How do you manage diabetes and blood pressure in chronic kidney disease patients?
The Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of blood pressure in CKD recommends a target systolic blood pressure for adults with high blood pressure and CKD of <120 mm Hg18. This can be achieved through the use of renin-angiotensin system inhibitors (RASi) for people with high blood pressure, CKD, and moderately-to-severely increased albuminuria with diabetes18.
The management of patients with type 2 diabetes (T2D) and CKD (Figure 1) should involve19:
- lifestyle therapy
- first-line treatment with metformin and a sodium-glucose cotransporter-2 (SGLT2) inhibitor
- additional drug therapy as needed for glycaemic control

Figure 1. Treatment algorithm for patients with type 2 diabetes and chronic kidney disease (Adapted19). Kidney icon indicates eGFR (mL/min/1.73 m2); dialysis machine icon indicates dialysis. CKD, chronic kidney disease; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter-2; TZD, thiazolidinedione.
The higher cardiovascular burden present in these patients also requires comprehensive management through lifestyle interventions that address the underlying comorbidities as well as appropriate pharmacotherapy depending on the severity and stage of the CKD20.
What treatments are available for chronic kidney disease with comorbid blood pressure control, cardiovascular disease, or diabetes?
Professor Hiddo Heerspink points out that the ultimate treatment goal for chronic kidney disease is to slow down the loss of kidney function, a goal that is becoming more achievable with recent approvals for SGLT2 inhibitors and mineralocorticoid receptor antagonists.
Novel treatments for patients with CKD or comorbid CKD have been developed, or approved for clinical use, including21:
- Sodium-glucose cotransporter-2 (SGLT2) inhibitors
- Mineralocorticoid receptor antagonists (MRA)
- Glucagon-like peptide-1 receptor agonists (GLP-1 RA)
- Dipeptidyl peptidase-4 inhibitors (DPP4i)
Drugs within these classes have been examined through large clinical trials to evaluate the cardiovascular and kidney outcomes in patients with T2D, CKD, and comorbid CKD19. The results from these trials were used as the basis for recommendations made within the KDIGO guidelines for patients with T2D and CKD19.
People with CKD have high cardiovascular risk, with cardiovascular death the leading cause of death22.
Several new treatments to decrease the risk of cardiovascular diseases in CKD are in clinical development or have been already approved, such as SGLT2 inhibitors or mineralocorticoid receptor antagonists, giving hope that cardiovascular risk in patients with CKD may be modifiable22
Currently, there is limited evidence on the use of specific antihypertensive agents to treat hypertension in CKD. In patients with CKD and high blood pressure, combination therapy with two or more antihypertensive drugs is recommended23. Antihypertensive treatment algorithms in CKD are based on expert opinion, pathophysiologic or pharmacodynamic considerations, or extrapolated from research findings23.
Renin-angiotensin system inhibitors (RASi) for diabetic kidney disease
RASi are recommended for patients with diabetes, hypertension, and albuminuria (albumin-creatinine ratio >30 mg/g)19. RASi slow the progression of CKD in patients with albuminuria and hypertension independent of their blood pressure effects24. KDIGO consider RASi as foundational therapy for diabetic kidney disease (DKD)25.
A network meta-analysis of 119 randomised trials (N = 64,768) of CKD patients, with or without diabetes and albuminuria, examined RASi for kidney and cardiovascular outcomes compared to other treatments and placebo26.
The results showed that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) both reduce the risk of kidney failure and major cardiovascular events. However, only ACEi reduced the risk of all-cause death compared to active control26.
