CKD in T1D – any advances in management?

27th December 2023, A/Prof Chee L Khoo


Not surprisingly, if dysglycaemia is the major contributor to microvascular complications in type 2 diabetes (T2D), the same complications must plaque our patients with type 1 diabetes (T1D. However, we haven’t had many major advances in the management for chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with T1D for decades. For example, why can’t we easily and safely add an SGLT2 inhibitor (SGLT2i) or GLP1-RA to the insulin regimen in T1D even if they have CKD and/or CVD. Is that about to change soon?

The sad statistics

The prevalence of CKD in T1D increases with diabetes duration, with approximately 33% and 25% of adults developing albuminuria and eGFR <60 ml/min/1.73 m2, respectively, after >40 years of diabetes. Overall, the lifetime risk of end staged kidney disease (ESKD) is 10–30% [1,2). The risk of CKD was 1.4- to 3.0-fold higher in individuals with type 1 diabetes at all ages than in those with type 2 diabetes [7]. Additionally, in Scandinavian cohort studies, event rates of heart failure (HF), stroke, incident CKD and ‘cardiorenal’-related death were higher in type 1 diabetes than in type 2 diabetes [3]. Compared with matched controls, individuals diagnosed with type 1 diabetes between 0 – 10 years of age have a nearly 30 X increased risk of coronary heart disease, with greater than seven times the risk of cardiovascular death [4].

Existing weapons

There was a decrease between the 1970s and the 1980s with the emergence of renin–angiotensin system (RAS) blockers (ACE inhibitors and ARBs). There was a decrease in the cumulative incidence of severe albuminuria in individuals diagnosed with type 1 diabetes in the 1980s compared with those diagnosed in the 1970s in Finland, although no further improvement was apparent in the 1990–1999 diagnosis cohort [5]. In a similar analysis of the Swedish National Diabetes Register, a decreasing trend in standardised incidence rates of diabetic nephropathy in people with type 1 diabetes was observed from 2001 to 2019, with no changes in the rates of ESKD over the same period [6]

Over the last decade, sodium–glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1-RAs) and non-steroidal mineralocorticoid receptor antagonists (MRAs) have emerged as potent kidney- and/or cardioprotective agents in type 2 diabetes. While these agents are now incorporated into treatment guidelines for management of T2D, we have yet to see them being integrated into T1D management.

SGLT2 inhibitors

In each of the dedicated renal outcome trials (CREDENCE, EMPA-KIDNEY and DAPA-CKD), treatment with an SGLT2i was associated with a ~30–40% reduction in the risk of eGFR decline, progression to ESKD or death due to kidney or CVD. SGLT2i may ameliorate hyperglycaemia-related kidney cell-specific changes in energy metabolism, thereby modulating mitochondrial function and autophagy. SGLT2i also have prominent haemodynamic effects, normalising tubule-glomerular feedback and reducing glomerular hyperfiltration by increasing distal tubular sodium delivery. Furthermore, SGLT2i have been demonstrated to reduce kidney tissue hypoxia and inflammation in experimental models and in humans. The very similar benefits seen in people with CKD with or without diabetes suggests that the effect on hyperglycaemia is probably of minor importance for the kidney benefit.

Naturally, the main barrier holding back the SGLT2i being integrated into the T1D guidelines is the lack of data from studies. There are studies adding SGLT2i to insulin therapy in T1D but the primary outcome is about glycaemic control. The EASE, DEPICT and inTandem (studying dual SGLT2 and SGLT1 inhibitor, sotagliflozin) trial programmes each consisted of a series of randomised placebo-controlled trials assessing the effects of SGLT2i on HbA1c levels in adults with type 1 diabetes over 24–52 weeks’ follow-up. Not unexpectedly, there were improvements in HbA1c, reductions in total daily insulin dose, weight and BP without increases in hypoglycaemia.

In pooled analyses from each of the three T1D trial programmes, among people with a UACR >3 mg/mmol at baseline, SGLT2i resulted in a reduction in uACR of as much as 30% over 52 weeks’ follow-up [7-9].

An observational study of 200 adults with type 1 diabetes demonstrated improvements in albuminuria and in eGFR with SGLT2i use over 12 months among adults with a baseline eGFR <90 ml/min per 1.73 m2 [10]. In another post hoc analysis of the inTandem trials using predictive modelling, sotagliflozin was reported to reduce the estimated risk of CVD and ESKD [11].

The elephant in the room is obviously, the worry about euglycaemic DKA when SGLT2i are used with insulin in T1D. A meta-analysis of 18 RCTs including >7000 participants identified a 2.8-fold greater risk of DKA with SGLT2i use compared with placebo in adults with type 1 diabetes [12]. Moving forward, before we can get SGLT2i integrated into guidelines for T1D, we need strategies to assess and mitigate DKA risk, including preventative measures, patient education and continuous ketone monitoring.


