Section 1 – Ravi

Ravi is a 49-year-old of Asian ethnic origin with type 2 diabetes diagnosed 4 years ago. He attends his primary care diabetes review, having not been seen for over 2 years, with the following results:

• HbA_1c 61 mmol/mol (7.7%).
• Total cholesterol 6.1 mmol/L; non-HDL 4.8 mmol/L.
• Normal liver function tests.
• Estimated glomerular filtration rate (eGFR) 78 mL/min/1.73 m².
• Urinary albumin:creatinine ratio (uACR) 6.2 mg/mmol.

Current medication: Metformin 1 g twice daily. Ravid has background retinopathy.

Clinic measurements: BMI 28.7 kg/m²; blood pressure (BP) 147/85 mmHg; urine dipstick all clear.

What aspects of Ravi’s diabetes do you think need addressing?

Section 2

Key issues in Ravi’s diabetes management that need attention are:

• Glycaemic control.
• Hypertension.
• Dyslipidaemia.
• Albuminuria.
• Overweight (Ravi’s BMI would classify as obesity given his ethnicity).

How would you respond to Ravi’s test for albuminuria? What is the significance of his urinary dipstick result?

Section 3

A uACR value of >3 mg/mmol is considered a positive test for albuminuria (NICE, 2021).

A urine dipstick would not test positive for proteinuria until uACR reached 30 mg/mmol. However, Ravi’s normal urinary dipstick test remains important in excluding urinary tract infection (UTI) as a confounding cause of albuminuria (CKS, 2024). If leucocytes, nitrites or blood are detected on dipstick, consider treatment for infection and/or mid-stream urine analysis to exclude it, and retest when the UTI has been treated. Persistent microscopic haematuria will require further investigation.

Further causes of a false-positive uACR result for albuminuria include strenuous exercise, febrile illness, congestive cardiac failure and vaginal bleeding/discharge (CKS, 2024).

A single positive uACR test needs to be repeated, ideally within 3 months, unless the initial uACR is 70 mg/mmol or more. Albuminuria is confirmed if there is one positive repeat out of the next two specimens. uACR should ideally be performed on a first-pass morning urine sample.

Ravi has a repeat uACR that returns as 8.7 mg/mmol, confirming positivity for albuminuria.

What factor in Ravi’s history suggests that his albuminuria is likely to be due to diabetic nephropathy, rather than another cause?

Section 4

The presence of retinopathy would suggest that Ravi’s albuminuria is likely to be a consequence of his diabetes; this association is particularly strong for people with type 1 diabetes (He et al, 2013; ADA Professional Practice Committee, 2025). It is reasonable to conclude that Ravi has diabetic nephropathy.

Diabetic nephropathy refers specifically to pathology within the renal glomeruli as a consequence of chronic hyperglycaemia. Diabetic neuropathy represents a microvascular complication of diabetes, as does diabetic retinopathy.

If other diabetes microvascular complications were absent, you should consider the possibility of alternative causes of albuminuria and the need for further investigation.

Apart from uACR, what other parameter characterises diabetic kidney disease?

Section 5

Estimated glomerular filtration rate (eGFR) is the other defining feature of diabetic kidney disease (DKD). In Ravi’s case, his eGFR of 78 mL/min/1.73 m² is satisfactory; an eGFR <60 would alone classify as chronic kidney disease (CKD), whether or not albuminuria is present.

DKD is a term used to describe CKD in a person with diabetes in whom the CKD is attributable to diabetes-related pathology. DKD is characterised by the following (de Boer et al, 2022):

• A gradually falling eGFR (a measure of kidney function), and/or:
• A steadily rising albuminuria – usually defined by uACR (a measure of renal damage).

Why is it important to screen for DKD in diabetes?

Section 6

Screening people with diabetes for DKD using eGFR and uACR is crucially important because in its early stages DKD is asymptomatic, and also because the consequences of DKD can be profound (see Section 8). An early diagnosis offers the opportunity for intervention to delay the progress of DKD and reduce the risk of complications.

