CardioNerds Journal Club is a monthly forum for Cardionerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the SOLOIST-WHF Trial.

Table of contents:

January 14th, 2021

Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure


Deepak L. Bhatt, M.D., M.P.H., Michael Szarek, Ph.D., P. Gabriel Steg, M.D., Christopher P. Cannon, M.D., Lawrence A. Leiter, M.D., Darren K. McGuire, M.D., M.H.Sc., Julia B. Lewis, M.D., Matthew C. Riddle, M.D., Adriaan A. Voors, M.D., Ph.D., Marco Metra, M.D., Lars H. Lund, M.D., Ph.D., Michel Komajda, M.D., Jeffrey M. Testani, M.D., M.T.R., Christopher S. Wilcox, M.D., Piotr Ponikowski, M.D., Renato D. Lopes, M.D., Ph.D., Subodh Verma, M.D., Ph.D., Pablo Lapuerta, M.D., and Bertram Pitt, M.D.

New Engl J Med 2020;384(2):117–28.


  1. Sodium–glucose co-transporter 2 inhibitors (SGLTi) were originally developed as an antihyperglycemic agent via urinary glucose excretion.  Trial data assessing cardiovascular (CV) risk, however, exhibited possible off-target benefits for CV disease and heart failure (HF).
  1. In recent data, SGLT2i’s have been shown to reduce the risk of hospitalization for HF or death from CV causes among patients with stable HF.1–3
  2. Sotagliflozin is an SGLT2 inhibitor that also inhibits gastrointestinal SGLT1.

Relevant Literature

Relevant Guidelines

Most recent European Society of Cardiology/European Association for the Study of Diabetes guidelines now recommend starting with an SGLT2i or a glucagon-like peptide-1 receptor agonists (GLP-1RA) before metformin in newly diagnosed type 2 diabetes (DM II) patients who are treatment naïve and either have established CV disease or are at very high CV disease risk4. Timing of initiation after an episode of decompensated HF had not been studied prior.

Study Rationale

  1. Potential safety concerns of initiating SGLT2i include the risks of hypotension and precipitation of kidney failure among patients with fluctuating volume status and renal function who are receiving treatment with other drugs that might also affect glomerular filtration rate (GFR). 
  2. Safety and efficacy of initiating a SGLT2 inhibitor shortly after an episode of decompensated heart failure has not been studied.


To determine the safety and efficacy of initiating an SGLT2 inhibitor shortly after an episode of decompensated heart failure, quantified by risk of death from cardiovascular causes, hospitalization for heart failure, and an urgent visit for heart failure.

SOLOIST-WHF Trial Design

  • Phase 3, double-blind, randomized, placebo-controlled trial.


  • Patients were randomized to Sotagliflozin or placebo prior to hospital discharge or within 3 days after discharge after admission for worsening heart failure.

Enrollment criteria 


*The primary end point was changed during the trial to the composite of the total number of deaths from CV causes, hospitalizations for HF, and urgent visits for HF.

Statistical Analysis

  • Intention-to-treat analysis

The trial stopped early due to loss of funding due to COVID-19


  • Initially planned for sample size of 4000 (with ejection fraction – EF ≥50% limited to 1100)
  • Enrollment closed early (6/15/2018 – 3/20/2020)
  • 1549 screened –> 1222 enrolled (78.9%)
    • 608 to Sotagliflozin
    • 614 to placebo
  • Population was predominantly white, male, with mean EF of 35%, on appropriate goal directed medical therapy for HF, and well controlled blood sugar.


  • Primary Outcomes
    • The primary endpoint of total CV death, HF hospitalization, or urgent visit for HF for Sotagliflozin vs. placebo, was 70 vs. 98 events/100 patient-years (hazard ratio 0.67, 95% confidence interval 0.52-0.85, p = 0.0009)
  • Secondary outcomes for Sotagliflozin vs. placebo:
    • Total CV death and hospitalization for HF (HHF): 60 vs. 86 events/100 patient-years (p = 0.003)
    • First CV death and HHF: 33% vs. 48% (p = 0.003)
    • CV death: 10.6 vs. 12.5 events/100 patient-years (p = 0.36)
    • Change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score: 17.7 vs. 13.6 (p = 0.005)
    • Change in eGFR: -0.34 vs. -0.18 (p = 0.78)