The kidney-protective effects of GLP1-RAs are believed to result from reductions in inflammation and oxidative stress, in part through direct binding to glucagon-like peptide 1 (GLP1) receptors present on kidney glomerular and tubular cells.

A meta-analysis of the ELIXA, LEADER, SUSTAIN-6, EXSCEL, REWIND and AMPLITUDE-O trials in type 2 diabetes estimated a 21% reduction in the risk of new-onset macroalbuminuria, eGFR decline, progression to ESKD or death attributable to kidney causes with GLP1-RAs compared with placebo [13].

As yet, there are no published trials to investigate the effect of GLP1-RA on major kidney outcomes. The ongoing FLOW trial (NCT03819153) will be the first large multinational randomised placebo-controlled trial to primarily investigate the effects of semaglutide, on major kidney outcomes in adults with T2D and CKD [50]. FLOW is expected to report at the end of 2024.

The effects of semaglutide on kidney oxygenation, albuminuria and eGFR will be assessed in people with type 1 diabetes as part of the REMODEL-T1D mechanistic trial (NCT05822609).

There are no trials looking at the effect of tirzepatide on kidney outcomes in patients with T1D but there is a trial looking at Tirzepatide for the Concurrent Treatment of Obesity and Type 1 Diabetes (TZP-T1D) (NCT06180616) awaiting recruitment at Royal North Shore Hospital.

Mineralocorticoid receptor antagonists (MRA)

Kidney effects of steroidal MRAs have primarily been investigated in type 2 diabetes and CKD. The use of spironolactone resulted in a 30–60% reduction in albuminuria compared with placebo. In a meta-analysis of 16 RCTs of adults with diabetes and CKD (some included people with T1D), spironolactone added to standard therapy was associated with a reduction in 24 h urinary albumin/protein excretion (14).

In the FIDELIO-DKD trial including adults with T2D and CKD, novel non-steroidal MRAs, finerenone reduced the risk of the primary kidney by ~20%. In the parallel FIGARO-DKD trial, finerenone demonstrated significant cardiovascular benefits in adults with T2D and CKD.

A Parallel-group, Randomized, Prospective, Interventional, Double-blind, Multicenter Global Phase 3 Study to Investigate the Efficacy and Safety of Finerenone Versus Placebo, in Addition to Standard of Care, in Participants With Chronic Kidney Disease and Type 1 Diabetes (NCT05901831) will be recruiting early in 2024 and expected to report in early 2026.

Newer weapons on the way?

These are agents developed primarily for improving kidney endpoints rather than glucose lowering effects.

Endothelin receptor antagonists

Endothelin (ET) is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family. ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure. ET receptor antagonists (ERA) are designed to preferentially target endothelin A receptors, associated with inflammation and podocytopathy, over endothelin B receptors, associated with vasodilation and natriuresis. The largest trial of ERAs, SONAR, including 2648 participants with type 2 diabetes and proteinuric CKD, demonstrated that atrasentan on top of RAS inhibition significantly lowered the risk of a doubling of serum creatinine or ESKD compared with placebo by 35% [15]. There are newer ERA trials on the way. A trial of zibotentan, a highly selective endothelin A ERA, in combination with dapagliflozin in participants with T2D (NCT05570305) is currently underway, with similar phase 2 trials in type 1 diabetes being proposed.

Soluble Guanylate Cyclase (sGC)

Nitrous Oxide (NO) plays a major role in the regulation of vascular health. In particular, it is essential for vasodilatation and maintenance of blood pressure. Reduced bioavailability and/or responsiveness to endogenous NO have been implicated in the pathogenesis of many disease processes. NO then readily crosses target cell membranes and binds to its primary receptor sGC, which in turn boosts the activity of sGC several hundred-fold to produce intracellular cGMP.

Two types of small molecules have been developed, namely, sGC stimulators and activators. sGC stimulators can activate sGC with or without NO signalling. Riociguat, a sGC stimulator is already used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, and another stimulator, vericiguat, was developed for the treatment of symptomatic chronic heart failure with reduced ejection fraction. Preclinical models have suggested that stimulation of sGC in diabetes can increase cGMP formation, with resultant improvements in kidney inflammation/fibrosis, glomerular permeability and kidney blood flow [16]. In a Phase II study of 156 individuals with type 2 diabetes and UACR >22.6 and <565 mg/mmol, the sGC stimulator praliciguat demonstrated a non-statistically significant placebo-adjusted decrease in UACR of 15%, accompanied by reductions in blood pressure [17].

Anti-inflammatory ~mabs

Targeting inflammatory pathways, specifically the NLR family pyrin domain containing 3 (NLRP3)/IL-1β/IL6/C-reactive protein (CRP) pathway, has emerged as another strategy for improving cardiorenal outcomes in high-risk populations. Canakinumab (CANTOS trial) have demonstrated efficacy in reducing CV events (18) and ziltivekimab (ZEUS trial) is yet to recruit participants which will include patients with T1D and CKD.