Are you aware of the KDIGO classification of CKD? How would you categorise Ravi’s DKD (eGFR 78 mL/min/1.73 m²; uACR 6.2 mg/mmol)?

Section 7

The Kidney Disease: Improving Global Outcomes (KDIGO) classification of CKD based on eGFR and uACR is shown below (KDIGO Diabetes Work Group, 2022):

Ravi’s DKD would be categorised as G2A2.

Why is a diagnosis of DKD of importance for Ravi?

Section 8

The diagnosis of DKD places Ravi at increased risk of cardiovascular events (e.g. myocardial infarction, ischaemic stroke, heart failure) compared to people with diabetes or CKD alone. Progression to end-stage renal disease (ESRD) is also more likely than in people without diabetes who have CKD (NICE, 2021; KDIGO Diabetes Work Group, 2022).

Both low eGFR and raised uACR are independently linked to an increased risk of cardiovascular and renal events and all-cause mortality in people with type 2 diabetes, and if both parameters are present then the risks are multiplied (Ninomiya et al, 2009; Toyama et al, 2013; NICE, 2021). Both in the UK and worldwide, DKD is the leading cause of end-stage renal disease, being responsible for around half of cases (Hoogeveen, 2022).

What are the key modifiable and non-modifiable risk factors for DKD?

Section 9

Hyperglycaemia and hypertension are the key modifiable risk factors for the development of DKD in both type 1 and type 2 diabetes. Cardiovascular risk factors can also adversely affect renal function, with hypertension, dyslipidaemia and obesity being prominent in type 2 diabetes, and of course, smoking (Hoogeveen, 2022).

Non-modifiable risk factors include:

• Duration of diabetes.
• Ethnicity (Asian, African, African-Caribbean, Hispanic, Chinese).
• Family history of DKD.

What would be your target blood pressure for Ravi?

Section 10

NICE guidance advises the following clinic BP targets in both type 1 and type 2 diabetes (NICE, 2021; NICE, 2022a):

• <140/90 mmHg if uACR is <70 mg/mmol.
• <130/80 mmHg if uACR is ≥70 mg/mmol.

Following these guidelines, Ravi’s target BP in clinic would be <140/90 mmHg. If ambulatory or home BP monitoring are being used to assess BP, the target would be <135/85 mmHg.

See Need to know: Making sense of blood pressure readings in people with diabetes for a quick guide.

How would you respond to Ravi’s raised BP reading?

Section 11

If this is Ravi’s first raised BP reading then home or ambulatory BP monitoring would be useful to confirm the presence of hypertension.

Take the opportunity to emphasise lifestyle measures that can benefit BP and reduce cardiovascular risk: reducing salt intake, avoiding excess alcohol, losing weight and taking regular exercise. The last three of these would also benefit glycaemic control.

Ravi would also benefit from BP-lowering medication.

What would be your first-line antihypertensive option for Ravi?

Section 12

Renin–angiotensin system (RAS) blockers – an ACE inhibitor (ACE-I) or angiotensin receptor blocker (ARB) – are the first-line agents in DKD because they provide protection against cardiovascular events and attenuate the progress of renal disease once albuminuria has developed (ACE Inhibitors in Diabetic Nephropathy Trialist Group, 2001; Lewis et al, 2001; Catalá-López et al, 2016). The latter is achieved by inducing glomerular efferent arteriole vasodilation, thereby reducing intraglomerular pressure and protecting the glomerular basement membrane.

It should be noted that in the absence of DKD, the first-choice antihypertensive for Ravi would still be an ACE-I or ARB because he has type 2 diabetes (NICE, 2023a).

See Prescribing pearls: A guide to ACE inhibitors and Prescribing pearls: A guide to ARBs for more information.

If Ravi was normotensive, would you still prescribe a RAS blocker?