Adverse events Sotagliflozin vs. placebo

  • Diarrhea: 6.9% vs. 4.1% (p = 0.032)5
  • Severe hypoglycemia: 1.5% vs. 0.3% (p = 0.037)5
  • Serious Adverse effects that led to withdrawal of medication: 3.0% vs 2.8%
  • Hypotension: 6.0% vs 4.6%
  • Acute kidney injury: 4.1% vs 4.4%
  • Genital fungal infections: 0.8% vs. 0.2% (p = 0.12)5

Brief synopsis

SOLOIST-WHF trial showed that Sotagliflozin (a nonspecific SGLTi) significantly reduced the rates of CV deaths and hospitalizations and urgent visits for HF in diabetics with worsening HF, compared to placebo.

Limitations & Considerations

  1. Multicenter, randomized, double-blind, placebo-controlled trial.
  2. Earlier termination limited enrollment, and thus statistical power to evaluate all endpoints.
  3. First randomized controlled trial  to show that initiation of SGLT2i in acute HF, in stabilized patients, prior to discharge or shortly thereafter, is safe and effective.
  4. Benefits also consistent in patients with preserved EF, however, under-powered to truly identify significance.
  5. Sotagliflozin was associated with a higher rate of hypoglycemia, diarrhea, and dehydration which could possibly limit therapy.

1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New Engl J Med 2019;381(21):1995–2008.

2. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. New Engl J Med 2020;383(15):1413–24.

3. Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al. Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol 2021;77(3):243–55.

4. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASDThe Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). Eur Heart J 2019;41(2):255–323.

5. Kumbhani AJ. Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure – American College of Cardiology [Internet]. American College of Cardiology. 2020 [cited 2021 Feb 13];Available from:


Dr. Luis Calderon, @LMCalderonMD, Hospitalist at MedStar Washington Hospital Center, Washington DC

Dr. Madiha Khan, @madhattans, internal medicine resident at Houston Methodist Hospital, Houston, TX


Dr. Teodora Donisan, @TDonisan, PGY2 Internal Medicine Resident, Beaumont, Royal Oak, MI


Dr. Patrick Zakka@PatrickZakka, PGY4 Internal Medicine Chief Resident, Emory University, Atlanta, GA.


Dr. Rick Ferraro, @RichardAFerraro, internal medicine resident at the Johns Hopkins Hospital, Baltimore MD

Dr. Eunice Dugan, @EuniceDuganMD, internal medicine resident at the Johns Hopkins Hospital, Baltimore MD


Dr. Carine Hamo, @CarineHamo, cardiology fellow at the Johns Hopkins Hospital, Baltimore, MD

The published archive features curated twitter highlights from the journal club event. This archive was developed by Dr. Patrick Zakka.

Dr. Ronald Witteles (@Ron_Witteles): We need to push the answer for routine SGLT2 inhibitor prescriptions for HFrEF patients toward “routinely”!

Dr. Greg Fonarow (@gcfmd): Optimal implementation of SGLT2i for HFrEF estimated to save over 34,000 lives a year in US.

Dr. Kavita Sharma (@KSharmaMD): At this time I do prescribe SGLT2i for my HFpEF patients with diabetes. Looking forward to the outcomes of SGLT2i in HFpEF with and without diabetes- PRESERVED-HF and EMPEROR-Preserved.

Dr. Chony Albert (@ChonyAlbertMD): More trials coming down the pike with SGLT2 in HFpEF- excited for results!

Dr. Amit Goyal (@AmitGoyalMD): Looking forward to results of DELIVER and EMPEROR-PRESERVED to broaden our understanding of SGLT2i and HFpEF!

Dr. Eldrin Lewis (@EldrinL): We also must consider the dose adjustments potentially needed in diuretics in HFpEF, especially given the possible aorto-ventricular coupling.

Dr. Maria A. Pabón (@mapabonp): 34% of participants were female which is a higher ratio compared to classic HF trials showing that even though we have room to improve we are doing better at it!

Dr. Wilson Tang (@WilsonTangMD): 6.5% N. America

Dr. Chony Albert (@ChonyAlbertMD): ~15% ARNI use and ~66% MRA use in the trial.

Dr. Mark Drazner (@MarkDrazner): From a severity of illness standpoint: pt’s had to have SBP100 and be transitioned to oral diuretics. About half of cohort started after discharge.

