CME INDIA Presentation by Dr N K Singh.

At American Heart Association Virtual Webinar, 13-17 November 2020, SCORED and SOLOIST-WHA trials have set a new stage in paradigm change. It also set a new perspective for SGLT1-Inhibitors, so far neglected and considered to be a spoiled child…

Now this is not the end. It is not even the beginning of the end. But it is, perhaps the end of the beginning.” – Winston Churchill.

At a Glance, Comparing SGLT1 and SGLT2

SGLT1 Inhibition: Opening of new vista in diabetes

• The small intestine is the major site of dietary glucose absorption. It occurs predominantly through SGLT1 on the brush border membrane
• Intestinal SGLT1 also regulates the release of intestinal hormones implicated in glucose balance glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1)
• Genetic mutations of SGLT1 in humans is well known to glucose-galactose malabsorption (GGM)
• Under normoglycemic conditions, renal SGLT1 contributes to ~3% of FGR  
• Notably, under conditions of hyperglycaemia or during SGLT2 inhibition, this contribution can increase substantially (up to 40–50%) when more glucose is delivered to the late proximal tubule.
•  Despite the fact that SGLT2 normally contributes to >90% of FGR but it is known to bring FGR reduction only to ~40–50%. This is the consequence of a compensatory role of SGLT1 in the late proximal tubule
• If you simultaneously block SGLT1 and SGLT2 in the kidney, it could be advantageous compared to only inhibiting SGLT2.
• SGLT1 inhibition would greatly impact intestinal glucose absorption, and the renal effects would be expected to be additive to the intestinal effect
• Elective SGLT1 inhibition has been shown to delay post-prandial intestinal glucose absorption and enhance plasma levels of GLP-1 and GIP.
• We are aware that pancreatic β-cells are stimulated by GLP-1 to increase insulin secretion and diminish glucagon secretion; additionally, GLP-1 decreases appetite and increased β-cell mass in preclinical studies. These effects are responsible for the anti-hyperglycaemic effect of GLP-1 receptor agonists.
• Blocking glucose transport in the upper small intestine will lead to a greater glucose delivery to further distal segments of the small intestine and colon. It has been speculated that the gut microbiome metabolizes glucose in the colon to form short chain fatty acids (SCFA),
• Colonic GLP-1 can be released in response to SCFA.
• Recent evidence suggests the gut dysbiosis contributes to the pathogenesis of T2DM.

What is Sotagliflozin?

• Sotagliflozin is a dual sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitor for the treatment of both type 1 and type 2 diabetes.
• It inhibits SGLT-2 in kidney in the same way the other SGLT2 Inhibitors do and at the same time also inhibits intestinal SGLT-1, delaying glucose absorption thus reducing post prandial glucose.

No Diarrhoea in Tandem 3

• It is expected that when you inhibit SGLT1 by sotagliflozin, it can lead to gastrointestinal side effects as reported in the in Tandem 3 trial (diarrhoea occurred in 4.1% of the sotagliflozin group vs 2.3% in the placebo group)

Beyond Glucose Sotagliflozin can do miracles

• Beyond the kidney and intestine, SGLT1 is expressed in salivary glands, liver, pancreatic alpha cells, lung, heart, skeletal muscle, and brain.
• The role of SGLT1 at many of these sites, as well as the consequences of SGLT1 inhibition, are poorly understood.
• A recent study showed that SGLT1 blockade should decrease the incidence of heart failure.

Mahagathbandhan (Big Alliance) wins

• It is being researched about the possible interactions of sotagliflozin with other common drugs (metformin, interacting through microbiota changes in the lower gut; DPP-4 inhibitors, prolonging sotagliflozin-induced GLP-1 secretion).
• It gives hope for significant positive interactions. Sotagliflozin alone or in combination with metformin or DPP-4 inhibitors in type 2 diabetes or, with an adequate insulin protocol, in type 1 diabetes could be a very significant advancement in management in future.
•  The dual inhibition of both SGLT-1 and SGLT-2 improves the efficacy of this SGLT inhibitor in mild and severe CKD. It suggests an extended use also in frail patients where therapeutic options are currently limited.

Paradigm Changing studies – SCORED and SOLOIST-WHF: Very recently presented at AHA 2020

• Good sample size-over 10,000 patients with type 2 diabetes. 
• Used in eGFR up to 25-Mild to moderate or stage 3 kidney disease with a GFR between 25 and 60 mL/min/1.73 m².
• An average of 16 months of follow-up.
• SCORED showed uniquely – a reduction in ASCVD, or atherosclerotic events.
•  SCORED trial had about 30% of patients with history of heart failure.
• A pooled analysis with the patients from SCORED and then also from SOLOIS which was also presented at AHA – In over 700 patients with heart failure and preserved ejection fraction, there was, in fact, a signal for a benefit with sotagliflozin.
• SOLOIST-WHF study showed that use of sotagliflozin significantly lowered the risk of death from cardiovascular causes and hospitalizations or urgent visits for HF.