Section 13

Even if Ravi did not have hypertension, an ACE-I or ARB would still be indicated, given his albuminuria, because their cardiorenal benefits are evident beyond those attributable to BP. This is true for both type 1 and type 2 diabetes in the presence of albuminuria (HOPE Study investigators, 2000; Brenner et al, 2001; NICE, 2021). In the absence of albuminuria, the renoprotective properties of ACE-Is/ARBs are less clear (ADA Professional Practice Committee, 2025).

NICE (2021) advises that the dose of ACE-I or ARB should be titrated up gradually to the highest licensed dose tolerated if ACR is 3 mg/mmol or more in people with type 1 or type 2 diabetes.

What follow-up would you arrange after starting an ACE-I or ARB, and what would you be on the lookout for?

Section 14

You should re-measure BP and arrange a check of renal function (eGFR) and electrolytes within 2 weeks of initiation of an ACE-I/ARB (and after any further dose increments). Be alert for the possibility of postural hypotension.

Hyperkalaemia and a large drop in eGFR may require the following responses (NICE, 2021; CKS, 2025a; CKS, 2025b):

• After initiation of an ACE-I/ARB, a potassium level of up to 5.4 mmol/L is acceptable. If K is between 5.5 and 6.0 mmol/L despite taking measures to reduce levels (such as withdrawing K-retaining medications), reduce the dose of ACE-I/ARB (or, if necessary, stop) to achieve K levels that are acceptable.
• If K rises above 6 mmol/L, stop the ACE-I/ARB (and any other K-retaining medications). If K remains >6 mmol/L on re-testing then refer to hospital. If there is evidence of acute kidney injury (look for reduced micturition and a sudden fall in eGFR) or if K is unduly high (e.g. ≥6.5 mmol/L), refer immediately to hospital.
• A cumulative fall in eGFR of <25% or a rise in serum creatinine of >30% from baseline are acceptable. However, if these are exceeded, look for other possible causes, including hypovolaemia or concurrent medication (e.g. NSAIDs), before stopping or reducing the dose of ACE-I/ARB.

Ravi is commenced on losartan 25 mg once daily and arrangements are made for a check of renal function 10 days later, followed by a BP check.

What would be your target HbA_1c for Ravi?

Section 15

Ravi is relatively young and in the early stages of his diabetes trajectory, without significant comorbidities. When intensifying glucose-lowering treatment, we should therefore aim for an HbA_1c of ≤53 mmol/mol (NICE, 2022b).

What would be your choice of add-on treatment to metformin to manage Ravi’s hyperglycaemia, and why?

Section 16

The agent of choice for Ravi would be an SGLT2 inhibitor which, in addition to improving glycaemic control, would offer Ravi the benefit of weight loss and, crucially, reduce the risk of both DKD progression and cardiovascular events. A further benefit of SGLT2 inhibitors would be a low propensity to induce hypoglycaemia.

NICE (2022b) recommends that people with type 2 diabetes who have CKD should, in addition to receiving treatment with an ACE-I or ARB:

• Be offered an SGLT2 inhibitor if uACR is >30 mg/mmol.
• Be considered for an SGLT2 inhibitor if uACR is between 3 and 30 mg/mmol.

It is important to recognise that the renal benefits of SGLT2 inhibitors are additive to those of ACE-Is/ARBs; additionally, they persist irrespective of eGFR value and, in the case of dapagliflozin and empagliflozin, have been demonstrated to extend equally to people without type 2 diabetes who have albuminuric CKD (Heerspink et al, 2020; Herrington et al, 2023).

If you would like to know more about the evidence underpinning the cardiorenal protective properties of SGLT2 inhibitors, see Section 21 at the end of this case study.

Dapagliflozin 10 mg once daily is added to Ravi’s regimen.

We have seen that ACE-Is/ARBs and SGLT2 inhibitors are first-line agents to prevent deterioration of DKD and provide protection against cardiovascular events. What other measures could you offer to strengthen Ravi’s cardiovascular protection?

Section 17

Given the high cardiovascular risk associated with CKD, Ravi should be offered atorvastatin 20 mg once daily for cardiovascular protection, without recourse to the QRISK® assessment tool (NICE, 2023b).

