Primary prevention
The only proven primary prevention interventions for DKD are blood glucose and blood pressure control.[1] Intensive treatment of hyperglycaemia prevents development of moderately increased albuminuria (previously known as microalbuminuria), as well as progression to severely increased albuminuria (previously known as macroalbuminuria), though there is little evidence that it slows the progression of established chronic kidney disease (CKD).[31]
There is no evidence that renin-angiotensin-aldosterone system (RAAS) inhibitors prevent the development of DKD in the absence of hypertension or albuminuria. Thus, the American Diabetes Association does not recommend routine use of these drugs solely for the purpose of preventing the development of DKD.[1]
Weight loss in patients with overweight or obesity may play a role in reducing the risk of DKD development. The Look AHEAD study, a multi-centre randomised controlled trial comparing the effect of a 12-year intensive lifestyle intervention with that of diabetes support and education on cardiovascular disease (CVD) and other long-term health conditions, found that participants with type 2 diabetes with evidence of any remission during follow-up had a 33% lower rate of CKD and 40% lower rate of CVD compared with participants who did not achieve remission.[32] Robust randomised trial evidence demonstrates that intentional weight loss can lead to remission of type 2 diabetes, with approximately 5% remission incidence over the first 1-2 years for each 1% of weight loss in those with diabetes duration <6 years.[33]
Secondary prevention
Glycaemic management
Intensive glycaemic management reduces the risk of developing moderately increased albuminuria.[31]
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Treatment of hypertension
Treatment of hypertension reduces progression of DKD.[1]
ACE inhibitors and angiotensin-II receptor antagonists
In addition to their beneficial effect on blood pressure (BP), the use of ACE inhibitors or angiotensin-II receptor antagonists in patients with normal BP (<130/80 mmHg) who have moderately or severely increased albuminuria stabilises albuminuria and may reduce progression of DKD, end-stage renal disease, and death.[236][237] UK National Institute of Health and Care Excellence (NICE) guidelines recommend that all patients with type 2 diabetes and chronic kidney disease (CKD) with albumin to creatinine ratio (ACR) ≥3 mg/mmol (≥30 mg/g) should be offered an ACE inhibitor or angiotensin-II receptor antagonist, titrated to the highest licensed dose that the person can tolerate (provided that they meet the criteria in the marketing authorisation, including relevant estimated glomerular filtration rate [eGFR] thresholds).[83][136] This differs from recommendations in the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, which limit the use of these medications to those with co-existing hypertension.[1][47] KDIGO guidelines, however advise that for patients with diabetes, albuminuria, and normal BP, treatment with an ACE inhibitor or angiotensin-II receptor antagonist may be considered.[47] The ADA notes that while ACE inhibitors or angiotensin-II receptor antagonists are often prescribed for moderately increased albuminuria (ACR 3-29 mg/mmol [30-299 mg/g]; previously known as microalbuminuria) without hypertension, trials have not been performed in this setting to determine whether they improve renal outcomes.[1] Moreover, two long-term, double-blind studies demonstrated no renoprotective effect of either ACE inhibitors or angiotensin-II receptor antagonists among people with type 1 and type 2 diabetes who were normotensive, with or without moderately increased albuminuria.[1][147][148]
Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists
In order to reduce DKD progression and cardiovascular (CV) events (including heart failure hospitalisation and CV death), guidelines recommend the use of SGLT2 inhibitors in people with DKD who have eGFR ≥20 mL/minute/1.73 m², particularly in (but not restricted to) those with albuminuria.[1][47][48] While the glucose-lowering effects of these drugs are blunted with eGFR <45 mL/minute/1.73 m², the renal and CV benefits are still seen at eGFR levels as low as 20 mL/minute/1.73 m², even with no significant change in glucose.[1] If patients do not meet their individualised glycaemic target with metformin and/or an SGLT2 inhibitor, or if these drugs are not tolerated/contraindicated, a GLP-1 receptor agonist with proven CV benefit should be started.[1][48] UK NICE guidelines differ and recommend an SGLT2 inhibitor for patients with type 2 diabetes and CKD with ACR >30 mg/mmol who are already taking an ACE inhibitor or angiotensin-II receptor antagonists titrated to the highest licensed dose they can tolerate (provided they meet the criteria in the marketing authorisation, including relevant eGFR thresholds). SGLT2 inhibitor therapy can be considered for those with lower ACR (3-30 mg/mmol); however, the guidelines comment that there is more uncertainty around the clinical and cost effectiveness in this group than in people with baseline ACR >30 mg/mmol.[83]
Finerenone
In patients with DKD with persistent albuminuria (≥3 mg/mmol [≥30 mg/g]) despite maximum tolerated doses of an ACE inhibitor or angiotensin-II receptor antagonist, finerenone should be started to reduce the risk of CV events (including heart failure hospitalisation) and DKD progression.[1][47][166][238] Finerenone should be used as add-on therapy to patients optimised on ACE inhibitor/angiotensin-II receptor antagonist therapy already, and can be used simultaneously with SGLT2 inhibitors.
Antiplatelet therapy
Although the risk for thrombotic and embolic events is high, the optimal antiplatelet and antithrombotic therapy in DKD has not been well studied.[47] Aspirin may be considered for primary prevention of cardiovascular disease (CVD) among high-risk individuals, but it should be balanced against an increased risk for bleeding, including thrombocytopathy with low eGFR.[47] The ADA recommends that aspirin may be considered as a primary prevention strategy (following discussion of the benefits versus increased risk of bleeding) in patients with diabetes aged ≥50 years who have at least one additional risk factor (e.g., hypertension, hyperlipidaemia, family history of premature coronary artery disease, current or past smoker, or CKD/albuminuria) with no indicators of high bleeding risk (e.g., older age, anaemia, renal disease, or prior significant bleeding episodes).[1]
Treatment for dyslipidaemia
ADA/KDIGO consensus guidelines recommend a statin for all patients with type 1 diabetes or type 2 diabetes and CKD: moderate-intensity statin therapy for primary prevention of atherosclerotic CVD (ASCVD), or high-intensity statin therapy for patients with known ASCVD and some patients with multiple ASCVD risk factors.[48] The Endocrine Society recommends that all adults with diabetes with CKD stages 1-4, as well as those post renal transplant, should receive statin therapy, irrespective of their CV risk score.[176] Guidelines from the American College of Cardiology/American Heart Association recommend that lipid treatment should be guided by ASCVD risk.[177]
Avoidance of nephrotoxic agents
Avoidance of non-steroidal anti-inflammatory drugs (NSAIDs), and caution when using radiocontrast media or other nephrotoxic drugs, is warranted. Gadolinium-based magnetic resonance imaging contrast agents should be avoided because of a risk of systemic sclerosis in patients with DKD, especially when eGFR is below 30 mL/minute/1.73 m².[239] In one randomised trial, hydration with sodium bicarbonate was not superior to hydration with sodium chloride in preventing contrast-induced nephropathy in patients with DKD undergoing coronary or endovascular angiography or intervention.[240] In another randomised trial, rosuvastatin significantly reduced the risk of nephrotoxicity in patients with diabetes mellitus and CKD undergoing arterial contrast medium injection.[241]
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