CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Director, Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor, www.cmeindia.in.

Based on the presentation at Diabetes India Conference 2022.

Amazing changes in heart of SGLT2-Inhibitor treated hearts occurs. What about Kidneys?

The great leap forward – 2022

• Initial concerns about SGLT2 inhibitors focused on possible detrimental effects on the renal system, particularly to increase Genito-urinary infections, compromise bladder health and aggravate acute kidney injury has eased.
• Apprehension that administration of an SGLT2 inhibitor caused a temporary dip in glomerular filtration rate and caused persistent reductions in plasma volume and blood pressure has taken a POSITIVE shape.
• Cardiovascular outcome trials and ‘real world’ studies have identified potentially advantageous effects of SGLT2 inhibitors to reduce the risk of onset and progression of several cardiovascular conditions and to preserve kidney function.

A SGLT2 Inhibitor a day Keeps heart failure, kidney disease and MI’s away

Diabetes and Kidney ये रिश्ता क्या है?

• Over the last two decades, at variance with cardiovascular (CV) morbidity and mortality, which has progressively declined in patients with diabetes over the last two decades, the trend in microvascular complications has remained substantially unchanged.
• In particular, diabetic kidney disease (DKD) accounts for up to 60% of new patients beginning renal replacement therapy (RRT) worldwide and its prevalence has shown only a slight reduction in recent years.
• Most common complications of diabetes are: CKD & DKD
• Leading cause of end-stage renal disease (ESRD) accounting for >45% of all cases.
• DKD a major contributor to CKD and ESRD, it also portends worse outcomes with a five-year survival rate of <40% in ESRD patients.
• DKD has been shown to be a large contributor to the excess risk for all-cause and cardiovascular disease-related mortality amongst type 2 diabetic patients.

Point of Utmost Concern: Diabetic kidneys subject to RAAS blockade still progressed to kidney failure at a fairly significant pace.

• To date, RAAS blockade has been the last successful drug class for GFR preservation, independent of the effect on blood pressure.
• That success takes us back almost two decades, to 2001, when the RENAAL and IDNT trials showed that losartan and irbesartan, respectively, reduced the composite kidney endpoint (ESKD, doubling of serum creatinine, and mortality) by 15-20%.

Nephrologists are using daggers to fight the fire breathing dragon?

• While advances had been made in the treatment of various glomerulonephritides, the mantra for DKD seemed to be fixed on the time-tested but archaic principles of managing any kidney disease, namely blood pressure control, proteinuria reduction, and use of ACEI/ARBs.
• This approach has an unsatisfactory high rate of kidney failure and death.
• It is important to remember that the majority of patients (~80%) in the early SGLT2i trials were on an ACEi or ARB and all of the patients.
• In CREDENCE were on maximally tolerated doses of ACEi/ARB therapy.
• So, SGLT2 inhibitors work in patients with DKD on RAAS blockade, which produces efferent vasoconstriction, but the crucial question remains: Why?

New Nectar in Diabetes?

In DKD, a multistep process results in the kidney misunderstanding an individual’s volume status

• Persistent hyperglycemia upregulates glucose reabsorption (and secondarily, sodium and chloride reabsorption) in the proximal tubule.
• This decreases sodium and chloride delivery to the macula densa which is mistaken for decreased kidney perfusion.
• This results in decreased adenosine production.
• A decrease in afferent arteriolar tone increasing blood flow to the glomerulus is signaled

Is it Hunt ‘Remedy-Never known to Fail?

Ketone bodies as a direct modulator of intracellular nutrient signals is talk of 2022

Credit: Issei Tomita, Shinji Kume, Sho Sugahara et al. SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition,Cell Metabolism,Volume 32, Issue 3,2020.

Numerous mechanisms that may be driving the Reno protective effects of SGLT2 inhibitors

2022: That Stands the Test of Time

Message is Crystal Clear from CVOT Trials

Credit: ADA-2021 Dr David Cherney, Nephrologist, Canada

The first landmark trial that highlights the power of SGLT2-Inhibitor was the CREDENCE trial

Credit: ADA-2021 Dr David Cherney, Nephrologist, Canada

More good news! Since CREDENCE

EMPEROR-Reduced Trial

• Empagliflozin Lowers Risk of Serious Kidney Events in HFrEF
  End-Stage Kidney Disease or Sustained Profound ↓ in eGFR

EMPEROR-Preserved

What DAPA-CKD established?

• DAPA-CKD: Significant Victory for CKD-With or Without Diabetes.