Take the opportunity to reinforce lifestyle measures that promote cardiovascular health, including diet, exercise, weight loss and, where appropriate, smoking cessation, alcohol moderation and dietary salt restriction (NICE, 2021; ADA Professional Practice Committee, 2025).

Antiplatelet medication, such as aspirin or clopidogrel, is not routinely recommended for primary prevention of cardiovascular disease in DKD, so Ravi does not require this. Antiplatelet therapy should, however, be used for secondary prevention of cardiovascular disease (i.e. in people with angina, peripheral vascular disease, previous myocardial infarction, stroke or transient ischaemic attack) (NICE 2021; KDIGO Diabetes Work Group, 2022).

Ravi is prescribed atorvastatin 20 mg once daily, with arrangements to check lipid profile and LFTs in 2 months’ time.

What might you consider next if Ravi’s hyperglycaemia remained above target?

Section 18

A DPP-4 inhibitor would be a reasonable and safe choice for Ravi’s DKD. They carry a low risk of hypoglycaemia, do not induce weight gain and can be safely used down to an eGFR of 15 mL/min/1.73 m². Whilst there is some evidence that they can reduce albuminuria (Deacon, 2018), DPP-4 inhibitors do not appear to provide cardiovascular benefit. Dose adjustment may be needed as eGFR falls, except in the case of linagliptin, which is minimally renally excreted.

A sulfonylurea, such as gliclazide, is likely to lead to weight gain and predispose to hypoglycaemia, so would be better avoided in Ravi’s case. Pioglitazone has the positive features of a low risk of hypoglycaemia, protection against cardiovascular events and compatibility with use at low eGFR levels, but it would likely lead to weight gain and can induce fluid retention and heart failure, making it a less favoured choice for Ravi.

A GLP-1 receptor agonist is an attractive choice for Ravi that would offer a large improvement in HbA_1c, weight reduction and a low risk of hypoglycaemia, and which can be safely used in advanced renal failure. What makes this option more compelling is that there is now evidence from clinical trials that semaglutide provides protection against cardiovascular events and improvement in renal outcomes for people with type 2 diabetes who have DKD (Perkovic et al, 2024; Brown, 2024).

A basal insulin would be an option to improve glycaemic control but is no more effective than a GLP-1 receptor agonist and has the disadvantages of weight gain, risk of hypoglycaemia and need for regular monitoring of blood glucose levels.

If you would like to know more about the evidence underpinning the cardiorenal protective properties of GLP-1 RAs, see Section 22 at the end of this case study.

We have seen that ACE-Is/ARBs, SGLT2 inhibitors and GLP-1 RAs offer cardiovascular benefits and renoprotection. Are you aware of any other agents that can bring cardiorenal benefit in DKD?

Section 19

Finerenone is a non-steroidal mineralocorticoid receptor antagonist (in contrast with spironolactone, a steroidal mineralocorticoid receptor antagonist) that has been shown to reduce the risk of CKD progression (Bakris et al, 2020) and improve cardiovascular outcomes (Pitt et al, 2022) compared with placebo in clinical trials in subjects with type 2 diabetes and albuminuric CKD.

Finerenone can be added to standard care for people with type 2 diabetes and CKD, including the highest tolerated dose of ACE-I or ARB and an SGLT2 inhibitor (NICE, 2023c). Finerenone is a potassium-retaining medication, so monitoring for hyperkalaemia is necessary, particularly when it is used alongside an ACE-I/ARB.

When would you consider referral of a person with DKD to a renal physician?

