Diabetes, Cardiorenal, and Metabolic Multispecialty Practice Recommendations and Early Intensive Management of Cardio-Renal-Metabolic Disease

ABSTRACT

In recent years, evidence has continued to mount showing a strong relationship between diabetes, cardiovascular disease, and chronic kidney disease. This, in turn, has driven a shift to a more integrated and holistic approach in the treatment of patients with cardio-renal-metabolic (CRM) disease. The 2022 Diabetes, Cardiorenal, and Metabolic (DCRM) multispecialty practice recommendations were the first multispecialty consensus on the comprehensive management of patients with diabetes, cardiorenal, and/or metabolic diseases, providing evidence-based recommendations that are simple to implement. The recommendations provide guidance on assessments and treatments, including both lifestyle therapy and pharmacotherapy, for patients across the DCRM spectrum, and are an invaluable tool for clinicians who need to develop treatment plans for complex patients with cardio-renal-metabolic disease. This article reviews the key elements of the DCRM recommendations and summarizes the updates included in the DCRM 2.0.

Am J Manag Care. 2024;30(suppl 10):S189-S196. https://doi.org/10.37765/ajmc.2024.89671

For author information and disclosures, see end of text.

Rationale and Development Process for the Original Diabetes, Cardiorenal, and Metabolic Practice Recommendations

There is a strong overlap and interconnection between diabetes, cardiovascular (CV) disease, and chronic kidney disease (CKD).1 Due to the interconnectivity between these conditions, there is a need for a holistic approach to the treatment of patients with cardio-renal-metabolic (CRM) disease.2 Despite this and the known poorer outcomes in patients with multiple CRM conditions, until recently, there was an unmet need for comprehensive clinical recommendations specifically for the management of patients with CRM disease. While there are several major guidelines and scientific statements that have been produced for diabetes, CV disease, and CKD that cover some of the overlap between CRM diseases, each of these societies’ recommendations have been somewhat limited in scope and focused mainly on their own disciplines. Examples of such guidelines include the American Diabetes Association (ADA) Standards of Care in Diabetes for managing patients with diabetes and its associated comorbidities including CV disease and CKD,3-5 the Kidney Disease Improving Global Outcomes (KDIGO) guidelines for managing CKD in patients with and without diabetic kidney disease,6,7 and the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for preventing atherosclerotic cardiovascular disease (ASCVD) and managing heart failure (HF), with specific recommendations for patients with diabetes or CKD.8,9

In 2022, the Diabetes, Cardiorenal, and Metabolic (DCRM) multispecialty practice recommendations were published (hereafter referred to as the DCRM).10 They were the first multispecialty consensus on the comprehensive management of patients with diabetes, cardiorenal, and/or metabolic diseases. The DCRM recommendations endorse a fundamental change in management, focusing on preventing the next ASCVD/HF/CKD event independent of patient risk, while continuing to manage conventional CV risk factors. Note that the DCRM has been using the term cardiorenal and metabolic diseases since 2021 in line with many other groups and organizations, whereas the recent 2023 AHA uses the term cardiovascular-kidney-metabolic (CKM) syndrome; however, the 2 terms generally refer to the same collection of conditions.10,11 The DCRM recommendations were developed by a group of 31 recognized experts in cardiology, endocrinology, diabetology, lipidology, coagulation, nephrology, hepatology, obesity, and primary care, with a focus on providing nonexperts (ie, primary care physicians, specialists from within the CRM spectrum who may lack expertise in areas other than their own specialty, and clinicians from other specialties) with the initial framework for diagnosis and a comprehensive treatment plan for patients with CRM diseases. A follow-up publication in 2023 updated the recommendations and emphasized the importance of early identification of these conditions and prompt intervention with intensive management.12

Current Recommendations for the Management of CRM

General Health and Background Considerations

The DCRM makes recommendations regarding 6 elements of lifestyle therapy—nutrition, physical activity, sleep, alcohol, smoking, and mental health (Figure).13 The mindset to be encouraged is that any effort the patient makes will be worthwhile, and clinicians should support patients by educating them about the importance of adhering to medication and lifestyle interventions. This includes staying up-to-date with vaccinations, as patients with CRM diseases are at high risk of complications following infection.14,15 The goal is for patients to know their numbers for the different tests used to monitor their conditions, appreciate the importance of a healthy lifestyle, and fully understand all aspects of their medication. This could include the use of validated apps and wearable fitness monitors to track the different elements of the patient’s lifestyle routine, which have been shown to improve the level of physical activity and diet quality.16 Similarly, patients with diabetes can be trained in the use of technology-based options for glucose monitoring and insulin delivery.17 Early intervention is key in patients with obesity, metabolic syndrome, or prediabetes to prevent progression to type 2 diabetes (T2D) and promote a return to normoglycemia. The key factor is sustained weight loss, either through lifestyle changes and/or drug therapy and exercise.18

