Liraglutide for the Treatment of Type 2 Diabetes and Safety in Diabetic Kidney Disease

Diabetes is a global emergency involving >463 million people as of 2019 and a projection for growth to nearly 700 million by 2045. The vast majority of people (>95%) with diabetes have type 2 diabetes. Despite what is known about effective lifestyle and pharmacologic interventions, the number of people living with diabetes will expand dramatically for the foreseeable future. As a consequence, the number with diabetes complications, including diabetic kidney disease, will also multiply. Diabetic kidney disease occurs in about 40% of those with type 2 diabetes, and it is the most common cause of CKD and kidney failure worldwide. However, death largely due to cardiovascular diseases outcompetes diabetic kidney disease progression by >2:1, and only 10% reach kidney failure. The standard of care for treatment of diabetic kidney disease is use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker—a strategy that has been in place for over two decades. Yet, residual risk of kidney disease progression remained high, and prevalence of diabetic kidney disease and kidney failure attributable to diabetes only escalated over the same time period. The arrival of sodium-glucose cotransporter 2 (SGLT2) inhibitors as kidney-protective agents for diabetic kidney disease prevention and treatment is a welcome advance (1). However, even with application of canagliflozin on top of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, many patients with diabetic kidney disease still have considerable residual risk for kidney disease progression or death. Therefore, great unmet need remains for a broad selection of agents to prevent or treat diabetic kidney disease.

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), a class of newer glucose-lowering agents, represent another potential avenue for diabetic kidney disease therapeutics. Similar to SGLT2 inhibitors, the initial observations for kidney protection came from postmarket-approval cardiovascular disease safety trials of GLP-1 RA that had kidney disease end points as secondary or exploratory outcomes. The Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (n=3297) and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER; n=9340) trial tested semaglutide and liraglutide, respectively, versus placebo in participants with type 2 diabetes at high cardiovascular risk. Both trials demonstrated reductions in new or worsening “nephropathy” (albuminuria, doubling of serum creatinine, kidney failure, or kidney disease death), which was mainly driven by a decrease in macroalbuminuria (2,3). Notably, in the LEADER trial, liraglutide reduced risk of atherosclerotic cardiovascular disease in participants with eGFR<60 ml/min per 1.73 m², with a significant between-group interaction indicating even greater benefit in those with low eGFR (4). In the largest cardiovascular disease trial to date, the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (n=9901) trial, testing dulaglutide versus placebo, similar results for kidney disease outcomes were reproduced along with a new exploratory finding of risk reductions for 40% or 50% eGFR decline (5).

The Study Comparing Dulaglutide with Insulin Glargine on Glycemic Control in Participants with Type 2 Diabetes (T2D) and Moderate or Severe CKD (n=577) trial tested dulaglutide versus an active comparator for glycemic control (insulin glargine) in patients with type 2 diabetes and moderate to severe CKD (mean eGFR =38 ml/min per m², 29% had microalbuminuria, and 46% had macroalbuminuria) (6). Following 52 weeks of treatment, both dulaglutide treatment groups experienced significantly less eGFR decline compared with those in the insulin glargine group. This benefit was greatest in participants with macroalbuminuria. In this group, mean eGFR decline was −5.5 ml/min per 1.73 m² in the insulin glargine group compared with −0.7 and −0.5 ml/min per 1.73 m² in the lower- and higher-dose dulaglutide groups, respectively. A prespecified exploratory analysis demonstrated that, in the higher-dose dulaglutide group, a composite end point of kidney failure or >40% eGFR decline was decreased by half compared with the insulin glargine group (5.2% versus 10.8%; P=0.04). In time to event analysis, the hazard ratio for this composite end point in macroalbuminuric participants was 0.25; 95% confidence interval, 0.10 to 0.86 (P=0.006) among those receiving higher-dose dulaglutide versus those receiving insulin glargine.

Although the mechanism of action of GLP-1 RA leading to kidney protection has not been fully elucidated, both indirect and direct pathways may be involved as reviewed elsewhere (7). For indirect pathways, GLP-1 RA reduces hyperglycemia, weight, and BP, all of which may decrease risk of diabetic kidney disease. Beyond affecting such traditional risk factors for diabetic kidney disease progression, activation of GLP-1 augments proximal tubular natriuresis via blocking the sodium-hydrogen exchanger-3, which could theoretically promote tubuloglomerular feedback, afferent constriction, and reduced glomerular hypertension. Studies in patients with and without diabetes have, however, shown that, although natriuresis does occur, kidney function does not change (7). Outside of solute handling, GLP-1 activation also inhibits a variety of injurious pathways within the kidney, including oxidative stress (NADPH oxidase inhibition), inflammation (reduced expression of cytokines and chemokines), and fibrosis (reduced expression of TGF-β1 and collagen IV) (7).

