs takeover of @cardiomet_CE continues!

We are 4 UK 🇬🇧 based doctors working across primary & secondary healthcare

Our interests are "what's new, and meaningful, in cardiorenal metabolic medicine"

Check out our YouTube channel youtube.com/c/GoggleDocs

Yesterday we had key messages from ReTune & diabetes remission & TriMASTER exploring “what next after metformin?”

Today @goggledocs will take you through some SGLT2 inhibitor highlights from #EASD2021 - the gift that keeps on giving!

Let’s start with some history!

SGLT2 inhibitors were originally developed from natural compounds found in what?

Phlorizin was first isolated from bark of apple tree in 1835

Oral ingestion of phlorizin was observed to cause glycosuria & weight loss

Phlorizin was found to be a competitive inhibitor of SGLT1 & SGLT2

SGLT2i's are more selective synthetic analogues of phlorizin

OK let’s kick off with SGLT2i use in older adults living with T2D

Now we all know age is just a number (as we always tell our oldest @goggledoc @patrickholmes!) & what is more important is functional status

But what is the risk/benefit ratio of SGLT2i in older adults? #EASD2021

A small real-world study presented at #EASD2021 looked at effects of SGLT2i's in 450 adults ≥70 years with T2D

✅Significant reduction in average HbA1c 7.7%>7.4% at 1y
✅Only 65 participants (14.4%) discontinued SGLT2i rx after 1y mainly driven by GU tract infections

Other messages:

✅ Volume depletion was only seen in 10 people & only in 1st 6m f/u
✅No DKA or amputation
✅AKI weight loss or inefficacy accounted for small numbers of discontinuations
✅Those who stopped SGLT2i were significantly older
✅eGFR was approx stable over 12m f/u

Conclusion was that SGLT2i is a valid therapeutic option in older people but caution suggested in those who are frail with guarded life expectancy

EMPA-ELDERLY is currently recruiting (@drpatrickholmes ?!) & is 1st RCT to assess effects of SGLT2i (empagliflozin) in older people

@drpatrickholmes @AmarPut @dr_amritlamba EMPA-ELDERLY will evaluate effects on body composition, skeletal muscle mass, muscle strength & physical performance as well as glycaemic management

It is an entirely elderly Japanese population so perhaps not widely generalisable but important study nevertheless #EASD2021

Ultimately we need to make a joint & informed decision with our older patients living with T2D about the risk/benefit ratio depending on their medical, functional & nutritional status, co-morbidities, support network and personal outlook on life

@EASDelearning @EASDnews @kamleshkhunti @scelee1 @dr_amritlamba @AmarPut @drpatrickholmes @PharmRJ Next SGLT2i & gout!

Gout is the most common form of inflammatory arthritis

Adults with gout have around a 30% higher rate of CVD & all-cause mortality than those without gout

The glycosuria from SGLT2 inhibition causes uric acid to be secreted into the urine

@EASDelearning @EASDnews @kamleshkhunti @scelee1 @dr_amritlamba @AmarPut @drpatrickholmes @PharmRJ Allopurinol & febuxostat reduce the risk of gout attacks; however, a recent RCT demonstrated an association between febuxostat & ⬆️CVD & all-cause mortality compared with allopurinol

People living with T2D are at increased risk of gout & CVD

@EASDelearning @EASDnews @kamleshkhunti @scelee1 @dr_amritlamba @AmarPut @drpatrickholmes @PharmRJ We know that SGLT2i lower uric acid: canagliflozin in the CANVAS trial programme was found to reduce gout flares in people living with T2D

@EASDelearning @EASDnews @kamleshkhunti @scelee1 @dr_amritlamba @AmarPut @drpatrickholmes @PharmRJ @HannahBeba @DSNforumUK @ABCDiab This posthoc analysis of EMPAREG OUTCOME study explored the impact of empagliflozin on new-onset gout& anti-gout meds in T2D

✅Empa ⬇️serum uric acid by 37%
✅Empa ⬇️time to new-onset gout or antigout meds by 33%

SGLT2i may be ideal rx for gout as ⬇️risk of gout & CVD!

Now, SGLT2i therapy & NAFLD!