The DCRM also recommends that clinicians undertake a full assessment of each patient, including obtaining their medical history, completing a physical exam, and measuring their blood pressure (BP), lipids, and glycemia. Where suspected, the diagnosis of white-coat hypertension can be confirmed by measuring BP with ambulatory or home BP monitoring kits.19 Patients with diabetes are at high risk not just for macrovascular disease but also for microvascular complications. Therefore, it is advisable to conduct an annual foot exam for these patients, and those with sensory loss or previous ulceration/amputation should be checked at every visit.20 In addition, estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) should be measured annually in patients with diabetes and in those with/at risk of CKD.6,7 A yearly eye exam should be included to assess for retinopathy.20

CV Risk Management

The DCRM recommends that lipid levels be monitored closely (ideally at least every 12 weeks, although some experts check every 6 weeks) until low-density lipoprotein cholesterol (LDL-C) levels are reduced by ≥50% from baseline or the patient reaches their risk-based goal, whichever is lower.21 Clinicians should also aim for a BP of <130/80 mm Hg in patients with hypertension.22 Assessments should be carried out both weekly at home and every 3 to 6 months in the office, as out-of-office BP measurements are important and are often more accurate than office measurements.23

Antithrombotic therapy selection should depend on the presence of risk factors and CV conditions such as chronic coronary artery disease and acute coronary syndrome. Recommended medications for primary and secondary prevention are shown in Table 1.13

Antihyperglycemic therapy should be tailored to each patient’s hyperglycemic goals. The goals may range from the ADA guideline recommendation of a hemoglobin A1c (HbA1c) level of <7.0% for most patients24 with some less stringent HbA1c goals (eg, <8.0% recommended for frail patients with significant comorbidities) to the American Association of Clinical Endocrinology guidance, which recommends goals of <6.5% for most patients and as close to normoglycemia as possible for recently diagnosed healthy patients in the absence of comorbidities.25 In addition, clinicians should consider prescribing a sodium-glucose cotransporter-2 inhibitor (SGLT2i) or glucagon-like peptide 1 receptor agonist (GLP-1 RA) independent of glycemic control in patients with T2D who are at risk of/or with established ASCVD, CKD, and/or HF. These drug classes have been shown to reduce cardiorenal diseases and mortality independent of their glucose-lowering effects.26,27 The risk of hypoglycemia should be minimized by prescribing antihyperglycemic agents from drug classes known not to induce hypoglycemia. For patients on insulin, insulin analogs should be used, and glucagon should be prescribed to treat severe hypoglycemic events as appropriate, with training provided for the patient and their family.3,28

Contemporary Prevention of Comorbidities and Mortality

Clinicians should check for metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease or NAFLD) by monitoring transaminase levels and, more importantly, using the FIB-4 (fibrosis 4) calculation annually in patients with obesity and/or T2D. This will help identify the disease before it progresses into metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis or NASH).29,30 Note that early fatty liver disease cannot be detected using liver function tests, hence the need for FIB-4 and/or imaging. Patients with MASLD should be managed primarily with lifestyle changes coupled with control of CV and renal risks. However, pioglitazone should be considered for patients with MASH or hepatic fibrosis (regardless of the presence of T2D), unless contraindicated, along with lifestyle and risk factor changes.31 Standard therapies should also be used to control lipids, hypertension, anticoagulation therapy, and hyperglycemia in patients with or at risk for ASCVD. Further primary and secondary risk reduction strategies are detailed in Table 2.13

Clinicians should aim to reduce the risk of HF using lifestyle changes, BP and glucose control, and ASCVD interventions as needed. An angiotensin II receptor blocker (ARB)/angiotensin-converting enzyme inhibitor (ACEi) and SGLT2i should be considered for high-risk patients with and without diabetes and CV risk factors. Patients with elevated natriuretic peptides who are at high clinical risk, and/or with the signs and/or symptoms of HF, should be referred to a cardiologist or multidisciplinary disease management program. In cases of suspected HF, clinicians should characterize left ventricular ejection fraction using an echocardiogram with Doppler flow studies.32 Patients who have HF with preserved ejection fraction (HFpEF, EF ≥50%) should be treated with an SGLT2i with proven efficacy such as empagliflozin and dapaglifozin.33 Quadruple therapy is indicated for patients with HF with reduced ejection fraction (HFrEF, EF < 40%) (ie, an angiotensin receptor neprilysin inhibitor [ARNI], beta blocker, mineralocorticoid receptor antagonist [MRA], and SGLT2i) and, if needed, with a diuretic for congestion.34 Patients with HF who have a mildly reduced ejection fraction (HFmrEF, EF 41%-49%) should be considered for treatment with an SGLT2i and additional elements of the quadruple therapy, if needed.

