renal.

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THE FILTER, THE PUMP AND
THE PILL
DR O.BHEEKHARRY
NEPHROLOGIST
VICTORIA HOSPITAL
 BACKGROUND

Diabetes Mellitus affects nearly ¼ of our

population and has various Microvascular and
Macrovascular complications.
The most important organs being affected are
the :
Heart - the ‘pump’
Kidney – the “filter”
Blood vessels – the “pipes”
Eyes
 OBJECTIVE

1. Discuss recent evidence of renal protective therapy in type 2 diabetes and

the potential mechanisms

2. Discuss the evidence of cardio-protective therapy in type 2 diabetes

 RENAL PROTECTIVE THERAPY IN DKD

1. RAAS blockade : ACEi(early 90s) / ARB (late 90s)

2. SGLT2i : appeared ~ 7 yrs ago, growing evidence of Reno-protective and, recently,

Cardio-protective effects

3. Possibly, 3rd gen mineralocorticoid receptor antagonists (MRA) awaiting

publication, ended phase III trial recently
 ADA 2020

Selection of Glucose-Lowering Medications for People With CKD

• SGLT2 inhibitors and GLP-1 receptor agonists should be
considered for patients with type 2 diabetes and CKD who require
another drug added to metformin to attain target A1C or cannot
use or tolerate metformin.
• these drug classes are suggested because they appear to reduce
risks of CKD progression, albuminuria, CVD events, and
hypoglycemia ( based on several large clinical trials)
SUMMARY OF EFFECTS OF SGLT2I VS GLP1RA VS DPP4 I
THE PILL : SGLT2 INHIBITOR
SGLT2 INHIBITORS : HOW DO THEY WORK?

• reduce blood glucose through glycosuria and natriuresis initiated by

inhibition of glucose reabsorption at the proximal tubule of the kidney

• pharmacodynamic studies revealed that SGLT2i are filtered from the

blood through the glomerulus and exhibit their inhibitory effects
exclusively on the extracellular side of the plasma membrane
 SGLT2 INHIBITORS : HOW DO THEY WORK?

• How do they work

Salt reabsorption- ATP- Adenosine – Vasoconstriction
RENO PROTECTIVE MECHANISM
CARDIOVASCULAR BENEFITS
KEY FINDINGS FROM THE DECLARE–TIMI 58 TRIAL
• Dapagliflozin did result in a lower rate of CV death and hospitalisation for heart
failure

• lower rate of CV death or hospitalisation for heart failure in the dapagliflozin

group than in the placebo group was consistent across multiple subgroups, which
shows that dapagliflozin prevented CV events, particularly hospitalisation for
heart failure

• In this broad population of patients with high risk for CV events, dapagliflozin was
noninferior to placebo with respect to the composite safety outcome of
cardiovascular death, myocardial infarction, or ischemic stroke (MACE), but it did
not result in a significantly lower rate of MACE than placebo.
ADVERSE EFFECTS

• UTI ( fungal)
• Hypotension
• DKA
• Amputations ? ( no evidence found in DECLARE TIMI 58)
FILTER, PUMP, PIPE & THE PILL
UPCOMING KIDNEY OUTCOME TRIALS

DAPA-CKD : Large MC RCT having as primary outcome effects of

Dapagliflozin vs Placebo on progression of CKD, renal and CV death.

FIDELIO-DKD : Finerenone in reducing KF and progression in DKD

DAPA-CKD
TAKE HOME MESSAGE

• Recent CV outcome trials have shown SGLT2 inhibitors slow the progression of CKD in type 2
DM at high CV risk
• Reduce Albuminuria
• Weight loss
• Reduce risk of hospitalisation for heart failure and CV death ( Dapagliflozin)
• Evidence that SGLT2i use in DM type 2, protects the kidneys (filter) , the heart (pump) and
the blood vessels (pipes)