When considering the treatment of hypertension in diabetic patients with chronic kidney disease, two main questions arise: What should our target blood pressure be, and what pharmacologic interventions should we use to achieve these targets? The answer to the first question has been the topic of much debate over the past decades, with a shift from a less intensive 130/80 goal historically to a trend toward tighter control post-SPRINT reflected in 2021 KDIGO Guidelines [1]. Post-hoc analysis of the IDNT [2] and RENAAL [3] show a strong association between tighter systolic blood pressure control and decreased progression of chronic kidney disease. In fact, post-hoc analysis of RENAAL reported that a 10-mm Hg rise in baseline SBP increased the risk for end-stage kidney disease (ESKD) or death by 6.7%. However, professional societies do not agree on a specific systolic goal, given the potential harm of hypotension when targeting very low blood pressure. As such, a pragmatic approach is required to personalize systolic blood pressure goals as tolerated but maximize benefit by using the correct tools.

2. Angiotensin Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers

Pharmacological blockade of the renin–angiotensin–aldosterone system (RAAS) using angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) has become the cornerstone for patients with type 2 diabetes (T2D) and kidney involvement. Several clinical trials have demonstrated that the use of RAAS inhibitors (RAASi) slows chronic kidney disease (CKD) progression and reduces proteinuria in patients with proteinuric CKD, including diabetic kidney disease (DKD) ^{[4][5][6][7][8][9]}[5,6,7,8,9,10]. There are two seminal randomized clinical trials showing kidney benefits from RAASi independent of their blood pressure-controlling effects: the IDNT [2] and the RENAAL [3] trials. The trials compared the use of ARB versus placebo or ARB versus calcium channel blockers (CCB) or placebo in a double-blinded design. RENAAL included patients with and without hypertension, while IDNT excluded those with normal BP. Both trials included patients with kidney impairment (IDNT: baseline serum creatinine of 1.67 mg/dL, RENAAL: baseline serum creatinine 1.9 g/dL) and severe albuminuria (IDNT: 2.9 g/d proteinuria, RENAAL: albumin–creatinine ratio 1237 mg/g). Irbesartan in the IDNT study resulted in a 20% (RR:0.80; 95% CI: 0.66–0.97) risk reduction in the primary composite endpoint (doubling of serum creatinine, ESKD, death from any cause) versus placebo and a 23% reduction versus amlodipine (RR:0.77; 95% CI: 0.63–0.93); while losartan in the RENAAL study caused a 16% (RR:0.84; 95% CI: 0.72–0.98) reduction in the composite outcome of death, dialysis, and doubling of serum creatinine compared to placebo. Unfortunately, in RENAAL, as part of the secondary outcomes, there was no mortality benefit (21% vs. 20.3% (p = 0.88), but overall, the trial has been a cornerstone for establishing RAASi as a major difference makers. On the other hand, for patients with CKD, hypertension, diabetes, and no albuminuria, current evidence does not support clear clinical benefits of RAASi for CKD progression, and other antihypertensive drugs are appropriate for BP management; however, the Kidney Disease Improving Global Outcomes guidelines (KDIGO) stated that these patients may be preferably treated with RAASi (ACEi or ARB), given the cardiovascular (CV) protection benefits, especially in patients with a higher glomerular filtration rate (GFR)1. There has been some criticism about the superiority of RAS inhibitors compared to other hypertensive agents in albuminuric patients ^[10][11], but generally, the presence of protein should be considered an indication for the use of ACEi or ARB. It is also important to consider that beyond the need for renoprotection, patients with kidney insufficiency have a substantially increased risk of cardiovascular death ^[11][12]. The HOPE study reported cardiovascular benefits with an ACEi versus placebo in people with diabetes at high CV risk, even those without a diagnosis of hypertension, and independent of the BP control effect ^[12][13]. In a pre-specified subgroup analysis, patients with CKD (1/3 had diabetes) with mild or no albuminuria, ACEi use reduced the incidence of the primary outcome (incidence of cardiovascular death (reduced by 20%), myocardial infarction (reduced by 26%), or stroke (reduced by 31%)) during a mean follow-up duration of 4.5 years. 