Dr. Ryan J Tedford (@RyanTedfordMD): The event curves separate quite early and continue to separate. Really speaks to consideration of starting in hospitalized patients.

Dr. Clyde Yancy (@NMHheartdoc): Important ??? – what was the impact of sponsor retreat? Power changed; how secure are the results? <300 with HFpEF; positive signal but is it anything more than a new hypothesis? Important to consider dual receptor inhibition and more side effects. Good study but ??

So here is my take on SOLOIST-WHF. The data are directionally consistent with a surfeit of positive SGLT inhibitor trials. The potential to modify post Acute HF outcomes is intriguing and perhaps there is a signal in HFpEF. Heads up now for EMPEROR-PRESERVED.

→Dr. Deepak L. Bhatt (@DLBHATTMD): The side effect profile is very similar to other SGLT2 inhibitors, other than a slight excess in diarrhea due to the SGLT1 inhibition. Regarding more data on HFpEF, stay tuned for @ACCinTouch 2021!

Dr. Amit Goyal (@AmitGoyalMD): I think still generalizable. Consistent benefit across all trials. And original primary end point was still (+).

Dr. Ronald Witteles (@Ron_Witteles): Despite the shortfall in enrollment, the results were pretty unequivocal. When taken with the other SGLT2 inhibitor studies, they pain a clear picture.

Dr. Gregg Fonarow (@gcfmd): Remarkable similarities in terms of timing of benefits in the various trials in those with established HF.

Dr. Mark Drazner (@MarkDrazner): Remarkable database accruing for this class of drugs. But how are they working? Emerging evidence of favorable cardiac remodeling but this mechanism seems unlikely to explain divergence showing early benefits.

Dr. Justin L Grodin (@JLGrodin): Although myocardial energetics with ketone bodies is interesting, I supect that the more likely reason is that we have a more favorable resetting to a more normal renal homeostasis through their actions on the proximal nephron.

Dr. Maria A. Pabón (@mapabonp): To me one of the most remarkable results of SOLOIST-WHF is the possible role for SGLT2/1 inhibition as new options for our HFpEF.

Dr. Omar K Siddiqi (@omarsiddiqi): Need to also think about heterogeneity of the HFpEF population and effect of SGLT2i in, say, cardiac amyloidosis vs hypertensive heart disease vs HCM etc.

Dr. Carine Hamo (@CarineHamo): I also wonder if there is any potential cardiac benefit to SGLT-1 inhibition or are cardiac benefits mainly from SGLT-2 inhibition?

Dr. Deepak L Bhatt (@DLBHATTMD): It will be a great topic for future basic science investigation.

Dr. Ryan M. Heer (@DrRyanHeer): We have to expect it to impact gut microbiome and may assist in many GI inflammatory conditions/IBS too through poss impact n incretin levels.

Dr. Martha Gulati (@DrMarthaGulati): Just a suggestion to reduce year infections with SGLT2i is ask your patients to eat yogurt daily or probiotic foods or even a probiotic. I find it reduces year infections in my patients with DM anyway.

Dr. Kavita Sharma (@KSharmaMD): In general in a HFrEF patient who is compensated with decent BP: ARNI (do not need to trial ACE/ARB before), BB, MRA, then SGLT2i. Start low doses of all as early as possible – together. Generally start low, go slow, but definitely GO.

Dr. Daniel Ambinder (@Dr_DanMD): Do you have issues with insurance approval for SGLT2i and doses this make it challenging to prescribe as inpatient?

→→Dr. Kavita Sharma (@KSharmaMD): We run the test Rx’s in house at the start of the hospitalization with our pharmacists so by the time the patient is ready for discharge we have insurance approval for SGLT2i therapy.

→→Dr. Ronald Witteles (@Ron_Witteles): Agree with Dr. Kavita Sharma 100%. Exactly what we do. A mistake to assume that a patient WON’T have coverage – can usually get it, just needs prior auth, etc. HF hospitalization is a great time to get these life-saving drugs on board.

Dr. Ronald Witteles (@Ron_Witteles): I’m not sure it needs to be this regimented. If K room, get MRA on early. Get SGLT2 inhibitors on early – simple to do, modest BP reduction. BB & ARNI both early/ASAP as tolerated by BP. Key is not to waste time over many months. So much to do for HF patients!