In the meantime, we are underusing therapies directed at heart and kidney protection. In the Scandinavian cohort, fewer people with T1D than T2D were on CVD medication (53.9% vs 82.1%), ACE inhibitors (22.5% vs 32.0%) and angiotensin receptor blockers (ARB) (16.7% vs 31.3%) (19).

In summary, the burden of CKD continues to weigh down on our patients with T1D. Over the last decade, SGLT2i, GLP1-RA and MRA have been shown to benefit patients with CKD with or without T2D. These agents should be equally beneficial in our patients with T1D as they both share similar pathophysiological process in the disease process. Clinical trials are emerging and in time, these agents will be integrated into the guidelines for patients with T1D. There are also other agents in the pipeline that were not developed as glucose lowering agents but has shown potential to improve renal outcomes.


  1. Bakris GL, Molitch M (2018) Are all patients with type 1 diabetes destined for dialysis if they live long enough? Probably not. Diabetes Care 41:389–390.
  2. Dena M, Svensson AM, Olofsson KE et al (2021) Renal complications and duration of diabetes: an international comparison in persons with type 1 diabetes. Diabetes Ther 12(12):3093–3105.
  3. Kristofi R, Bodegard J, Norhammar A et al (2021) Cardiovascular and renal disease burden in type 1 compared with type 2 diabetes: a two-country nationwide observational study. Diabetes Care 44:1211–1218.
  4. Graves L, Donaghue K (2019) Management of diabetes complications in youth. Ther Adv Endocrinol Metab 10:2042018819863226.
  5. Jansson Sigfrids F, Groop PH, Harjutsalo V (2022) Incidence rate patterns, cumulative incidence, and time trends for moderate and severe albuminuria in individuals diagnosed with type 1 diabetes aged 0–14 years: a population-based retrospective cohort study. Lancet Diabetes Endocrinol 10:489–498.
  6. Halminen J, Sattaer N, Rawshani A et al (2022) Range of risk factor levels, risk control, and temporal trends for nephropathy and end-stage kidney disease in patients with type 1 and type 2 diabetes. Diabetes Care 45:2326–2335.
  7. van Raalte DH, Bjornstad P, Persson F et al (2019) The impact of sotagliflozin on renal function, albuminuria, blood pressure, and hematocrit in adults with type 1 diabetes. Diabetes Care 42:1921–1929.
  8. Cherney DZI, Bjornstad P, Perkins BA et al (2021) Kidney effects of empagliflozin in people with type 1 diabetes. Clin J Am Soc Nephrol 16:1715–1719.
  9. Groop PH, Dandona P, Phillip M et al (2020) Effect of dapagliflozin as an adjunct to insulin over 52 weeks in individuals with type 1 diabetes: post-hoc renal analysis of the DEPICT randomised controlled trials. Lancet Diabetes Endocrinol 8:845–854.
  10. Palanca A, van Nes F, Pardo F, Ampudia Blasco FJ, Mathieu C (2022) Real-world evidence of efficacy and safety of SGLT2 inhibitors as adjunctive therapy in adults with type 1 diabetes: a European two-center experience. Diabetes Care 45:650–658.
  11. Stougaard EB, Rossing P, Vistisen D et al (2023) Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, reduces the risk of cardiovascular and kidney disease as assessed by Steno T1 Risk Engine in adults with type 1 diabetes. Diabetes Obes Metab 25(7):1874–1882.
  12. Musso G, Sircana A, Saba F, Cassader M, Gambino R (2020) Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: a meta-analysis and meta-regression. PLOS Med 17:e1003461.
  13. Sattar N, Lee MMY, Kristensen SL et al (2021) Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 9:653–662
  14. Hou J, Xiong W, Cao L, Wen X, Li A (2015) Spironolactone add-on for preventing or slowing the progression of diabetic nephropathy: a meta-analysis. Clin Ther 37:2086-2103.e10.
  15. Heerspink HJL, Parving HH, Andress DL et al (2019) Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet 393:1937–1947.
  16. Hohenstein B, Daniel C, Wagner A, Stasch JP, Hugo C (2005) Stimulation of soluble guanylyl cyclase inhibits mesangial cell proliferation and matrix accumulation in experimental glomerulonephritis. Am J Physiol Ren Physiol 288:685–693.
  17. Hanrahan JP, de Boer IH, Bakris GL et al (2021) Effects of the soluble guanylate cyclase stimulator praliciguat in diabetic kidney disease: a randomized placebo-controlled clinical trial. Clin J Am Soc Nephrol 16:59–69.
  18. Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131
  19. Kristofi R, Bodegard J, Norhammar A et al (2021) Cardiovascular and renal disease burden in type 1 compared with type 2 diabetes: a two-country nationwide observational study. Diabetes Care 44:1211–1218