Chapter 7 Diabetic kidney disease

7.1 Glycaemic control

Intensive glycaemic control slows progression of diabetic nephropathy.

DCCT (1993): - intensive vs. conventional insulin therapy in T1DM (achieving HbA1c ~7 vs. ~9 %). Intensive control reduced risk of micro- and overt albuminuria (and retinopathy). Frequent hypos in the intensive group (in the era of isophane insulin).

UKPDS 33 (1998): - intensive vs. conventional glycaemic control in T2DM (achieving HbA1c ~7.0 vs. ~7.9 %; n ~5000). Intensive control reduced risk of microalbuminuria.

10-year follow-up data from UKPDS (in 2008) showed that early good glycaemic control exerted a beneficial “legacy” effect on micro-vascular outcomes, MI and death whereas early good ABP control did not exert a legacy benefit.

STENO-2 (2017): conventional management vs. multi-factorial intervention in T2DM with microalbuminuria. Multi-factorial intervention conferred benefits for nephropathy, retinopathy and autonomic neuropathy.

7.2 RAS blockade

RASi slow progression in DM with overt albuminuria.

Lewis et al. (1993): - captopril vs. placebo in T1DM with PER > 0.5 g/day. Captopril delayed time to doubling of SCr and reduced risk of composite of death and ESRF independent of effects on blood pressure.

IDNT (2001): - irbesartan vs. amlodipine vs. placebo in T2DM with HTN and PER > 0.9 g/day. Irbesartan reduced risk of composite (doubling of SCr, ESRF, death) compared to both other groups. Effects independent of blood-pressure.

RENAAL (2001): - losartan vs. placebo in T2DM and ACR > 30 or PER > 0.5 g/day. Losartan reduced risk of composite end-point (doubling SCr, ESRF, death). Effects independent of blood-pressure.

RASi slow progression to overt nephropathy in microalbuminuria:

ACEi in DN Trialist Group (2001): - ACEi delay progression to overt albuminuria in T1DM and microalbuminuria.

Parving et al. (2001): - irbesartan vs. placebo in T2DM with HTN and microalbuminuria. Irbesartan delayed progression to overt albuminuria.

Are RASi beneficial even before the onset of microalbuminuria?

ROADMAP (2011): - olmesartan vs. placebo in T2DM without microalbuminuria. In the olmesartan group, there was delayed onset of microalbuminuria but a greater number of cardiovascular deaths.

7.3 Dual RAAS blockade

Dual RAAS blockade increases the risk of adverse events:

VA NEPHRON-D (2013): - losartan plus placebo vs losartan plus lisinopril in T2DM and ACR > 30. Terminated early for safety concerns. No benefit from dual RAS blockade (on composite of change in eGFR, ESRF and mortality) but increased risk of AKI and hyperkalaemia.

See also ONTARGET trial in hypertension chapter. See also CO-OPERATE trial (retracted).

7.4 SGLTi

See also SGLT2i in non-diabetic DKD.

CREDENCE (2019): - canagliflozin 100 mg od vs. placebo in T2DM with eGFR 30–90 (predominantly eGFR 30–60) and uACR >30. Mean GFR 56; median uACR 90. Primary composite outcome (ESKD, doubling of SCr, death from renal or CVS cause). Terminated early (median follow-up 2.6 yrs) because of efficacy. RR of primary outcome 30% lower in flozin group. Also reductions in risk of ESKD, CVS death, MI, CVA, hospitalisation for CCF.

EMPA-REG (2016): - empagliflozin vs. placebo in T2DM with eGFR >30. Mean GFR 74; ACR < 3 in 60%. Empagliflozin slowed rate of decline in eGFR and progression to ESRF.

CANVAS (2018): - canagliflozin vs. placebo in T2DM for primary and secondary prevention of CVS events and renal composite outcome (40% reducing in eGFR, RRT, death). Canagliflozin reduced CVS and renal events in both primary and secondary prevention cohorts.

7.5 GLP1ra

FLOW (2024): - semaglutide 1 mg weekly s.c. vs placebo in T2DM with CKD and albuminuria (eGFR 25 – 75 with albuminuria). n = 3500. 95% on RASi; 15% on SGLT2i. Primary composite outcome (ESKD, 50% reducton in eGFR, renal or CVS death). RRR ~25% for primary outcome; 20% reduction in all-cause mortality. No safety signal.

7.6 Four pillars

Neuen at al. (2024): - combined data from major RCTs to estimate benefit of combination SGLT2i, nsMRA, GLP1ra therapy in terms of years of life gained.