In CKD patients without diabetes and severely increased albuminuria, three phase 3 trials in the nineties also highlighted the potential cardiovascular benefits of RASi compared to placebo in addition to renal benefits27–29:
- REIN 1 Phase 3 trial: 2-arm Ramipril Efficacy in Nephropathy Stratum-1
- REIN 2 Phase 3 trial: 3-arm Ramipril Efficacy in Nephropathy Stratum-2
- AIPRI Phase 3 trial: 2-arm Angiotensin-converting enzyme inhibition in progressive renal insufficiency
The early 2000’s also saw two phase 3 studies that demonstrated a beneficial effect of RASi independent of blood pressure control, in CKD compared to placebo30,31:
- IDNT Phase 3 trial: 3-arm Irbesartan Diabetic Nephropathy Trial
- RENAAL Phase 3 trial: 2-arm Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study
Metformin for diabetes
Since its approval in the nineties, metformin has been prescribed for the management of T2D for over 20 years32. While prescribing metformin, the eGFR should be monitored and the dose reduced when the rate is less than 45 mL/min/1.73 m2 or withdrawn when eGFR drops to <30 mL/min/1.73 m2 or kidney failure develops19.
Currently, treatment with metformin and a SGLT2 inhibitor is recommended in most patients with an eGFR of ≥30 mL/min/1.73 m2, diabetes, and CKD19
Metformin may increase risk for lactic acidosis and vitamin B12 deficiency; therefore, monitoring of levels is recommended with long-term use33. When these drugs are not well tolerated or are insufficient to attain glycaemic goals, additional drugs can be considered based on various factors, such as patient preferences, comorbidities, eGFR, and costs (Figure 2)19.

Figure 2. Patient factors influencing selection of glucose-lowering drugs other than SGLT2 inhibitors and metformin in type 2 diabetes and CKD (Adapted19). AGI, alpha-glucosidase inhibitor; ASCVD, atherosclerotic cardiovascular disease; DPP4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP1RA, glucagon-like peptide-1 receptor agonist; SU, sulfonylurea; TZD, thiazolidinedione.
GLP-1 RAs are notably recommended as additional agents due to their beneficial effects in reducing cardiovascular events as well as their potential to prevent macroalbuminuria or a reduction in eGFR decline19.
Mineralocorticoid receptor antagonists for diabetic kidney disease
The mineralocorticoid receptor antagonist finerenone is indicated by the US Food and Drugs Administration (USFDA) to reduce the risk of sustained eGFR decline, end-stage kidney disease (ESKD), cardiovascular death, non-fatal myocardial infarction, and hospitalisation for heart failure (HF), in adult patients with CKD associated with type 2 diabetes34,35.
In the phase II ARTS trial (Arterial Revascularization Therapies Study) with >450 patients with CKD and congestive heart failure (HF), the mineralocorticoid receptor antagonist (MRA) finerenone reduced the urinary albumin-creatinine ratio and NT-proBNP (N-terminal pro-BNP) as much as spironolactone, with significantly lower rates of deteriorating kidney function and hyperkalemia36.
In the phase III trials FIDELIO-DKD (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease), >13 000 T2D patients with CKD were evaluated to determine whether finerenone can reduce cardiovascular morbidity and mortality or prevent progression of kidney disease37,38.
In FIDELIO-DKD, during a median follow-up of 2.6 years, a primary outcome event (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) occurred in 504 of 2,833 patients (17.8%) in the finerenone group and 600 of 2,841 patients (21.1%) in the placebo group (HR 0.82; 95% CI, 0.73–0.93; P=0.001). A key secondary outcome event (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for HF) occurred in 367 patients (13.0%) in the finerenone group, and 420 patients (14.8%) in the placebo group (HR 0.86; 95% CI, 0.75–0.99; P=0.03)37.
In FIGARO-DKD, among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3,686 patients (12.4%) in the finerenone group, and in 519 of 3,666 (14.2%) in the placebo group (HR 0.87; 95% CI, 0.76–0.98; P=0.03), with the benefit driven by a lower incidence of hospitalisation for HF (HR 0.71; 95% CI, 0.56–0.90). The secondary composite outcome (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) occurred in 350 patients (9.5%) in the finerenone group, and in 395 (10.8%) in the placebo group (HR 0.87; 95% CI, 0.76–1.01)38.
