Therapeutic Considerations for Antihyperglycemic Agents in Diabetic Kidney Disease

Abstract

Diabetic kidney disease is among the most frequent complications of diabetes, with approximately 50% of patients with ESRD attributed to diabetes in developed countries. Although intensive glycemic management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced GFR in patients with diabetes, conservative dose selection and adjustment of antihyperglycemic medications are necessary to balance glycemic control with safety. A growing body of literature is providing valuable insight into the cardiovascular and renal safety and efficacy of newer antihyperglycemic medications in the dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, and sodium-glucose cotransporter 2 inhibitor classes of medications. Ongoing studies will continue to inform future use of these agents in patients with diabetic kidney disease.

The United Nations General Assembly has recognized diabetes mellitus (DM) as a condition of major global concern in recognition of the growing numbers of people with DM and the tremendous effect of this disease on health worldwide.¹ In 2015, an estimated 415 million people worldwide had DM, with a projected increase to 642 million by the year 2040.² Notably, these figures include a disproportionately large number of individuals in low- to middle-income countries.³ Similar to the global trends, the prevalence of DM among adults in the United States increased from 10% from 1988 to 1994 to an estimated 12% from 2011 to 2012.⁴ Approximately 30% of those with type 1 DM and 40% of those with type 2 diabetes mellitus (T2DM) develop diabetic kidney disease (DKD).⁵ Adults with DM are at 1.5-fold higher risk of all-cause death compared with those without DM, and the risk is greatly amplified among those with DKD.^6,7 Prevention of diabetic microvascular complications, particularly DKD, by long-term intensive glycemic control is well established for both type 1 DM and T2DM.^8,9 Optimizing glycemic control in this population, however, is complicated by alterations in the kidneys’ role in maintaining glucose homeostasis, increased risk of hypoglycemia, and alterations in the pharmacokinetics of antihyperglycemic agents.¹⁰

This review will provide a discussion of challenges associated with glycemic management in patients with DKD. Additionally, considerations for the use of antihyperglycemic agents in patients with DKD will be discussed, including findings from cardiovascular outcome trials (CVOTs) recently reported with newer agents approved for the treatment of DM.

Diabetes Management: Challenges in the Setting of DKD

Kidneys and Glucose Homeostasis

Under physiologic circumstances, the kidneys play a significant role in glucose homeostasis via (1) gluconeogenesis, (2) reabsorption of glucose from the glomerular filtrate, and (3) uptake of glucose from the circulation to satisfy its own metabolic needs.¹¹ An estimated 20%–25% of glucose released into the circulation during the postabsorptive (fasting) state originates from gluconeogenesis in the kidneys.^11,12 Interestingly, renal gluconeogenesis increases in the postprandial state and accounts for approximately 60% of endogenous glucose release during this time, which has been hypothesized as a function to facilitate repletion of glycogen stores in the liver.^11,12 Approximately 160–180 g/d filtered glucose is reabsorbed from the glomerular filtrate primarily in the proximal convoluted tubule via the sodium-glucose cotransporter type 2 (SGLT-2).^12,13 The remaining glucose reabsorption from the glomerular filtrate is achieved via SGLT-1 transporters in the straight segment of the descending proximal tubule^12,13 as illustrated in Figure 1.

Figure 1.

SGLT-2 and SGLT-1 work together to reabsorb virtually all glucose filtered through the glomeruli under normal conditions.^12,13 Approximately 180 g of glucose are filtered by the glomeruli on a daily basis. Of this filtered glucose, essentially all of it is reabsorbed by SGLT-2 and SGLT-1, with SGLT-2 reabsorbing the majority of filtered glucose (approximately 90%).

In DM, both postabsorptive gluconeogenesis and glomerular filtration of glucose are increased. Notably, gluconeogenesis by the kidney is comparable with that of the liver (2.6 and 2.2 μM/kg per minute, respectively).¹¹ The amount of glucose filtered into the urine increases in a linear manner with increasing plasma glucose concentrations. As an adaptive response to this increase, there is an amplified expression of SGLT-2 transporters resulting in a raised set point for urinary glucose secretion.^14,15 Metabolic derangements seen in DM, including hyperglycemia and hyperaminoacidemia, contribute to renal hemodynamic changes of glomerular hyperfiltration that culminate in injury leading to structural changes typical of DKD (Figure 2).¹⁶

Figure 2.