Delay Me Not my Cardiologist and Nephrologist

• Mind boggling finding in SOLOIST-translated into 51.0 primary endpoint events per 100 patient-years in the sotagliflozin arm versus 76.3 per 100 patient-years in the placebo arm (HR 0.67; 95% CI 0.52-0.85).
•  The benefit was driven by a reduction in hospitalization and urgent visits for heart failure (HR 0.64; 95% CI 0.49-0.83).
• Stratified by EF, it was observed that a significant reduction in the risk of the primary endpoint
•  In those with EFs less than 50% (HR 0.72; 95% CI 0.56-0.94).
•  In those with higher EFs (HR 0.48; 95% CI 0.27-0.86).
• The treatment benefit in those with heart failure with preserved ejection fraction (HFpEF) is the first time a treatment effect with an SGLT2 inhibitor has been demonstrated in this patient population.
• Dual SGLT1 and SGLT2 Inhibitor Sotagliflozin meets primary endpoint composite of total CV deaths, HF hospitalizations & urgent HF visits by 33% in patients w Diabetes & recent worsening HF.
• Do not delay the initiation of Sotagliflozin-Message is loud.

AHA Presentation Slides – AHA2020

Nothing matches its uniqueness

• So far, we understood that cardiovascular benefit of SGLT2 inhibitors in the early trials of type 2 diabetes was driven by a reduction in HF hospitalizations.
• Now SCORED adds a new TWIST by suggesting sotagliflozin may influence ischemic and HF events,
• Sotagliflozin significantly reduced HbA1c levels in SCORED patients with eGFR < 30 mL/min/1.73 m2 and those with less impairment.
• We know that issues with SGLT2 inhibitors is that while efficacy for reducing HF events is preserved in patients with low eGFR, the ability to lower HbA1c levels is impaired.
• But Sotagliflozin brings new horizon-a greater HbA1c reduction at low levels of eGFR in [SCORED and SOLOIST] pointing that the SGLT1 is found in the GI tract and this might be a nonrenal mechanism in which blood glucose is regulated at low levels of eGFR.
• Sotagliflozin is the first SGLT2 inhibitor to show a beneficial effect on stroke among patients with diabetes,
• It appears that Sotagliflozin modifies atherosclerosis, or plaque build-up in the coronary and brain arteries.
• SCORED is also the first trial to show the benefits of SGLT2 inhibitors across the full range of albuminuria which is common in people with Type 2 diabetes.

CME INDIA Learning Points:

• Sotagliflozin is an SGLT2 inhibitor, but also inhibits SGLT1, which primarily exists in the gut and appears to delay glucose absorption.
• Sotagliflozin has salutary effects on CV outcomes among patients with T2DM and CKD.
• The benefit again has been said primarily by reduction in Heart Failure events.
• But new twist is reduction in CV death/MI/stroke and said primarily due to reduction in MI and stroke.
• A reduction in renal events was not observed. It is likely due to early cessation of the trial due to loss of funding. [COVID halted the trial]
• The results of this trial are similar to those noted with canagliflozin in the CREDENCE trial and with empagliflozin in the EMPA-REG OUTCOME trial.
• As a class, these agents will likely play a prominent role among patients with CKD and HF
• It will be valuable even in the absence of T2DM, it appears.
• How to use after careful patient selection and monitoring
  1. Admitted with acute decompensated heart failure.
  2. With heart failure with either reduced or preserved EF.
  3. With CKD across the full range of proteinuria Unlike with pure SGLT2, the SGLT1 inhibition from sotagliflozin provided glycaemic control even at the lower range of eGFR.
  4. The lower rate of MI and stroke with sotagliflozin suggests an additional relatively early anti-ischemic effect of SGLT1 inhibition.
• Current Status: (Courtesy Dr AK Singh at ADC webinar on 21/11/20)

Completed CVOTs /CKD trials (Courtesy Dr AK Singh at ADC webinar on 21/11/20)

CME INDIA Tail Piece:

Further reading:

1. Bhatt DL, Szarek M, Pitt B, et al., on behalf of the SCORED Investigators. Sotagliflozin in Patients With Diabetes and Chronic Kidney Disease. N Engl J Med 2020;Nov 16:[Epub ahead of print]
2. Presented by Dr. Deepak Bhatt at the American Heart Association Virtual Scientific Sessions, November 16, 2020.
3. Cefalo, C.M.A., Cinti, F., Moffa, S. et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol 18, 20 (2019). https://doi.org/10.1186/s12933-019-0828-y
4. Dominguez Rieg JA, Rieg T. What does sodium-glucose co-transporter 1 inhibition add: Prospects for dual inhibition. Diabetes Obes Metab. 2019;21 Suppl 2(Suppl 2):43-52.doi:10.1111/dom.13630

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