As FIDELIO-DKD and FIGARO-DKD show, in patients with CKD and T2D, finerenone therapy can provide cardiorenal protection, compared with placebo37,38
SGLT2 inhibitors for chronic kidney disease and diabetic kidney disease
In patients with diabetes and CKD, SGLT2 inhibitors have been investigated in various trials for the treatment of diabetes in CKD (Table 1)39-42. Three SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, have been approved by the USFDA and EMA, are recommended by the KDIGO guidelines for the treatment of hyperglycaemia in T2D, and as foundational therapy in diabetic kidney disease (DKD)19,25,43. In an important regulatory shift, some SGLT2 inhibitors are no longer indicated as therapy only for comorbid CKD; they have been approved for treating CKD itself44–46.
Canagliflozin
Canagliflozin is USFDA and EMA indicated to reduce the risk of ESKD, doubling of serum creatinine, cardiovascular death, and hospitalisation for heart failure in adults with T2D, and diabetic nephropathy with albuminuria47,48.
The CANVAS programme (Table 1) comprised two double-blind, randomised trials (CANVAS and CANVAS-R) that aimed to evaluate the long-term renal effects of canagliflozin40. In the CANVAS study (N = 4,330), patients with T2D were randomised 1:1:1 to receive 300 mg canagliflozin, 100 mg canagliflozin, or placebo49. Similarly, CANVAS-R (N = 5,812) patients were randomised 1:1 to receive canagliflozin 100 mg or a matching placebo49.
Sustained doubling of serum creatinine, ESKD, and death from renal causes occurred less frequently in the canagliflozin group, compared with the placebo group (HR 0.53; 95% CI, 0.33–0.84; P heterogeneity = 0.21 and >0.50, respectively) in the overall CANVAS programme population40,50.
In the more recent CREDENCE study (N = 4,401), the first study of an SGLT2 inhibitor with a combined renal end-point as a primary outcome, patients with T2D, CKD, and albuminuria were randomised to receive canagliflozin (100 mg/day) or placebo41.
The CREDENCE study was prematurely ended after a planned interim analysis due to the clear benefit of canagliflozin compared to placebo41
The results of the CREDENCE trial showed that the relative risk of the renal-specific composite of ESKD, a doubling of the creatinine level, or death from renal causes was lower by 34% (HR 0.66; 95% CI, 0.53–0.81; P<0.001), and the relative risk of ERSD was lower by 32% (HR 0.68, 95%, CI 0.54–0.86; P = 0.002)41.
Table 1. Overview of selected large, placebo-controlled clinical outcome trials assessing the benefits and adverse effects of SGLT2i in chronic kidney disease (Adapted51,25). ACR, albumin-creatinine ratio; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; GMI, genital mycotic infections; MACE, major adverse cardiovascular events; NA, data not published. ↔, no significant difference; ↓, significant reduction in risk [hazard ratio (HR) estimate >0.7 and 95% confidence interval (CI) not overlapping 1]; ↓↓, significant reduction in risk [HR estimate ≤0.7 and 95% CI not overlapping 1].

Dapagliflozin
Dapagliflozin is USFDA indicated to reduce the risk of sustained eGFR decline, ESKD, cardiovascular death, and hospitalisation for HF in adults with CKD at risk of progression45. It became the first SGLT2 inhibitor to receive approval by the EMA for the treatment of adults with CKD, with or without diabetes44.
DECLARE-TIMI 58 (Table 1) was a randomised, double-blind, multi-national phase III trial that studied the effects of dapagliflozin on hard renal outcomes42.
In T2D patients at risk for atherosclerotic cardiovascular disease, dapagliflozin resulted in a lower rate of cardiovascular death or hospitalization for heart failure42
The results from the trial showed that dapagliflozin met the prespecified criterion for non-inferiority to placebo in terms of major adverse cardiovascular events (P<0.001)42.