Metabolic derangements present in diabetes contribute to renal hemodynamic changes of glomerular hyperfiltration. (A) Normal glomerulus. The balance between vasodilation and vasoconstriction in the afferent (upstream) and efferent (downstream) arterioles determines intraglomerular pressure, a major regulator of GFR. Distal tubular delivery of solute, particularly sodium chloride, at the macula densa regulates afferent arteriolar tone via tubuloglomerular feedback. (B) Glomerulus in diabetes. The afferent arteriole opens in response to vasodilatory factors, such as hyperglycemia and high blood levels of amino acids. Because of a high filtered load of glucose, reabsorption of glucose and sodium chloride is increased in the proximal tubule. The afferent arteriole also dilates in response to decreased delivery of sodium chloride to the distal tubular macula densa via tubuloglomerular feedback. The efferent arteriole vasoconstricts in response to high local production of angiotensin II. Overall, the balance shifts to glomerular hyperfiltration as a result of high intraglomerular pressure from afferent arteriolar vasodilation and efferent vasoconstriction. Reprinted from ref. 16, with permission.

Hypoglycemia Risk

Patients with diabetes and impaired kidney function are at increased risk for hypoglycemic events. A retrospective cohort analysis of nearly 244,000 patients with and without DM showed a higher frequency of hypoglycemic events in patients with chronic kidney disease (CKD) (defined by an eGFR<60 ml/min per 1.73 m²) when compared with those without CKD.¹⁷ Among patients with DM, the rate of hypoglycemia (blood glucose <70 mg/dl) was 11/100 versus 5/100 patient-mo among patients with and without CKD, respectively.¹⁷ A post hoc analysis of 3700 participants from the Action to Control Cardiovascular Risk in Diabetes Trial who met criteria for CKD stages 1–3 showed that intensive glucose lowering to a glycated hemoglobin (HbA1C) <7% was associated with both an approximately 30% higher all-cause mortality (1.306; 1.065–1.600) and a 40% higher cardiovascular (CV) mortality (1.42; 1.052–1.892).¹⁸ Among patients with CKD, intensive glucose lowering was associated with higher rates of hypoglycemic episodes requiring assistance when compared to those in the standard treatment group (22% versus 9%, respectively).

In the setting of advanced CKD, another loss of function performed by the kidney is lower capacity for gluconeogenesis and release of glucose into blood, thus placing patients at increased risk for hypoglycemia.¹⁷ Another contributor to the increased risk of hypoglycemia in people with DKD is altered metabolism and elimination of glucose-lowering medications.¹⁹ For example, exogenous insulin is normally metabolized by the kidney and thus, exhibits a prolonged half-life in patients with CKD. Similarly, decreased clearance of many other antihyperglycemic agents results in prolonged exposure to higher drug levels, requiring dose de-escalation for many agents.¹⁹

Glycemic Monitoring in CKD

HbA1C is the gold standard biomarker of glycemic control, but this measure has noteworthy limitations related to precision and interpretation in the DKD population.²⁰ A prospective cohort study assessed the relationship between HbA1C and blood glucose in various stages of CKD, including ESRD. After up to 10 years of follow-up, there was a strong inverse relationship between HbA1C and declining kidney function. However, later CKD stage modified the relationship between HbA1C and blood glucose, such that there was a bias to the low. In general, HbA1C measures lower at given levels of ambient glycemia in patients with advanced CKD (stages 3b–5, including those treated by dialysis).^21,22 Factors associated with increased red blood cell turnover (e.g., shortened red blood cell lifespan, decreased erythropoiesis, blood transfusions, and treatment with iron or erythrocyte-stimulating agents [ESAs]) also lowers the HbA1C relative to ambient blood glucose.^22–24 Indeed, use of ESAs was identified as a key risk factor for low HbA1C in a study involving patients with diabetes and CKD (stages 3–5), and the discordant relationship between glucose and HbA1C values is likely most relevant in those receiving ESA therapy.²⁵ In the past, formation of carbamylated hemoglobin in advanced kidney failure was reported to falsely increase HbA1C values.^22,26 However, this effect is now uncommon with current standardized HbA1C assays.