3. Mineralocorticoid Receptor Antagonists

Though the combined use of ACEi and ARBs is not recommended, there is certainly a role for additive blockade of the RAS system with the addition of mineralocorticoid receptor antagonists. This class of medication has been studied extensively in patients with heart failure, in whom ACEi and ARBs are the standard care. Non-specific MRAs, such as spironolactone, eplerenone, and drospirenone are steroidal in nature. These drugs bind directly and block the mineralocorticoid receptor, preventing its activation by aldosterone or 11-deoxycorticosterone. They also inhibit the receptors stimulated by testosterone and dihydrotestosterone, leading to common side effects such as gynecomastia, breast tenderness, and feminization. Specific MRAs are non-steroidal and were designed to minimize those adverse effects, including finerenone and esaxerenone. As previously discussed, patients with DKD are at high risk of cardiovascular events. Though not specific for patients with diabetic kidney disease, the EPHESUS trial assessed the efficacy of eplerenone in patients with heart failure and myocardial infarction, demonstrating a benefit in decreasing mortality (RR 0.85, 95% CI 0.75–0.96 p = 0.008), lower risk of sudden cardiac death (RR 0.79, 95% CI 0.64–0.97% p = 0.03), and improvement in systolic and diastolic blood pressure compared with placebo. Notably, these benefits came with a small additional risk of hyperkalemia (5% versus 3.9% in placebo) despite the exclusion of patients with hyperkalemia at initiation ^[13][24]. The EMPHASIS-HF trial also demonstrated significant cardiovascular benefits in patients with HFrEF < 35% and NYHA class II randomized to eplerenone vs. placebo ^[14][25]. The later FIGARO trial confirmed these cardiac benefits in a diabetic population when comparing finerenone to placebo in diabetic CKD patients already on ACEi/ARB; the mean difference in change from baseline in systolic blood pressure was −3.5 mmHg at month 4 and −2.6 mmHg at month 24 ^[15][26]. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. In 3.4 years, this composite occurred in 12.4% of the finerenone group compared to 14.2% of the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; p = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure. Not all individual secondary endpoints were significant, but the trial was positive overall for the composite endpoint. The benefits of MRA addition are not limited to decreased cardiac mortality. However, the addition of MRA to ACEi/ARB in proteinuric diabetic patients has long been a treatment strategy to improve albuminuria and, theoretically, slow the progression of kidney disease. Though no large clinical trials had investigated the addition of a mineralocorticoid receptor antagonist to standard RAS blockade (ACEi/ARB) in diabetic patients for renoprotection with eGFR endpoints, meta-analyses showed a significant and dramatic (near 30%) reduction in albuminuria with this combination ^[15][26]. Then, in the FIDELIO-DKD trial, patients with CKD and type 2 diabetes mellitus were randomized to finerenone or placebo ^[16][27]. In the study, finerenone demonstrated a modest change in mean systolic blood pressure (baseline to 1-month change of –3.0 mmHg) but a significant and more robust improvement in the composite outcome of kidney failure, 40% decreased eGFR, or death from renal causes. In 2.6 years, 17.8% of patients in the treatment group experienced this outcome compared to 21.2% in the placebo group. A secondary benefit was seen in the decreased cardiac events and death, which occurred in 13.0% of the treatment group versus 14.8% of the placebo group. The study provided the first evidence that mineralocorticoid receptor antagonists were effective at preventing the progression of kidney disease in diabetic patients, rather than relying on the surrogate outcome of proteinuria as in prior trials.

4. Sodium-Glucose Co-Transporter 2 Inhibitors

Although thought of as a glucose-lowering medication with proven cardiovascular benefits, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have shown positive effects on blood pressure. Early evidence in the EMPA-REG OUTCOME and CANVAS trials demonstrated reduced blood pressure in treatment groups, the cause of which has been the subject of debate and research ^[17][18][30,31]. The mechanism of this observed blood pressure-lowering effect is thought to be secondary to natriuresis and osmotic diuresis via local inhibition of RAAS. The increased sodium delivery to the juxtaglomerular apparatus is thought to cause an increase in sodium excretion by 15–20% ^[19][32]. These hemodynamic effects may provide protection against heart failure by improving filling conditions and reducing whole-body sodium content. This effect was demonstrated by Ferrannini et al. that one dose of empagliflozin given to individuals with diabetes led to mild diuresis and blood pressure reduction within one hour of treatment, in addition to a drop in creatinine clearance, an effect that persisted with chronic use ^[20][21][33,34]. In 2015, investigators evaluated the blood pressure effect of empagliflozin in patients with type 2 diabetes and hypertension, observing a systolic BP reduction of 3.4 mmHg with 10 mg of empagliflozin and 4.1 mmHg with 25 mg of empagliflozin, respectively (95% CI –4.78 to –2.09; p < 0.001) ^[22][38]. In a trial of dapagliflozin compared to placebo, systolic BP was reduced by –4.28 mmHg (95% CI 6.54 to –2.02; p = 0.0002). SGLT2i had a synergistic effect with calcium channel blockers and beta-blockers but not with thiazide diuretics ^[23][39]. Ferdinand et al. randomized patients to either a placebo or a slowly titrated dose of empagliflozin and observed a blood pressure difference of –8.39 mmHg (95% CI –13.04; p = 0.0025) at 24 weeks ^[24][40]. A post hoc analysis of the CREDENCE trial revealed a high burden of patients with hypertension; 25% of patients had a systolic BP > 150 mmHg, 30% had resistant hypertension, and 20% were on four or more antihypertensives. This analysis found a reduction of BP of –3.5 mmHg from baseline at week 3, consistent in all hypertensive groups treated with SGLT2i ^[25][41]. In all these trials, reductions in blood pressure were seen after several weeks and persisted for at least several months ^[26][42]. 