The two primary efficacy analyses showed that, while dapagliflozin did not produce a lower rate of major adverse cardiovascular events (defined as cardiovascular death, myocardial infarction, or ischemic stroke) compared to placebo (8.8% vs 9.4%; HR 0.93; 95% CI, 0.84–1.03; P=0.17), dapagliflozin resulted in a lower rate of cardiovascular death or hospitalisation for heart failure (4.9% vs 5.8%; HR 0.83; 95% CI, 0.73–0.95; P=0.005)42.
In the more recent Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, the long-term efficacy and safety of dapagliflozin in patients with chronic kidney disease, with or without T2D, was assessed51.
The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes51.
It was found that, over a median of 2.4 years, CKD patients receiving dapagliflozin had a significantly lower risk of experiencing a primary outcome event than patients receiving placebo (9.2% vs 14.5%; HR 0.61; 95% CI, 0.51–0.72; P<0.001)51. Moreover, death occurred in fewer patients receiving dapagliflozin than patients receiving placebo (4.7% vs 6.8%; HR 0.69; 95% CI, 0.53 to 0.88; P=0.004)51.
Empagliflozin
Empagliflozin is USFDA and EMA indicated to reduce the risk of cardiovascular death in adults with T2D, and to reduce the risk of cardiovascular death and hospitalisation for HF and reduced ejection fraction52,53.
The EMPA-REG OUTCOME study (N = 7,020) randomised patients with T2D to 10 or 25 mg of empagliflozin compared to placebo (Table 1). Of these patients, 5,665 were also receiving treatment with an ACEi or an ARB39.
In T2D patients at high cardiovascular risk, empagliflozin is associated with slower kidney disease progression and lower rates of renal events than placebo when added to standard care39
The results showed that patients treated with empagliflozin had a reduced incidence in the combined endpoint of progression to macroalbuminuria, renal replacement therapy initiation or death from renal disease (HR [Hazard Ratio] 0.61; 95% CI, 0.53–0.70; P<0.001) compared to placebo39.
Patients in the intervention treatment arm also had lower rates of a post-hoc defined renal composite outcomes: initiation of renal replacement therapy, doubling of serum creatinine, or death from renal disease (HR 0.54; 95% CI, 0.40–0.75; P<0.001)39.
The EMPA-KIDNEY study, a double-blind, randomised, placebo-controlled trial, evaluated the efficacy and safety of empagliflozin in patients with CKD with or without diabetes. The trial, in which more than 6,600 patients were recruited, was stopped early, in March 2022, after an interim analysis of the results showed a clear benefit for patients with CKD54. Publication of the full results is pending.
Glucagon-like peptide 1 receptor agonists (GLP-1 RA) for diabetic kidney disease
A number of trials have investigated glucagon-like peptide 1 receptor agonists (GLP-1 RA) for the treatment of diabetes in chronic kidney disease (Table 2)25.
GLP-1 receptor agonists and DPP-4 inhibitors are beneficial for managing patients with T2D across a range of haemoglobin A1C (HbA1c) levels; separately and in addition to glucose lowering therapies55. Overall, GLP-1 receptor agonists are preferred over DPP-4 inhibitors due to a greater reduction in HbA1c and clinically significant weight loss55.
Liraglutide and semaglutide
In the randomised, placebo-controlled Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (N = 9,350) and Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) preapproval trial (N = 3,297), the effect of liraglutide and semaglutide on composite renal outcomes was assessed (Table 2)56,57:
- Overt albuminuria development
- Serum creatinine doubling and eGFR <45 mL/min/1.73 m2
- Renal replacement therapy
- Kidney disease-related death
Composite renal outcomes were decreased in the GLP-1 receptor agonist treatment group compared to placebo (LEADER: HR 0.88; 95% CI, 0.81–0.96; P=0.005 and SUSTAIN-6: HR 0.74; 95% CI, 0.62–0.89; P=0.002)56,57.
Table 2. Overview of selected large, placebo-controlled clinical outcome trials assessing the benefits and adverse effects of GLP-1 RA in chronic kidney disease (Adapted25). eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; GI, gastrointestinal symptoms; MACE, major adverse cardiovascular events; NA, data not published. ↔, no significant difference; ↓, significant reduction in risk [hazard ratio (HR) estimate >0.7 and 95% confidence interval (CI) not overlapping 1]; ↓↓, significant reduction in risk [HR estimate ≤0.7 and 95% CI not overlapping 1].