NAFLD is the commonest liver disease in the Western world

NAFLD is seen in up to 70% of people with T2D & up to 80% of those living with obesity

Importantly you can still develop NAFLD with a BMI in the healthy range (ethnically adjusted)

@AmarPut @dr_amritlamba @drpatrickholmes @AbdTahrani @EASDelearning @EASDnews @kamleshkhunti @DSNforumUK @VickiaDSN @ABCDiab Worringly, NAFLD accounts for 8.4% of liover transplantations annually in Europe

There is a bidirectional relationship with features of the metabolic syndrome and NAFLD

The presence of T2D increases the risk of cirrhosis, AF, MI, ischameic stroke & CV mortality

Healthy lifestyle & weight reduction remain pivotal to prevention & treatment of NAFLD

5-7% weight loss ⬇️ hepatic fat content & steatohepatitis

Weight loss >10% can ⬇️ fibrosis irrespective of method

No current approved therapies for NAFLD but many drugs in development

@ABCDiab audit programme has suggested SGLT2i use associated with sig ⬇️ in ALT levels & we know ALT correlates with liver inflammation

Other trials have demonstrated improvements in transient elastography (e.g. Fibroscan) & LFTs with dapa

@ABCDiab This @ABCDiab audit explored the impact of SGLT2i use on serum ALT in >20000 people with T2D & followed-up for 18m

✅Sig ⬇️ ALT if baseline >30U/L
✅Greatest ⬇️ in those with ALT>60U/L
✅ALT⬇️ associated with weight loss but this is unlikely to account for full effect

#EASD2021 tirzepatide found to reduce liver fat by nearly half in SURPASS-3 MRI trial with associated improvements in ALT & AST

However histopathological improvements in NASH were not assessed

Currently @NICEComms recommend pioglitazone & vitamin E regardless of diabetes status

And finally more kidney outcomes from DAPA-CKD

Dapagliflozin had a consistent effect across all CKD stages

Dapaglifozin reduced albuminuria by 29% compared with placebo

This effect was observedd to be greater in those living with T2D

Dapagliflozin had a consistent effect across CKD aetiology e.g. IgA nephropathy

The benefit of dapagliflozin in DAPA-CKD on the primary composite endpoint was consistent across a range of HbA1c levels

And to conclude some tantalising observations about possibility of diabetes prevention from a pooled analysis of DAPA-HF & DAPA-CKD

This was first observed in an exploratory analysis of DAPA-HF where dapa ⬇️ the incidence of new-onset T2D by 32% in those w/o T2D at baseline

@AmarPut @dr_amritlamba @drpatrickholmes @DSNforumUK @EASDelearning @EASDnews Dapagliflozin ⬇️ new onset diabetes by 33% in addition to its cardiorenal benefits

This might appear entirely predictable given SGLT2i's are antidiabetic drugs...

But there were no significant hba1c differences between placebo & dapa groups suggesting a possible direct effect

@AmarPut @dr_amritlamba @drpatrickholmes @DSNforumUK @EASDelearning @EASDnews And we're done with SGLT2i highlights from #EASD2021!

As you can see it really is the gift that keeps on giving!

From 1835 to 2021 ✅

And what about the next 186 years?!

Well, this presenter reckons SGLT2i's will likely remain a mainstay of treatment for the next 100 years!

@AmarPut @dr_amritlamba @drpatrickholmes @DSNforumUK @EASDelearning @EASDnews SGLT2i's remind me of the below quote from Sir William Osler (whom i believe went to medical school with @drpatrickholmes ...)

Over my 21-year medical career to date SGLT2i's are the most compelling therapeutic option spanning a number of comorbidities available to me in PC

@AmarPut @dr_amritlamba @drpatrickholmes @DSNforumUK @EASDelearning @EASDnews @HannahBeba @kamleshkhunti @Amandaepps123 @PharmRJ And it's a wrap for today folks! Join us tomorrow for our last day of #EASD2021 key take-home messages from @GoggleDocs @cardiomet_CE takeover! @drkevinfernando @drpatrickholmes @dr_amritlamba

Check out our YouTube channel youtube.com/c/GoggleDocs