EMPA-KIDNEY-Illuminating Findings

• EMPA-KIDNEY trial stops early due to evidence of efficacy 16 March 2022
• EMPA-KIDNEY is the largest and most inclusive SGLT2 inhibitor trial in chronic kidney disease to date.
• EMPA-KIDNEY, the trial enrollment criteria aimed to include adults with CKD who are frequently seen in practice but were underrepresented in previous SGLT2 inhibitor trials.
• The success of empagliflozin in EMPA-KIDNEY follows its positive results in both the EMPEROR-Reduced and EMPEROR-Preserved trials.

EMPA-KIDNEY includes a broad spectrum of adults with CKD, including people:

• With mildly to severely reduced egfr (a measure of kidney function);
• With normal and increased levels of albumin (a type of protein present in the urine);
• With and without diabetes;
• With CKD attributable to a wide range of underlying causes;
• Many of these patients have been under-represented in previous trials.

Message from DARE 19

• SGLT2 inhibitors decrease proinflammatory and oxidative stress pathways, suppress cytokines, and improve endothelial function and oxygen carrying capacity, which may prevent organ damage and improve AKI outcomes after COVID-19 infection.
• Inflammation, oxidative stress, and endothelial dysfunction are frequently present in patients with CKD and are implicated in the progressive decline of kidney function in these patients, suggesting that the relative and absolute benefits of SGLT2 inhibitors may be more pronounced in patients with COVID-19 and CKD.
• The trial demonstrated that dapagliflozin was well tolerated but did not result in a statistically significant risk reduction in the primary outcomes of organ dysfunction or death or improvement in recovery.

Big Picture

1. Slowing in eGFR Decline by 0.5-1 mL/min/1.73m²/year, Predicts Long-term Risk-Reduction for CKD Events.
2. Average patient would delay develop eGFR 10 by over 15 years by taking Canagliflozin (CANVAS Trial).
3. Only SGLT2-inhibitor exert improve HHF and Kidney disease progression.

Credit: ADA-2021 Dr David Cherney, Nephrologist, Canada

Quick Take-Aways

2022 therapies are effective down to eGFR of 25 ml/min/1.73 m², it is critical for cardio-kidney-metabolic physicians to discard the old, obsolete eGFR threshold of 45 or 60 ml/min/1.73 m² that were based on glycemic factors, rather than heart or kidney protection.

• Large SGLT2-i- RCTs in diabetic and non-diabetic CKD patients on RAS blockade have shown that they slow kidney disease progression, decrease CV events and improve survival independent of the presence of diabetes. The benefits appear to extend beyond diabetes to include patients with the second (hypertension/vascular nephropathy) and third (glomerulonephritis) most common causes of CKD.
• With all of this promising evidence, are we using SGLT2 inhibitors appropriately? And if not, why not?  SGLT2 Inhibitors are an important weapon in our arsenal against not only type 2 diabetes, but also the conditions that we encounter that go hand-in-hand, including CKD and cardiovascular disease.
• Frontline clinicians should initiate SGLT-2 inhibitors for patients with type 2 diabetes and diabetic kidney disease who have an eGFR of at least 30 mL/min/1.73 m2.
• Deferring initiation of SGLT-2 inhibitors to a specialist (a nephrologist or endocrinologist) will result in a faster progression of diabetic kidney disease irrespective of glycemic control, and it is crucial to initiate these medications as early as possible.
• Prescribers should be aware of the initial reversible drop in eGFR of approximately 5 to 8 mL/min/1.73 m2 (up to a 20% drop) in the first 2 weeks after starting SGLT-2 inhibitors, which is due to the hemodynamic effects of the drug

अनुगृहीतोऽस्मि

References:

1. Heerspink HJL, et al. Kidney Int 2018;94:26–39; 2. Tamargo J. Eur Cardiol 2019;14:23–32
2. Perkovic V, et al. N Engl J Med. 2019;380(24):2295-2306.
3. 3. Wanner C. Presented at 56^th Annual EASD meeting, Sept 23, 2020.
4. 5. Zannad F et al. Circulation. 2021 Jan 26;143(4):310-21.
5. 6. Anker S et al. N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMoa2107038.
6. https://www.empakidney.org/news/empa-kidney-trial-stops-early-due-to-evidence-of-efficacy. Accessed 22 Mar
7. Leoncini, G.; Russo, E.; Bussalino, E.; Barnini, C.; Viazzi, F.; Pontremoli, R. SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits. Int. J. Mol. Sci. 2021, 22, 4441. https://doi.org/10.3390/ ijms22094441

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