The foundation and the four pillars of treatment for cardiorenal protection in people with chronic kidney disease and type 2 diabetes

Of the 8 billion people who share this planet, it is estimated that one in eight have chronic kidney disease (CKD). The prevalence of type 2 diabetes (T2D) is also estimated to be one in eight. According to the Centers for Disease Control, one in three people with T2D have CKD. CKD and T2D collaborate to increase the risk of all-cause mortality, cardiovascular mortality, cardiovascular morbidity (such as myocardial infarction, strokes, peripheral artery disease and hospitalizations for heart failure) and the progression of kidney disease to kidney failure. In the USA alone, 13% of people >18 years of age are estimated to have diabetes and 34.5% meet the criteria for prediabetes [1]. CKD and T2D together contribute to a major health burden for individuals, constitute a major public health burden and urgently need strategies to address them.

BUILDING THE FOUNDATION

The foundation of management of the cardiovascular and kidney complications of T2D rests on lifestyle modifications. These include the following: cessation of tobacco smoking; glycemic control, the level of which is individualized; lowering blood pressure (BP) to <130/80 mmHg; management of dyslipidemia that is centered on the administration of statins; a healthy diet with a low glycemic index and restricted sodium; maintenance of a healthy weight and optimizing physical behaviors. The latter is summarized in the 2022 guidelines by the six S's as limit sitting, increase stepping, improve sleep duration and quality, encourage at least 150 min/week of sweating, improve strength through resistance exercise and reduce sarcopenia [2]. The studies initiated at the Steno Diabetes Center 3 decades ago demonstrate that reducing cardiorenal risk is optimal when the risk factor intervention is multifactorial [3].

Albuminuria as a cardiorenal risk factor

Studies pioneered by Carl Erik Mogensen at the Steno Diabetes Center demonstrated the association of excess mortality in people with T2D and albuminuria. In a landmark 1982 study, he demonstrated among just 300 people with T2D followed for 10 years that the urinary concentration of albumin is associated with excess mortality [4]. Subsequently, urinary albumin concentration measurement was paired with urinary creatinine concentration to refine the predictive performance of the urinary albumin:creatinine ratio (UACR) for determining a surprising array of outcomes, including all-cause mortality, cardiovascular mortality, kidney disease progression and even determining the risk of acute kidney injury [5]. A prognostic risk factor is valuable in stratifying patients in clinical trials, targeting the intensity of therapies or timing treatments such as placement of an access for dialysis. However, when the risk factor is modifiable, it becomes an even more valuable clinical tool. For example, the Framingham Heart Study established that BP and low-density lipoprotein (LDL) cholesterol are both prognostic cardiovascular risk factors. However, what makes them clinically indispensable is they are modifiable. Lowering BP and lowering LDL cholesterol both confer cardiovascular protection. Although the Framingham Heart Study recognized that any degree of proteinuria—even when measured by a dipstick—is a cardiovascular risk factor [6] and several large studies have identified that UACR is a cardiorenal risk factor [5], we now have direct clinical trial evidence that targeting the mineralocorticoid receptor in patients with T2D with elevated UACR (≥30 mg/g creatinine) can mitigate cardiovascular and kidney disease progression [7]. Thus, like BP and LDL cholesterol, we now have strong evidence that UACR is a modifiable cardiovascular risk factor.

BUILDING THE PILLARS OF TREATMENT ON THE FOUNDATION

There are three established pillars of therapy and a fourth emerging pillar in the management of CKD in people with T2D.

The first pillar

In people with T2D and very high albuminuria, the use of losartan or irbestartan slows kidney disease progression. This was first convincingly demonstrated in 2001 by the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial [8] and the Irbesartan Diabetic Nephropathy Trial (IDNT) [9]. The primary endpoint in each of these trials was similar: time to first doubling of serum creatinine, end-stage kidney disease (ESKD) or death from any cause. The relative risk reduction was 16% in RENAAL [8] and 19% in IDNT [9]. In addition, RENAAL demonstrated a 28% relative risk reduction for the endpoint of occurrence of ESKD. This endpoint was not statistically significant in IDNT. Furthermore, each of the two studies demonstrated a reduction in the need for hospitalization for heart failure in people with CKD and T2D with the use of these drugs. Accordingly, to protect from kidney disease progression in people with T2D and albuminuria, angiotensin receptor blockers became the standard of care.

The second pillar

For the next 18 years there were many attempts to end cardiorenal disease in T2D, but these were unsuccessful. In 2019, the discovery of cardiorenal protection with the sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin in people with T2D and very high albuminuria led to approval of this drug for this indication [10]. On the heels of this discovery, dapagliflozin-based treatments extended this option to people without diabetes [11]. These data provided strong evidence to establish that glycemic control alone was not the sole mechanism by which SGLT2 inhibitors conferred cardiorenal protection.

