Drugs that are derived from nature are prevalent in nephrology. For example, the first angiotensin-converting enzyme inhibitor (captopril) was isolated from the venom of the Brazilian pit viper, Bothrops jararaca (1). Interestingly, the first sodium glucose co-transporter (SGLT) inhibitor (phlorizin) was isolated from the bark of the apple tree (2). What else does nature have in store?
An unlikely place to look is the saliva of Heloderma suspectum, better known as the Gila monster. This is a venomous lizard native to the United States and Mexico. It turns out that the Gila monster only eats 5 to 10 times per year. Thus, these meals are huge, and as a result, considerable biological adaptation has occurred to deal with this food bolus. One of the mechanisms the Gila monster uses to metabolize this massive caloric hit is to upregulate the incretin system (3).
Incretins, such as human glucagon-like peptide 1 (GLP-1), are a group of gut hormones that stimulate the release of insulin from pancreatic β cells and inhibit glucagon in response to hyperglycemia and nutrient intake. The Gila monster has evolved to release an incretin hormone called exendin-4 in response to these food boluses. Incretin-4 has 53% amino acid sequence homology to human GLP-1 (4). Importantly, exendin-4 is resistant to enzymatic inactivation by dipeptidyl peptidase 4 (DPP-4); thus, it has a prolonged duration of action. Exenatide, a synthetic form of exendin-4 administered subcutaneously, was the first GLP-1 agonist and was approved by the US Food and Drug Administration (FDA) in 2005. Since that time, six GLP-1 agonists have been approved by the FDA (subcutaneous: exenatide, dulaglutide, albiglutide, liraglutide, and lixisenatide; oral: semaglutide). In addition, four DPP-4 inhibitors are FDA approved (oral: sitagliptin, saxagliptin, linagliptin, and alogliptin) (5).
GLP-1 receptor agonists are effective therapies for diabetes mellitus (lowering A1c by 0.8%–1.7%) and reduce adverse cardiovascular outcomes that have been available for 15 years. They have an additional benefit in that they result in weight loss. However, they might not be on the tip of the tongue of many nephrologists (like SGLT2 inhibitors are). However, GLP-1 agonists might just be the next blockbuster in the treatment of diabetic kidney disease (DKD). Let's take a look at where we are.
GLP-1 trials are encouraging
Some early signs from recent trials suggest that GLP-1 receptor agonists may have a role in slowing progression of chronic kidney disease (CKD) in DKD. The cardiovascular outcome trials for the GLP-1 receptor agonists showed a reduced risk of major adverse cardiovascular events among those taking liraglutide, semaglutide, and dulaglutide (6–8). Some early signals in these trials suggest they may be of benefit in slowing decline of the estimated glomerular filtration rate (eGFR) and reductions in albuminuria. However, these studies all have a cardiovascular primary outcome.
Secondary outcomes in a recent trial (AWARD-7) of 577 patients suggest that in patients with macroalbuminuria, the risk of reaching a composite endpoint of kidney failure or >40% decline in eGFR was >50% lower in those receiving dulaglutide than in those receiving insulin glargine (9). A prespecified secondary analysis of the LEADER trial in which 9340 patients with type 2 diabetes mellitus and high cardiovascular risk were randomized to the GLP-1 receptor agonist liraglutide and placebo showed reductions in kidney outcomes primarily driven by fewer episodes of new-onset macroalbuminuria in those taking liraglutide (10). Similar results were seen in the 3297-patient SUSTAIN-6 randomized clinical trial in which secondary outcomes in patients with type 2 diabetes mellitus demonstrated reduced new or worsening kidney outcomes with semaglutide (6).
We are awaiting the results of clinical trials in which kidney outcomes are the primary focus. The FLOW trial will be the first and most impactful (11). It will be assessing kidney disease outcomes in 3500 patients with type 2 diabetes, comparing the GLP-1 receptor agonist semaglutide (subcutaneous route) with placebo, and has finished recruitment and is expected to be complete in 2024 (Table 1). Other semaglutide trials to watch include the SOUL study (12), examining cardiovascular outcomes in type 2 diabetes mellitus, and the SELECT (13) trial, observing cardiovascular outcomes in patients with obesity and no diabetes (Table 1).
Promising trials focusing on kidney outcomes
Because GLP-1 receptor agonists can be used in individuals with an eGFR >15 mL/min/1.73 m2, they are recommended in those who cannot receive SGLT2 inhibitors or metformin, such as those with an eGFR between 15 and 25 mL/min/1.73 m2. As noted above, each of the GLP-1 receptor agonists is given subcutaneously, except that semaglutide has an oral formulation. Since these drugs are more potent and decrease blood sugar, adjustment of other antiglycemic agents could be indicated.
Studies in DPP-4 inhibitors are not as convincing as GLP-1 receptor agonists. Although DPP-4 inhibitors are effective at reducing hemoglobin A1c, they have failed to exhibit a cardiovascular benefit (14–16). Moreover, saxagliptin and alogliptin show a signal for increased hospitalizations for heart failure. The mechanism for this is not completely understood but is thought to be related to the degradation of other proteins by DPP-4, which include SDF-1 (stromal cell-derived factor 1), NPY (neuropeptide Y), and substance P. Thus, these could activate the sympathetic nervous system and stimulate β-adrenergic receptors (17). Kidney outcomes in DPP-4 inhibitors, like GLP-1 receptor agonists, are derived from secondary outcomes of cardiovascular trials. DPP-4 inhibitors have been shown to reduce albuminuria, but the effects on kidney function have not been seen (18).
Will we see the fifth pillar of DKD therapy with GLP-1 receptor agonists? We await the FLOW trial results eagerly. It is clear that the outpatient nephrologist should stay well versed in the latest research in diabetes. It is exciting to see these developments materialize.
References
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ClinicalTrials.gov. A Research Study to See How Semaglutide Works Compared to Placebo in People with Type 2 Diabetes and Chronic Kidney Disease (FLOW). https://clinicaltrials.gov/ct2/show/NCT03819153
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ClinicalTrials.gov. A Heart Disease Study of Semaglutide in Patients with Type 2 Diabetes (SOUL). https://clinicaltrials.gov/ct2/show/NCT03914326
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ClinicalTrials.gov. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT). https://clinicaltrials.gov/ct2/show/NCT03574597
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Kanasaki K, et al. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes 2014; 63:2120–2131. doi: 10.2337/db13-1029
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