Several other markers of glycemic control, such as glycated albumin, glycated fructosamine, and 1,5-anhydroglucitol, are under study.²² To date, there are no prodigious data or assay validation to support clinical use of these alternative glycemic markers over HbA1C. Despite the inherent limitations of HbA1C measurement, it remains a key biomarker for glycemic management in people with DM and CKD.²⁷ Self-monitoring of blood glucose (SMBG) provides crucial information about glycemic control and daily fluctuations.²⁸ Continuous glucose monitoring holds promise for daily glycemic assessment but remains to be validated in patients with CKD.²⁹ At this time, HbA1C results should be interpreted carefully in conjunction with SMBG to achieve glycemic goals and mitigate hypoglycemic risk.

Guideline-recommended HbA1C goals for patients with DM and CKD have been informed by a series by results of several landmark studies. The Diabetes Control and Complications (DCCT) Trial and the United Kingdom Prospective Diabetes Study (UKPDS) in early-stage T1DM and T2DM, respectively, showed beneficial effects of intensive glycemic control on development of microvascular complications, including DKD.^8,30–32 However, studies enrolling patients with long-term T2DM and a high burden of comorbidity showed greater risks of hypoglycemia and no benefit on all-cause or CV mortality with intensive glycemic control compared with standard therapy (achieved HbA1C of 6%–6.5% versus 7.3%–8.4%, respectively).^18,33–35 In a subset with CKD, these risks were greatly amplified.¹⁸ The American Diabetes Association currently recommends a less stringent target HbA1C, such as <8.0%, for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and comorbid conditions, such as CKD.³⁶ Table 1 provides a summary of glycemic target recommendations from several recent guidelines and consensus papers.^19,33,36

Table 1.

Select glycemic target recommendations for patients with DKD

Guideline/Consensus Report	Recommendations/Suggestions
ADA standards of medical care in diabetes 201736	Less stringent HbA1C goals (such as <8%) may be appropriate for patients with advanced complications, including CKD
DKD: a report from an ADA consensus conference19	HbA1C<8% when GFR<60 ml/min per 1.73 m2 due to increased hypoglycemia risk
	Reliance on SMBG in making treatment decisions due to imprecision of HbA1C
KDOQI clinical practice guideline for diabetes and CKD: 2012 update33	Recommend not treating to an HbA1C of <7.0% in patients at risk of hypoglycemia
	Suggest that target HbA1C be extended above 7.0% in individuals with comorbidities or limited life expectancy and risk of hypoglycemia, such as those with CKD

ADA, American Diabetes Association; KDOQI, Kidney Disease Outcomes Quality Initiative.

Antihyperglycemic Medications: Considerations in the Setting of CKD

Despite lingering uncertainties concerning glycemic monitoring and adjustment of targets, glycemic management and CV risk reduction remain essential cornerstones of DM management in patients with CKD. Given the increased risk for hypoglycemia and potential for altered metabolism and kidney clearance of antihyperglycemic drugs, prudent use of available agents is appropriate. Table 2 provides a summary of dosing recommendations for noninsulin therapies currently available in the United States in patients with DM and CKD.^19,37,38

Table 2.