The third pillar

In 2020, trials with finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist (MRA), demonstrated both kidney protection and cardiovascular protection in one trial [12]. The renal endpoint was distinct from the cardiovascular endpoint and the trial was powered to evaluate each of the two endpoints independently. An 18% relative risk reduction was seen in this trial of 5734 patients. Given the magnitude of absolute risk reduction of ≈3% in the renal endpoint, 29 patients if treated for 3 years would be protected from one kidney failure outcome. The Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation (CREDENCE) trial had a 30% relative risk reduction, whereas the Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD) trial had an 18% relative risk reduction and it was perceived that the third pillar was weaker than the second. However, there were important differences in the patients recruited for the two trials and the outcomes. When matched for the baseline characteristics and outcomes, the cardiorenal benefits of the two molecules were similar [13]. The Study of Heart and Kidney Protection With Empagliflozin (EMPA-KIDNEY) trial was prematurely stopped for efficacy. This trial has a representation of patients who have no albuminuria and also those not on an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) [14]. The latter patients had not been represented in earlier trials, which is where the results of this important trial will illuminate our understanding.

The fourth emerging pillar

The glucagon-like receptor 1 receptor agonists (GLP1RAs) are a class of molecules that were developed for the management of glycemic control in people with T2D. They improve glycemic control by stimulating insulin release in response to glucose load through incretin release. By delaying gastric emptying and effects on the satiety center in the brain, they provoke weight loss. In people with albuminuria and T2D they reduce the albumin excretion rate [15]. In addition to the remarkable weight loss provoked by GLP1RAs that make these drugs attractive for many obese patients, these drugs reduce the risk of myocardial infarction [16]. In a meta-analysis of 11 trials, it was demonstrated that GLP1RAs reduce the risk of myocardial infarctions by 11% [16]. In contrast, no protection from heart failure is seen with these agents. This is in sharp contrast to the large benefits in incident heart failure seen for both the SGLT2 inhibitors and finerenone. Both SGLT2 inhibitors and finerenone reduce the risk of hospitalization from heart failure by 25–35% [17, 18]. Therefore the antiatherosclerotic cardiovascular protection conferred by GLP1RAs appears to be complimentary to the SGLT2 inhibitors. Given that the effects on kidney failure outcomes are being tested in the FLOW trial (NCT03819153) [19], the definitive place of this class of drugs in the management of people with T2D and CKD remains to be established.

The dual GLP1RA and Glucose-dependent insulinotropic polypeptide (GIP) activator tirzepatide has salutary effects on glycemic control, weight loss and BP reduction [20]. In post hoc analyses of a randomized trial in people with T2D at high risk of cardiovascular events or established cardiovascular disease, reductions in UACR and slowing of the rate of decline in estimated glomerular filtration rate (eGFR) has been reported. Tirzepatide was recently approved by the US Food and Drug Administration for the treatment of T2D. Like GLP1RAs, this drug looks promising for cardiovascular and kidney protection. However, definitive trials are needed to establish kidney and cardiovascular protection in people with T2D and albuminuria.

Finally, this class of drugs is critically important for glycemic control, especially in people with more advanced CKD. In the latter patients, SGLT2 inhibitors lose efficacy and metformin may be contraindicated, however, GLP1RAs retain their efficacy in effecting glycemic control [2].

BARRIERS TO BUILDING THE HOUSE

Education, adherence and access are the key barriers to implementation of research into practice. Education of clinicians is important. Despite decades-old guidelines, screening of kidney disease is suboptimal. In an analysis of electronic health record data from 513 165 adults with T2D receiving primary care from 24 healthcare organizations and 1164 clinical practice sites, the 1-year median testing rate across organizations was 51.6% for both UACR and eGFR, 89.5% for eGFR and 52.9% for UACR. The average prevalence of detected elevated albuminuria increased linearly with UACR testing rates at sites, with an estimated prevalence of 6%, 15% and 30% at UACR testing rates of 20%, 50% and 100%, respectively [21]. Thus a large fraction of patients with CKD who have T2D are left undiagnosed. Educating clinicians that UACR is similar to the measurement of BP or LDL cholesterol, because it should trigger treatments that reduce cardiovascular and kidney risks in people with T2D, is important. Without screening, effective treatments cannot be prescribed. Access to therapies has become an important barrier to implementing therapies. However, this access is complex. For example, in the USA, prior authorization is still required for the prescription of all accepted first pillars of care for many health insurance plans. In some countries, such as India and Brazil, access to the second pillar of care is not an issue; in India, because of the availability of dapagliflozin as a generic drug at a price similar to some of the antihypertensive drugs, and in Brazil, because the healthcare system provides dapagliflozin at no cost to all who need this drug. Adherence to treatments is much more complicated, especially for chronic diseases, and the importance of taking these treatments on a long-term basis cannot be overemphasized.

