EBM Tools for Practice: Navigating the Complexities: Cardiometabolic Disease Management in Chronic Kidney Patients

Introduction

Cardiometabolic syndrome is an aggregation of cardiovascular, metabolic, and renal abnormalities that includes central/visceral obesity, hyperinsulinemia, hypertension, and dyslipidemia.¹ Approximately 47 million individuals in the United States are currently living with cardiometabolic disorders, placing them at a higher risk of developing chronic conditions.² There is an overwhelming amount of epidemiologic evidence demonstrating that obesity leads to the development and progression of chronic kidney disease (CKD).¹ Obesity increases the risk of kidney disease through various pathways such as insulin resistance, lipotoxicity, adipocytokine dysregulation, increased blood pressure, and enhanced glomerular blood pressure.^3,4 There are numerous emerging initiatives aimed to reduce cardiometabolic risk through targeted intervention, particularly emphasizing obesity management to improve patient outcomes. To date, the existing literature involving obesity and mortality in chronic kidney patients is conflicting.^4.5 It is unclear whether higher body mass index (BMI) increases the mortality risk in this population. Furthermore, the role of intentional weight loss in patients with CKD remains ambiguous. This review will discuss the relationship between obesity and CKD, and the pharmacotherapy management for obesity in chronic kidney patients.

Mortality in Obese Adults with CKD

Obesity is a modifiable risk factor for CKD. Recent estimates show that 24% to 33% of all kidney disease could be directly or indirectly caused by obesity.⁴ It is hypothesized that obesity directly impacts CKD due to compensatory hyperfiltration which occurs in order to meet heightened metabolic demands. Furthermore, the downstream consequences of chronic cardiometabolic conditions can lead to the production of adiponectin, leptin, and resistin which leads to inflammation, oxidative stress, and activation of the renin-angiotensin aldosterone system.⁶ Continuous inflammation will eventually also lead to glomerular hypertension and increased glomerular permeability correlated with the  hyperfiltration-related glomerular filtration injury.⁶ Obesity can also indirectly trigger other risk factors like diabetes and hypertension, thus contributing to the development and progression of CKD.

Patients with a BMI >35 kg/m² have 7-fold and 6-fold increased odds of being diagnosed with diabetes and hypertension, respectively.⁴ The World Health Organization classifies obesity using BMI criteria, however this definition lacks the ability to distinguish between fat, muscle, and extracellular volume.^6,7 Currently, the existing literature surrounding obesity in patients with CKD and mortality is conflicting.^4,5 The Atherosclerosis in Communities (ARIC) study demonstrated that in patients with CKD, higher BMI was associated with lower risk of mortality compared to lower BMI.⁴ Further analysis in the same study also identified that there was no association noted between BMI >25 kg/m² and mortality in this population. Similarly, Madero et al. also reported that there was no association between sex-specific BMI and all-cause or cardiovascular mortality after a median follow-up period of 10 years.⁴

An alternative and even stronger predictor of mortality in patients with CKD is abdominal fat, however utilization of this variable is limited due to high cost associated with DXA scans, computed tomography, and magnetic resonance imaging.⁴ However, abdominal obesity can be measured by waist circumference and literature has demonstrated a strong association between abdominal obesity, metabolic syndrome, and CKD.⁴ In the general population, a waist circumference of >88 cm in women and >102 cm in men is a reliable indicator for development of cardiometabolic syndrome.⁶ Pooled data from the ARIC Study and the Cardiovascular Health Study (CHS) demonstrated that the highest waist/hip ratio (>1.02 and 0.96 in men and women, respectively) had a 36% relative risk of cardiac events compared to the patients with lowest waist/hip ratio.⁴

Mortality in Obese Adults with CKD Receiving Dialysis

Among obese adults with CKD receiving dialysis, there is an increased amount of visceral fat which is associated with higher plasma insulin and triglycerides and a higher prevalence of carotid atherosclerosis.⁴ The literature encompassing BMI and mortality in obese patients with end stage kidney disease (ESKD) is also conflicting and lacking.^4,7 Observational studies suggest that a higher BMI is associated with improved survival in this subset of population. A study conducted by Johansen et al. ⁴ demonstrated that cardiovascular mortality rates were two-fold higher among patients with BMI <22 kg/m² compared to those with BMI >37 kg/m². Those with BMI <22 kg/m² were associated with the highest mortality risk. Further analysis by Beddhu et al. demonstrated that adults with BMI >25 kg/m² had a 14% increased risk of death compared to those with normal BMI. Other studies have demonstrated that baseline BMI >30 kg/m² among hemodialysis patients was associated with a 20% increase of mortality compared to those with ideal BMI. Regardless of BMI, patients receiving dialysis who had higher muscle mass had better survival than those with low muscle mass.^4,7 Most studies evaluating BMI and mortality with ESRD have an average follow up of <2 years whereas the general population have follow up durations that exceed 5 years.⁴

Pharmacotherapy in Obese Adults with CKD

The 2022 Kidney Disease Improving Global Outcomes (KDIGO) guideline emphasizes the significance of multifactorial interventions to target modifiable risk factors to reduce the onset and progression of kidney disease.⁸ Approaches should include lifestyle and behavioral modification as the foundation followed by pharmacological intervention. Patients with risk factors such as BMI >30 kg/m², increased weight circumference, diabetes, and CKD⁸ should be encouraged to lose weight, particularly those with an eGFR >30 mL/min per 1.73m². Intentional weight loss may reduce urinary albumin excretion, improve blood pressure, and provide kidney benefits in those with mild to moderate kidney disease.⁸ 