Exenatide and lixisenatide
In the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) study (N = 14,752), there was no significant difference (P=0.39) in eGFR levels between exenatide and placebo (Table 2). New macroalbuminuria was observed in 2.2% and 2.5% of the exenatide and placebo groups, respectively (P=0.19). The renal composite outcome (composite of 40% eGFR decline, renal replacement and renal death) was also not significantly different between the groups (HR 0.88, 95% CI, 0.74–1.05; P=0.164)58.
In the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial (N = 6,068), patients on lixisenatide were approximately 19% less likely to develop new-onset macroalbuminuria (HR 0.808; 95% CI, 0.660–0.991; P=0.0404). No differences were observed in normoalbuminuria progression to macroalbuminuria or in the proportion of macroalbuminuria showing regression to micro-/normoalbuminuria (Table 2)59.
Dipeptidyl peptidase-4 inhibitors (DPP-4i) for diabetes
DPP-4 inhibitors, also known as gliptins, have been shown to have a low hypoglycaemic risk and weight-neutral effects. Moreover, saxagliptin, sitagliptin, alogliptin, and linagliptin have had their cardiovascular safety assessed in a number of randomised clinical trials25.
However, while DPP-4 inhibitors have displayed satisfactory cardiovascular safety, the results of their renal outcomes have been conflicting (Table 3)25,60.
Saxagliptin
In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial (N = 16,492), patients were randomised to saxagliptin or placebo (Table 3)61.
Compared to placebo, saxagliptin was more likely to improve the urine albumin-to-creatinine ratio (UACR) (10.7% vs 8.7%, P<0.001), and less likely to have a worsening UACR (13.3% vs 15.9%, P<0.001) at the end of treatment. Moreover, the difference in mean UAC between groups was –3.88 mg/mmol (P<0.004) at 2 years. However, the eGFR change from baseline was similar between groups, and there was no benefit or harm seen in hard renal outcomes61.
Alogliptin
In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial (N = 5,380) the primary end-point of a death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke composite was met in 11.3% patients receiving alogliptin (HR 0.96; P<0.001 for non-inferiority). Glycated haemoglobin levels were significantly lower with alogliptin than placebo (−0.36; P<0.001). Incidences of hypoglycaemia, cancer, pancreatitis, and initiation of dialysis were similar between groups (Table 3)62.
Table 3. Overview of selected large, placebo-controlled clinical outcome trials assessing the benefits and adverse effects of DPP-4i in chronic kidney disease (Adapted25). eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; HF, heart failure hospitalisation; MACE, major adverse cardiovascular events; NA, data not published. ↔, no significant difference; ↓, significant reduction in risk [hazard ratio (HR) estimate >0.7 and 95% confidence interval (CI) not overlapping 1]; ↓↓, significant reduction in risk [HR estimate ≤0.7 and 95% CI not overlapping 1].

Sitagliptin
In the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (N = 14,671) median UACR levels at 4 years were lower with sitagliptin than placebo, with a mean difference of –0.02 mg/mmol (P=0.031). Mean eGFR was lower with sitagliptin compared to placebo with a difference of –1.34 ml/min/1.73 m2 (P<0.001). Incidence rates of microalbuminuria and renal failure were similar between sitagliptin and placebo (Table 3)63.
Linagliptin
The Cardiovascular and Renal Microvascular Outcome (CARMELINA) study (N = 6,991) had a higher proportion of participants (74%) with chronic kidney disease (Table 3)64.
The progression of albuminuria was 14% less likely with linagliptin compared to placebo (HR 0.86; 95% CI, 0.78–0.95; P=0.003). The hard renal outcomes were similar in the linagliptin and the placebo arms (9.4% vs 8.8%; HR 1.04; 95% CI, 0.89–1.22; P=0.62)64.