CKD should be diagnosed by measuring both eGFR and UACR and reassessed at least annually. Regular risk assessments are very important as CKD is associated with ASCVD, HF, end-stage kidney disease, hypertension, arrhythmia, and hypoglycemia.35,36 Clinicians should aim to reduce CKD risk through lifestyle changes and goal-directed therapies to lower BP, glucose, and lipid levels.6,7 First-line drug therapy for patients with CKD includes controlling elevated lipids with statins and blood pressure with a renin-aldosterone system inhibitor (ACEi/ARB) in patients with hypertension, and SGLT2is (irrespective of T2D status).37 Additionally, the nonsteroidal MRA finerenone and the GLP-1 RA semaglutide have also demonstrated CV and kidney benefits in patients with diabetic kidney disease.38,39

HF and CKD frequently occur together and require special consideration of their high risk of progression and mortality. Due to this high risk, SGLT2is should be prescribed as indicated, as they have demonstrated efficacy beyond reducing glucose levels in the treatment of comorbid HF and CKD and are suitable to initiate in patients with an eGFR of ≥20 mL/min per 1.73 m2 (and can be continued even when eGFR falls below this threshold until renal replacement therapy or transplantation is required).40 In cases where the patient is congested, diuretics should be initiated, in addition to the agents from the 4 therapeutic classes recommended for management of HFrEF (beta-blockers, ARNIs [or ACEi/ARBs], SGLT2is, and MRAs). These patients should also be monitored for eGFR decline, as a modest decline is expected with initiation of ACEi/ARBs, MRAs, and SGLT2is (in the case of SGLT2is, this decline is known to return to baseline within a few months) and should not be a reason to discontinue therapy, as ultimately these medications facilitate eGFR stabilization and slow long-term eGFR decline. They should also be monitored for hyperkalemia as a result of treatment with ACEi/ARBs, and especially MRAs. UACR and natriuretic peptides should be used to evaluate disease progression. Patients with HFpEF will benefit from SGLT2is, GLP-1 RA when body mass index is 30 kg/m2 or higher, and ARNI (or ACEi/ARBs) and MRAs for patients with an ejection fraction up to 55% to 60%.

In addition to the more well-known complications and comorbidities, there are other effects that may be ameliorated or prevented by proper management of the risk factors for CRM diseases (eg, cognitive dysfunction).

It is important to note that while lifestyle changes can play a significant role in any treatment plan, they are generally not sufficient to address the multiple conditions needing management in patients with CRM. As a result, pharmacotherapy is usually required; medication should be prescribed based on patients’ needs and using the latest clinical practice guidelines, taking all relevant factors into account (eg, patient characteristics and products’ attributes and contraindications; see Table 3).13

SGLT2is are recommended for patients with HF and CKD with and without T2D, due to beneficial effects on weight, BP, prevention of HF hospitalization, prevention of CKD deterioration, as well as reductions in mortality.10,37 However, they are not indicated to initiate for patients with eGFR < 20 mL/min per 1.73 m2. Potential adverse effects may include genital mycotic infections (GMI) and ketoacidosis. However, it should be noted that GMIs are generally mild and can be treated with topical agents or a single dose of oral fluconazole, and the risk of ketoacidosis is infinitely small in people with HF and CKD; GMIs do not impact patients who do not have diabetes.10,37 GLP-1 RAs are recommended for patients with T2D with established or who are at high risk for ASCVD to prevent myocardial infarction, stroke, and mortality. They improve hyperglycemia, help with weight loss, and improve diabetic CKD and quality of life in people with HFpEF. The GLP-1 RA semaglutide has also been shown to reduce major adverse cardiovascular events in persons with preexisting CVD and overweight or obesity but without diabetes.41 Potential adverse effects include mild-to-moderate gastrointestinal adverse events.1,3,39,42,43 GLP-1 RAs do not cause hypoglycemia; however, if patients are receiving insulin, sulfonylureas, or glinides, hypoglycemia is possible. Such patients should be monitored, and if hypoglycemia occurs, the doses of insulin, sulfonylureas and glinides should be reduced or stopped if possible.3 Lipid-lowering medications are essential in patients with diabetes and/or cardiorenal and metabolic diseases (the DCRM patient) to prevent or reduce the risk of ASCVD. Nonstatin lipid-lowering therapy in combination with statins can be used to reach risk-based LDL-C goals. Nonstatins should be used in people with statin intolerance.44 MRAs and ARNIs are recommended for patients with HF, and nonsteroidal MRAs are indicated for patients with diabetic kidney disease. Patients who receive MRAs should be monitored for the risk of hyperkalemia.