Despite their emerging salutary effects, the use of GLP-1 RA is generally low in patients with diabetic kidney disease and low kidney function—a situation perhaps in part related to uncertainty about safety or use of these agents in moderate to severe CKD. Accordingly, in their manuscript in this issue of CJASN, Mann et al. (8) report the result of a post hoc analysis assessing the safety of liraglutide in patients with and without CKD in the LEADER trial (2). In this cohort, 2158 patients had CKD defined as eGFR<60 ml/min per 1.73 m², and 220 participants had an eGFR<30 ml/min per 1.73 m². In the overall cohort, 966 patients had macroalbuminuria, and 2456 had microalbuminuria. Mean eGFR at baseline was 45.7±10.9 ml/min per 1.73 m² in patients with CKD and 90.8±21.6 ml/min per 1.73 m² in those without CKD. Participants with CKD had more serious adverse events versus patients without CKD, but there was no imbalance between liraglutide- versus placebo-treated patients. Fewer liraglutide- versus placebo-treated participants experienced a serious adverse event leading to treatment discontinuation. Although numerically more patients with CKD had nausea leading to discontinuation and acute gallstone disease in the liraglutide group versus the placebo group, these differences were not statistically significant. For other gastrointestinal adverse events, nausea, vomiting, and diarrhea leading to permanent discontinuation were, as expected, numerically more common with liraglutide versus placebo (not significantly different), but they occurred at similar rates in patients with CKD versus patients without CKD. From a metabolic perspective, severe hypoglycemia risk was 27% lower in patients with CKD randomized to liraglutide versus placebo, and a similar trend was present in participants without CKD. For AKI, the risk was higher in participants with CKD versus participants without CKD, but there were no differences observed across liraglutide- versus placebo-treated participants. In summary, no new safety concerns were identified in the CKD cohort, and liraglutide was associated with less hypoglycemia, an important cause of morbidity and mortality in patients with diabetes.

Several major themes have, therefore, emerged from recent GLP1-RA trials. First, these agents exert clinically significant glycemic and weight-lowering effects in patients with and without CKD. Importantly, glycemic lowering is similar compared with insulin therapy with reduced risk of hypoglycemia (6,9). Second, GLP1-RA agents are (in cardiovascular safety trials and in a dedicated study of patients with CKD) associated with clinically relevant reductions in albuminuria and lower risk of eGFR decline (6,9). Third, as shown in the analysis by Mann et al. (8), GLP1-RA therapy with liraglutide was safe and well tolerated by patients with CKD compared with patients without CKD.

In patients with CKD, as kidney function declines toward 30 ml/min per 1.73 m², patients tend to be switched from oral agents to insulin, which promotes volume expansion, weight gain, higher BP, and an increased risk of hypoglycemia. The analysis by Mann et al. (8) is clinically important because it offers additional evidence around both efficacy and safety with liraglutide—a drug in a class that avoids many deleterious effects associated with insulin. Accordingly, as with other newer glucose-lowering therapies that have major cardiovascular- and/or kidney-protective effects, such as SGLT2 inhibitors, nephrologists need to become familiar with GLP-1 RA, which has been shown to reduce cardiovascular risk. Regardless of the mechanism, it is becoming increasingly clear that GLP-1 RA should be used preferentially in appropriate patient groups, including those with atherosclerotic cardiovascular disease and patients with diabetic kidney disease who do not tolerate SGLT2 inhibition (10). In clinical practice, uptitration of GLP-1 RA agents should occur approximately every 4 weeks to reduce gastrointestinal side effects. In addition, in patients taking other agents that can induce hypoglycemia, such as insulin or sulfonylureas with appropriate glycemic control (hemoglobin A1c about <7%), these background therapies may be downtitrated.

Ultimately, the completion of dedicated diabetic kidney disease trials with GLP-1 RAs is required to fully understand the role of these agents in kidney protection. Fortunately, the Research Study to See How Semaglutide Works Compared with Placebo in People with Type 2 Diabetes and CKD with Semaglutide (NCT00696657) is recruiting patients across a range of eGFR and albuminuria—including patients with and without SGLT2 inhibition as background therapy. Until the results of these studies are complete, the analysis by Mann et al. (8) offers clinicians reassurance that GLP-1 RA can be used safely in patients with diabetic kidney disease.

Disclosures

Dr. Cherney has received honoraria from Abbvie, AstraZeneca, Bayer, BMS, Boehringer Ingelheim-Lilly, Janssen, Merck, Mitsubishi-Tanabe, Novo-Nordisk, Prometic, and Sanofi and has received operational funding for clinical trials from AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck, Novo-Nordisk, and Sanofi. Dr. Tuttle has received consulting fees, speaking honorarium, or both from Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Janssen, Lilly, and Novo Nordisk.