The Filter, The Pump and The Pill

This is an abstract followed by the slides in pdf and video formats of the presentation made by Dr O Bheekharry for The Kidney Club on 16 July 2020.

Diabetes mellitus (DM) affects around 25% of the Mauritian population and has important microvascular and macrovascular complications.
Approximately 40% of DM type 2 patients have chronic kidney disease and another 40% is believed to have heart failure with around 30% having coronary artery disease.

Would it not be perfect to have a pill which can potentially prevent or slow down these complications? Is there such a pill that could eventually protect the kidneys (our body’s filter), the heart ( body’s pump) and the blood vessels (pipes)?

Renal protective therapies

Since the early 90’s, Renin- Angiotensin-Aldosterone system (RAAS) blockade has been the mainstay of renal protection in DM type 2 through Angiotensin Converting Enzyme inhibitors (ACE-i)1 and Angiotensin II Receptor blockers (ARB). There was a large gap afterwards with nothing new until around 7 years ago when the Sodium-glucose co-transporter 2 inhibitors (SGLT2 I) appeared and there is growing evidence of its reno-protective and cardio-protective effects.

SGLT2 inhibitors

These are a class of oral medications used for diabetes type 2 patients to achieve good glycaemic targets. They act on the proximal tubules of the kidney to reabsorb glucose and sodium back into the tubules to be excreted into the urine. Some of the most important agents are : Dapagliflozin, Canagliflozin and Empagliflozin amongst others.

Apart from lowering glucose, recent clinical trials have shown other interesting benefits.
By preventing hyperfiltration in the early stages of diabetic nephropathy, SGLT2i have demonstrated a decrease in eGFR loss (RRR 27-40%)2 and in albuminuria. Cardiovascular benefits evidentiated in various clinical trials are to decrease incidence of cardiovascular death (RRR 17-30%)3 , hospitalisation in heart failure (by nearly 30%).

Some key clinical trials are the DECLARE-TIMI 58 (largest multi-centered randomized controlled trial with 17 160 patients) 3, DAPA-HF, CREDENCE (dedicated renal outcome trial), EMPA-REG 4 and CANVAS5. At the time of writing, DAPA-CKD is another eagerly awaited trial that has recently ended and the results will hopefully be published in a few months.

However, the main adverse effects associated are genital mycotic infections, UTIs, Diabetic ketoacidosis amongst a few others.

So, do we have our pill which can protect the heart, the vessels and the kidneys in diabetic patients? My answer would be yes.

This presentation was made possible with the support of AstraZeneca* and Unicorn Trading.

*Disclaimer: “This presentation is solely intended for educational purpose and does not replace independent professional judgement. Statements of fact and opinions expressed are those of the speaker and, unless expressly stated to the contrary, not the opinions or position of AstraZeneca. AstraZeneca does not endorse or approve, and assumes no responsibility for, the content, accuracy or completeness of the information presented.”

1. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: 1456-62

2. Perkovic V,  Jardine MJ, Neal B, Bompoint S, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380:2295-2306.

3. S.D. Wiviott, I. Raz, M.P. Bonaca et al. for the DECLARE–TIMI 58 Investigators*. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019;380:347-57. DOI: 10.1056/NEJMoa1812389.

4.Bernard Zinman, M.D., Christoph Wanner, M.D., John M. Lachin, Sc.D., David Fitchett, M.D. et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128

5.Bruce Neal, M.B., Ch.B., Ph.D., Vlado Perkovic, M.B., B.S., Ph.D., Kenneth W. Mahaffey, M.D., Dick de Zeeuw, M.D., Ph.D. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657. DOI: 10.1056/NEJMoa1611925.

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