There are several medications available for weight loss, however a majority of these agents have not been adequately studied in patients with Stage 3-5 CKD. One of the oldest classes of medication available for weight loss are sympathomimetic amines such as phentermine and phentermine/topiramate which activates the central nervous system to suppress appetite.^3,4,6,9 Topiramate triggers GABA activity which also suppresses appetite and enhances satiety.¹⁰ This drug class is associated with cardiometabolic benefits such as decreased weight circumference, modest decrease in glycemia and blood pressure however therapy duration is limited due to risk of tachyphylaxis.³ Additionally, there is an increased risk of elevated blood pressure and heart rate for phentermine and the risk of renal tubular acidosis and nephrolithiasis from topiramate.^6,9,10 Given the high cardiovascular risk of this population, further long-term safety data is warranted before recommending the use of sympathomimetic amines.³ Another class also indicated for weight loss is a combination of dopamine/norepinephrine reuptake inhibitor and an opioid antagonist known as bupropion-naltrexone.⁶ Similarly, it decreases the desire for food intake and increases satiety.¹¹ Studies also have shown that higher rates of serum creatinine were seen at follow-up along with elevated blood pressure, therefore this class should be used with caution due to uncertain effects on the kidney.³ Lastly, Orlistat is an alternative oral medication indicated for weight loss. Orlistat is an inhibitor of gastric and pancreatic lipase which reduces the absorption of dietary fat.^3,4,6 In comparison, this class does not require renal dose adjustment and long-term duration has been studied. There have been reports of renal oxalosis leading to acute kidney injury. Beyond weight reduction, orlistat can also lead to incremental reductions in free fatty acids, total cholesterol, and low-density lipoprotein cholesterol levels and improve insulin resistance.³

In addition to oral agents, glucagon-like peptide-1 (GLP-1) receptor agonists not only modulates glycemic control but also supports inflammation and weight loss. The mechanism as to why GLP-1 receptor agonists may have kidney protective effects remains unclear.¹² Possible indirect factors can be due to appropriate weight loss which reduces albuminuria and glomerular-sclerosis by suppressing oxidative stress and local inflammation.¹³ There is an abundance of robust cardiorenal data supporting the benefits of GLP-1 receptor agonists.³ Studies have demonstrated that GLP-1 receptor agonists have a greater protective effect than dipeptidyl peptidase 4 inhibitors in terms of decline in eGFR >50% and progression to ESRD with dialysis.¹³ The selection of GLP-1 receptor agonists should be individualized based on the patient’s existing comorbidities and preference. Currently, the agents that are indicated for weight loss in patients not living with diabetes are liraglutide (Saxenda®) and semaglutide (Wegovy®). Patients living with diabetes and CKD, the choice of GLP-1 receptor agonists expands to liraglutide (Victoza®), semaglutide (Ozempic®), and dulaglutide (Trulicity®). Historically, the inclusion of CKD patients within these cardiovascular outcome trials is often limited. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial demonstrated that liraglutide decreased the risk of secondary composite renal endpoint (new-onset microalbuminuria, sustained serum creatinine duplication, initiation of RRT, or renal death) by 22% (HR, 0.78, 95% CI, 0.67-0.92; P = 0.003). This trial^12,14 also included 23% of participants with moderate-to-severe CKD and 220 individuals with an eGFR of 15-30 mL/min per 1.73m². Following the LEADER trial, the trial that evaluated Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) also demonstrated that semaglutide reduced the risk of secondary combined renal endpoints by 36% (HR, 0.36; 95% CI, 0.46-0.88; P = 0.005).^12,15 The most evident decline in reduced eGFR in patients with macroalbuminuria was demonstrated in two studies evaluating dulaglutide. The trial that evaluated Dulaglutide versus Insulin Glargine in Patients with Type 2 Diabetes and Moderate-to-Severe Chronic Kidney Disease (AWARD-7) included 577 patients with moderate-to-severe CKD and 10% reduction of eGFR was observed with dulaglutide 1.5 mg.^12,16 The trial that evaluated at Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes (REWIND) demonstrated the largest reduction in the development of macroalbuminuria in the dulaglutide group (HR, 0.77; 95% CI, 0.68-0.87; P=0.0004).^12,17 Adverse effects of GLP-1 receptor agonists include gastrointestinal side effects, risk of acute gallbladder disease, and no increased risk of acute kidney injury. Despite the uncertain nephroprotective effects, GLP-1 receptor agonists should be considered for weight loss and glycemic control given its strong secondary renal outcome data.^3,12

Pharmacotherapy for Obese Adults with CKD and Dialysis

The role and safety of intentional weight loss in patients with kidney failure has not been studied. Previous cardiovascular outcome trials with GLP-1 receptor agonists have mainly excluded advanced diabetic kidney disease and completely excluded those with ESRD¹³, especially those with an eGFR of <30 mL/min per 1.73m². Pharmacotherapy options for intentional weight loss are limited in this subset of population. Most oral agents are contraindicated and GLP-1 receptor agonists are recommended to be used with caution due to the limited clinical evidence. Small short-term liraglutide studies have demonstrated efficacy in patients with type 2 diabetes receiving hemodialysis but with increased reports of nausea/vomiting.¹⁸ A multidisciplinary and individualized approach is needed to determine whether intentional weight loss is appropriate for patients with advanced CKD and dialysis.

Conclusion

Obesity is an independent risk factor for the development and progression of CKD through various proposed mechanisms. Intentional weight loss may reduce albuminuria and subsequently slow the decline of stimulated glomerular filtration rate. Given that intentional weight loss has not been well studied in this population, an individualized approach on choosing pharmacotherapy options is crucial to improve kidney and cardiovascular outcomes.

Dr. Chan has no financial relationships to disclose. Dr. Cardinale has no financial relationships to disclose. 

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