56. Guidelines on SGLT2 and Non-Steroidal MRAs on Hypertension Management

In the most recent guidelines for hypertension, SGLT2i, and non-steroidal MRAs are mentioned as having mild to moderate BP effects in comparison to classical anti-hypertensives but with the added benefit of improving cardiovascular and kidney outcomes. The 2023 European Society of Hypertension, in addition to the standard recommendation of starting with ACEi/ARBs, suggests adding SGLT2i for patients with diabetic and non-diabetic CKD if eGFR is at least 20 mL/min/1.73 m². The non-steroidal MRA finerenone is recommended in patients with CKD and albuminuria if eGFR is at least 25 mL/min/1.73 m² as a class I recommendation with an “A” level of evidence ^[27][54]. The AHA/ACC/HFSA guidelines for the management of heart failure recommend SGLT2i (2A). However, it is acknowledged that there is a gap in evidence to recommend non-steroidal MRAs for the treatment of heart failure ^[28][55]. In the ADA-KDIGO joint statement for the management of diabetes in patients with CKD, SGLT2i is recommended as a first-line add-on therapy, and non-steroidal MRAs are recommended as additional risk-based therapy in patients with persistent albuminuria despite maximum dose of RAAS blockade ^[29][56]. Not all patients will be able to tolerate SGLT2i in addition to ACEi or ARB. These patients should be considered for non-steroidal MRA addition if they meet indication and lab qualifications.

67. Novel Therapies

It is an exciting time for those who care for patients with diabetic kidney disease. Several agents are being tested for efficacy in this population for additional benefit beyond hypertension control. SGLT2i have been increasingly studied on the secondary downstream effects. Some evidence has suggested that chronic hypoxia may be the primary pathophysiological pathway driving diabetic kidney disease and CKD, among other causes. Diabetes mellitus is thought to compromise the oxygen balance by impairing oxygen delivery owing to hyperglycemia-associated microvascular damage and exacerbating oxygen demand owing to increased sodium reabsorption as a result of SGLT upregulation and glomerular hyperfiltration. Adding an SGLT2i may decrease hypoxia-inducible factor-1alpha (HIF-1alpha) in the kidney, revealing less tissue hypoxia ^[30][57]. Pentoxifylline is a nonspecific phosphodiesterase inhibitor that has anti-inflammatory properties. In vitro, it showed promise as it reduced proliferation and differentiation of renal fibroblasts ^[31][58]. Meanwhile, while GLP-1 agonists have gained popularity for their role in weight loss and glucose control, their independent renoprotective effects have also come into the limelight. The GLP-1 receptor is expressed in the renal blood vessels, cortex, and tubules, and its inhibition has been shown in vivo and in animal models to decrease pro-fibrotic signaling.  Other novel therapies are upcoming in the kidney space for CKD that may offer unknown insights and clinical improvements. Tirzepatide (LY3298176), a novel insulinotropic polypeptide and GLP-1 combination injection is being studied in combination with ACEi/ARB in the TREASURE-CKD trial (Clinicaltrials.gov: NCT05536804). The study will look at patients with diabetes and outcomes of kidney oxygenation, UACR change, and body weight. Improvements in these parameters may have a positive impact on measured blood pressure concomitantly. The ZENITH-CKD trial (ClinicalTrials.gov: NCT04724837) is ongoing, which combines SGLT2i dapagliflozin with ETA receptor antagonist zibotentan in patients with CKD ^[32][62]. Primary outcomes will be UACR change and secondary eGFR slope.