Lifestyle modifications are the foundation on which the pillars are built; the foundation is for all people with T2D and CKD. Lifestyle modifications cost little, but adherence to these lifestyle changes is difficult. On the other hand, building the pillars of therapy is easy, but is associated with increasing costs as we move from the first to the fourth pillar. The additive benefit of treatments is also a matter of opinion, but randomized trials are in progress to ascertain the value of combination therapies. As an example, the CONFIDENCE trial will randomize 807 patients with T2D with an eGFR >25 ml/min/1.73 m² and a UACR >300 mg/g and a maximally tolerated dose of ACE inhibitor or ARB to either empaglifozin alone (10 mg/day), finerenone alone (target dose 20 mg/day) or a combination of the two treatments to test the hypothesis that combination therapy has greater UACR-lowering ability from baseline to 6 months compared with single treatments [22]. Secondary endpoints will include changes in systolic BP, potassium and eGFR. Episodes of hyperkalemia, acute kidney injury and symptomatic hypotension will be recorded in the trial.

THE COMMISSIONED ARTICLES AND THEIR CONTRIBUTIONS

With the above background in mind, we as editors commissioned a series of five articles that explore these new developments in greater detail.

Bonifant and Weir cast a broad net to discuss the techniques of BP measurement, the treatment goals and targets, the gaps in our knowledge about people with T2D and proteinuric CKD, and pharmacological choices, especially in people with CKD [23]. They make a clear distinction between people with and without diabetes. In the absence of data, as seasoned clinicians they advocate for individualizing the treatment goals to prevent cardiorenal disease progression. One size does not fit all.

Lo et al. [24] tell the story of the development of MRAs from the early days (steroidal MRAs) to the present (nonsteroidal MRAs) for the prevention of cardiorenal outcomes in CKD. They highlight the differences between steroidal and nonsteroidal MRAs and discuss the trials with an emphasis on heart failure.

Given the development of hyperkalemia with MRAs, Gregg and Navaneethan [25] discuss the strategies of potassium control in the setting of MRAs. They reason that cost, clinical availability, pill burden and patient selection call for alternative potential strategies to mitigate hyperkalemia. Conservative strategies that include increased monitoring and the use of loop or thiazide diuretics to increase urinary potassium excretion might be more practical.

In an international collaboration, Zhang et al. [26] summarize a large body of literature on the methodology of guideline development and provide in a nontechnical, readable format, evidence-based recommendations for the frequency and nature of screening for CKD in T2D, lifestyle modifications and balancing the use of older and newer therapies, including glycemic and arterial pressure management.

Finally, Nee et al. [27] deal with a very important subject of getting guideline-approved, evidence-based therapies to the bedside. They discuss the myriad and complex reasons that delay implementation of lifesaving therapies and suggest a multifaceted action plan from the patient to policy. It will take the entire global kidney community to work together to break these barriers to implementation.

We believe that these up-to-date, state-of-the-art, yet pithy reviews will help clinicians improve therapeutic choices at the dawn of a new era, unseen in 30 years.

CONCLUSIONS

In conclusion, CKD in T2D is a self-evident risk factor for kidney failure, but much more important, it is a modifiable cardiovascular disease risk factor. If we are to mitigate the risk for kidney failure and cardiovascular complications of T2D and CKD we need to act early. Implementation and adherence to guidelines to screen for UACR at the time of diagnosis of T2D and annually thereafter is critical to the identification of patients with a stage of kidney disease where they have only kidney injury and not kidney failure. Early identification will allow early intervention to prevent kidney failure and cardiovascular complications of T2D by the simple expedient of UACR testing. Implementation of this strategy at a population level is key. The pillars of care—ARBs or ACE inhibitors, SGLT2 inhibitors, finerenone and GLP1RAs are built on the foundation of lifestyle modifications that include cessation of smoking, BP control, lipid management, physical activity, maintenance of a healthy weight and a diet low in sodium. From being in a desert of therapeutic options prior to 2019, we are rich with multiple strategies to contain the kidney failure and cardiovascular epidemic in people with CKD and T2D. Education, adherence and access to these effective treatments provide a tremendous opportunity to contain this public health enemy. There is no time for therapeutic inertia—the time to act is now.

FUNDING

Funding was provided by the National Heart Lung and Blood Institute (R01 HL126903).

CONFLICT OF INTEREST STATEMENT

R.A. has received personal fees and nonfinancial support from Bayer Healthcare Pharmaceuticals, Akebia Therapeutics, Boehringer Ingelheim, Eli Lilly and Vifor Pharma; personal fees from Lexicon and Reata; is a member of data safety monitoring committees for Vertex and Chinook, steering committees of randomized trials for Akebia Therapeutics, Bayer and Relypsa and adjudication committees for Bayer; has served as Associate Editor of the American Journal of Nephrology and Nephrology Dialysis and Transplantation and has been an author for UpToDate; and has received research grants from the National Institutes of Health and the U.S. Veterans Administration. D.F. reports personal fees and nonfinancial support from Eli Lilly, Vifor Pharma, AstraZeneca, GlaxoSmithKline, Astellas, Fresenius Kabi and Dr Schär and is the Editor-in-Chief of Nephrology Dialysis and Transplantation.