Summary of Updates in DCRM 2.0

An updated version of the DCRM (DCRM 2.0) has been recently published, accompanied by a revised slide deck.13 Since the original DCRM practice recommendations were published, the scope of conditions thought to play a role in CRM diseases has expanded, with heightened recognition of the role of inflammation; sleep and breathing disturbances; lung disorders; and especially increased understanding of the impact of obesity on heart, lung, and kidney diseases. Therefore, the DCRM 2.0 updated the original recommendations with a special focus and recommendations on obesity and inflammation. Unlike the original DCRM, which was US-based, the DCRM 2.0 is extended globally with the contribution of top experts from Europe and Canada. The DCRM 2.0 further features novel medications, new indications for existing medications, and advanced management of DCRM diseases. In addition, the DCRM 2.0 highlights early intervention and intensified management with increased focus on implications for clinical practice. It includes a revised summary of medications to help clinicians choose the most relevant therapies with CV outcomes for their patients based on efficacy and potential adverse effects. New evidence will be evaluated for inclusion in the update based on scientific strength, clinical relevance, and ultimately, benefit to patients.

As mentioned, due to intense international interest, the DCRM 2.0 has been transformed from a US perspective to a global outlook so it can be easily adopted worldwide. This has been achieved by cooperation with international experts addressing the DCRM topics and their relevance to different populations, allowing local adoption. Approximately 60% of the authors are from the original DCRM, and the remaining 40% are international leaders, primarily from Europe and Canada.

Conclusions

Cardiorenal and metabolic diseases comprise many conditions and diseases, including obesity, T2D, CKD, ASCVD, HF, and fatty liver disease. Because cardiorenal and metabolic diseases share pathophysiology, 2 or more conditions are often present in the same individual. Evidence supports the benefits of some agents on several of the cardiorenal-metabolic diseases. The complexity of the DCRM patient who typically displays more than 1 disease requires a multispecialty approach for the diagnosis and management of their conditions. The needed holistic approach generally incorporates the involvement of several specialists. Because of this, the DCRM 2.0 practice recommendations combine expertise from multiple specialties into a comprehensive standalone document designed for use by nonexpert physician specialists and primary care physicians alike. The recommendations are based on strong evidence, represent the consensus of top experts, are clinically relevant, and most importantly, are simple to follow and implement. These recommendations provide an invaluable tool for clinicians who do not have the support of a specialists’ network and who need to develop treatment plans for complex cases of patients with CRM diseases. Ultimately, the DCRM 2.0 aims to help improve the health and well-being of patients with DCRM.

Acknowledgments

The author meets criteria for authorship as recommended by the International Committee of Medical Journal Editors. The author did not receive payment related to the development of the manuscript. Writing support was provided by Andy Shephard of Elevate Scientific Solutions, LLC, contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI) and Lilly USA, LLC. BIPI and Lilly were given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Author Affiliation: Metabolic Institute of America, Tarzana, CA.

Funding Source: This supplement was supported by Boehringer Ingelheim Pharmaceuticals, Inc and Lilly USA, LLC.

Author Disclosures: Dr Handelsman reports receiving research grants and consultant and speaker honoraria from 89Bio; Amgen; Applied Therapeutics; AstraZeneca; Bayer; Boehringer Ingelheim; Corcept Therapeutics; Endogenex; Esperion; Ionis Pharmaceuticals, Inc; Lilly; Mankind Pharma; Merck; Merck-Pfizer; Novartis; Novo Nordisk; Regeneron Pharmaceuticals, Inc; Sanofi.

Authorship Information: Acquisition of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address Correspondence to: Yehuda Handelsman, MD, Metabolic Institute of America, 18372 Clark St #212, Tarzana, CA 91356. Email: yhandelsman@gmail.com

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