Dr. Chony Albert (@ChonyAlbertMD): I think it depends on the stability and the volume status of patients. Stable outpatients with adequate BP: BB+ARNI then MRA and SGL2. Need to monitor response/electrolytes to each addition.

Dr. Eldrin Lewis (@EldrinL): Mt. Rushmore of HFrEF includes ACE/ARB/ARNI + Beta blocker + MRA. The sculptor is getting ready to add SGLT2i as the fourth agent.

Dr. Chony Albert (@ChonyAlbertMD): DAPA HF, Emperor Reduced, and SOLOIST all suggestive of class effect of SGLT2 and HFrEF mortality and morbidity. However VERTIS CV with ertugliflozin fell short.

Dr. Fred Wu (@FredWuMD): We find ourselves asking this every time a landmark HF study comes out! In pts with two ventricles + systemic left ventricle there’s probably benefit, but in ACHF, right heart failure, RV failure, and single ventricle failure is where need is greatest and data is most lacking.

Dr. Martha Gulati (@DrMarthaGulati): Dr. Bhatt, can you tell us what the impact of having to stop the study early because of covid? Would we have had a reduction in ASCVD events had we followed longer?

Dr. Deepak L Bhatt (@DLBHATTMD): In the SCORED trial we did have enough power to see a significant reduction in MACE, including a significant reduction in stroke.

Dr. Eldrin Lewis (@EldrinL): The consistent direction is reassuring. Convergent validity! It is a strong signal and consistent. Let’s get more data on HFpEF coming soon.

Dr. Gregg Fonarow (@gcfmd): Initiate ARNI + BB + MRA + SGLT2i in all eligible HFrEF patients without contraindications ASAP. HFmrEF/HFpEF with either CKD or T2DM Rx consider SGLT2i for the CKD or DM indications. Trials in HFpEF for this indication forthcoming.

Dr Ronald Witteles (@Ron_Witteles): My own feeling is that diuretics were NOT a priori titrated in the (blinded) clinical trials, so we shouldn’t do so in our patients. But must watch BMP closely, ideally within a week or so after starting.

Dr. Wilson Tang (@WilsonTangMD): In my experience to date, there hasn’t been any need to adjust diuretics immediately when initiating, but over time as patients improve and with other GDMT uptitration many can be off diuretics completely.

Dr. Jane Wilcox (@WilcoxHeart): If euvolemic in clinic I will halve the loop and start the SGLT2i.

Dr. Eldrin Lewis (@EldrinL): In more advanced patients, I have seen improved diuresis. We often tell our patients to call for weight gain; it should be for weight loss as well! No need to decrease dose empirically but must follow.

Dr. Kavita Sharma (@KSharmaMD): We are not a priori changing diuretics in all. Key is early follow up. Every HF patient seen within 7 days post discharge.

Dr. Ryan J Tedford (@RyanTedfordMD): Regardless of initiation of SGLT-2, patients still need to be seen within 7-10 days of discharge. If euvolemic, probably need to reduce loop diuretic by 30-50%. If overloaded, close follow up.

Dr. Gregg Fonarow (@gcfmd): In trials most patients did not require changes in diuretic dosing, yet some do. Avoiding volume depletion as important as avoiding persistent congestion. Recognize that ARNI and SGLT2i cause expected decrease in eGFR that is is not aki AND LT renoprotective.

Dr. Amit Goyal (@AmitGoyalMD): Great point! The acute and expected decreased in eGFR is more than compensated for by longer-term renal benefits.

Dr. Ravi Karra (@DrRKarra): Anecdotally have had some success with amyloid – seems to find the “right” filling pressure. Still no idea how it works.

Dr. Ronald Witteles (@Ron_Witteles) :We need to better define a “CardioOnc” patient. All are not created equal! As of now, SGLT2 inhibitors make sense for CardioOnc patients who have appropriate HF (or DM) indications, but I wouldn’t use in “CardioOnc” patients in general.

Dr. Eldrin Lewis (@EldrinL): It would be nice to get any HF specific med started on cardionc patients. ACE-I consistently would be a good start. Diarrhea and dehydration from SGLT2i will have to be monitored.

Dr. Chony Albert (@ChonyAlbertMD): Unfortunately there is always inertia to dissemination of new drug therapies in clinical practice. Similar issues 5 years ago with ARNI. Now ARNI has permeated HFrEF patients population well. I think it’s about education and having more conversations like this!

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