Section 20

While most cases of DKD can be managed in primary care, significant progression of DKD (as judged by screening eGFR and uACR results) or onset of metabolic problems may require referral to a renal specialist (NICE, 2021). Consider referral when:

• eGFR falls below 30 mL/min/1.73 m².
• Rapid decline in renal function: 25% or greater sustained fall in eGFR. Immediate referral may be necessary in the situation of acute kidney injury.
• Sustained fall in eGFR of 15 mL/min/1.73 m² or more per year.
• Very high levels of albuminuria (e.g. nephrotic syndrome). In contrast to other causes of CKD, if the diagnosis of DKD is clear then referral with a uACR >70 mg/mmol may not be necessary if appropriate treatment has been instituted.
• uACR >30 mg/mmol with microscopic haematuria.
• Hypertension poorly controlled despite use of four antihypertensive agents.
• Metabolic complications of CKD (e.g. anaemia, hypocalcaemia, hyperphosphataemia, secondary hyperparathyroidism).
• Suspected renal artery stenosis (e.g. >25% fall in eGFR following initiation of an ACE-I or ARB).
• Known or suspected medical cause of CKD other than diabetes (e.g. vasculitis, genetic renal conditions).

A urological referral would be required in cases of macroscopic haematuria (urgently) or if an obstructive uropathy was suspected.

This ends the case study. If you would like to know more detail on the evidence base underpinning the recommendations for use of SGLT2 inhibitors and GLP-1 receptor agonists in DKD, this can be found in the final two sections.

Section 21: Evidence supporting the use of SGLT2 inhibitors in DKD

Double-blind, randomised, placebo-controlled trials in subjects with type 2 diabetes and CKD with a primary renal outcome (typically a composite of renal function decline, end-stage renal disease and death from a renal or cardiovascular cause) have been performed.

The trials with canagliflozin, dapagliflozin and empagliflozin demonstrated improved renal outcomes and reduced cardiovascular mortality irrespective of baseline eGFR (Perkovic et al, 2019; Heerspink et al, 2020; Herrington et al, 2023). Importantly, the vast majority of people in these studies were already established on ACE-I/ARB therapy, indicating that the benefits from these agents and the SGLT2 inhibitors are additive. The dapagliflozin and empagliflozin trial populations also included people without type 2 diabetes and, significantly, this group received similar benefits to those with type 2 diabetes.

Specific NICE Technology Appraisal recommendations for use of dapagliflozin and empagliflozin in CKD (with or without type 2 diabetes), including eGFR and uACR values at initiation, are available (NICE, 2022c; NICE, 2023d).

The SGLT2 inhibitors protect the glomerular basement membrane by reducing intraglomerular pressure via vasoconstriction of the glomerular afferent arteriole. This accounts for a small reduction in eGFR seen on initiation of these agents. Subsequently, eGFR stabilises and albuminuria is reduced.

Section 22: Evidence supporting the use of GLP-1 receptor agonists in DKD

The cardiovascular outcome trials of liraglutide, semaglutide and dulaglutide demonstrated benefits compared with placebo in people with type 2 diabetes and established atherosclerotic cardiovascular disease or risk factors for this, including DKD (Marso et al, 2016a; Marso et al, 2016b; Gerstein et al, 2019).

The secondary renal outcomes from cardiovascular outcome trials with GLP-1 RAs consistently show benefit in DKD, largely through restricting the progression of albuminuria (Kristensen et al, 2019). More recently, the FLOW trial with semaglutide in people with type 2 diabetes and CKD – the first randomised controlled trial with a dedicated renal outcome for GLP-1 RAs – demonstrated a reduction in the composite primary renal outcome, including a reduction in both uACR and rate of decline of eGFR and deaths from a renal or cardiovascular cause, with semaglutide compared to placebo (Perkovic et al, 2024; Brown, 2024).

In a post hoc analysis of the open-label SURPASS-4 trial in people with type 2 diabetes and high cardiovascular risk, the first-in-class dual GIP/GLP-1 receptor agonist tirzepatide was found to reduce albuminuria and slow the rate of eGFR decline compared with insulin glargine (Heerspink et al, 2022).

Thus, GLP-1 RAs are an important consideration for use in type 2 diabetes where DKD has been identified, because they bring both cardiovascular and renal benefits (ADA Professional Practice Committee, 2025).