Dosing recommendations for noninsulin antihyperglycemic agents currently available in the United States in the setting of CKD^19,37,38

Medication	Recommended Dosing with Impaired GFR, ml/min per 1.73 m2
Biguanides
Metformin	No dose adjustment if eGFR>45
	Do not initiate or assess risk/benefit if currently on metformin if eGFR=30–45
	Discontinue if eGFR<30
Second generation sulfonylureas
Glipizide	No dose adjustment required
Glimepiride	Initiate conservatively at 1 mg daily
Glyburide	Avoid use
Meglitinides
Repaglinide	Initiate conservatively at 0.5 mg with meals if eGFR<30
Nateglinide	Initiate conservatively at 60 mg with meals if eGFR<30
Thiazolidinediones
Pioglitazone	No dose adjustment required
Rosiglitazone	No dose adjustment required
α-Glucosidase inhibitors
Acarbose	Avoid if eGFR<30
Miglitol	Avoid if eGFR<25
GLP-1 RAs
Exenatide	Not recommended with eGFR<30
Liraglutide	No dose adjustment recommended by manufacturer
Lixisenatide	No dose adjustment required for eGFR=60–89
	No dose adjustment required for eGFR=30–59, but patients should be monitored for AEs and changes in kidney function
	Clinical experience is limited with eGFR=15–29; patients should be monitored for AEs and changes in kidney function
	Avoid if eGFR<15
Albiglutide	No dose adjustment required for eGFR=15–89 per manufacturer
Dulaglutide	No dose adjustment recommended by manufacturer
DPP-4 inhibitors
Sitagliptin	100 mg daily if eGFR>50
	50 mg daily if eGFR=30–50
	25 mg daily if eGFR<30
Saxagliptin	5 mg daily if eGFR>50
	2.5 mg daily if eGFR≤50
Linagliptin	No dose adjustment required
Alogliptin	25 mg daily if eGFR>60
	12.5 mg daily if eGFR=30–60
	6.25 mg daily if eGFR<30
Amylinomimetic
Pramlintide	Specific guidelines for dosage adjustment in CKD are not available
SGLT-2 inhibitors
Canagliflozin	No dose adjustment required if eGFR≥60
	100 mg daily if eGFR=45–59
	Avoid use and discontinue in patients with eGFR persistently <45
Dapagliflozin	Avoid initiating if eGFR<60
	Not recommended with eGFR=30–60
	Contraindicated with eGFR<30
Empagliflozin	No dose adjustment required if eGFR≥45
	Avoid use and discontinue in patients with eGFR persistently <45

AE, adverse event.

Update on Use of Conventional Antihyperglycemic Agents in Diabetes and CKD

Metformin

In the year 2016, the US Food and Drug Administration (FDA) revised warnings regarding the use of metformin in patients with DKD.³⁷ Revisions made to the prescribing information for metformin-containing products included indicating that metformin may be safely used in patients with mild to moderate “renal impairment” and recommending that serum creatinine–based eGFR be used as the standard measure of kidney function for metformin dose adjustments as opposed to serum creatinine, such as was previously recommended.³⁷ This labeling change represents the first time that the FDA has amended their recommendations for the use of metformin in CKD since the drug was approved in the United States in 1995 (Table 3).³⁷ Of note in the revised labeling, metformin should still be used cautiously in patients with heart failure or liver disease and during acute illness and/or instances of tissue hypoxia, where the risk of lactic acid accumulation is increased.^39,40 However, a recent systematic review of metformin use in patients with moderate to severe DKD with congestive heart failure or chronic liver disease with associated hepatic impairment showed that metformin use was associated with reduced all-cause mortality.⁴¹ Specific clinical data on the risk of metformin-associated lactic acidosis in patients with DKD are limited, with current evidence suggesting that the overall risk is low.⁴⁰

Table 3.

2016 Revised recommendations for metformin use in patients with impaired renal function³⁷

eGFR, ml/min per 1.73 m2	FDA Recommendations for Metformin Use
>45	No contraindications
	Obtain eGFR at least annually
30–45	Starting metformin is not recommended
	Assess the benefits and risks of continuing treatment for patients currently receiving metformin
<30	Contraindicated
Metformin should be discontinued in patients with	History of liver disease, alcoholism, or heart failure
	Upcoming iodinated contrast imaging procedure and eGFR between 30 and 60 ml/min per 1.73 m2 (may restart 48 h after procedure if kidney function stabilizes)
	Upcoming administration of intra-arterial iodinated contrast (may restart 48 h after procedure if kidney function stabilizes)

Obtain an eGFR before initiating metformin therapy.

Insulin

In contrast to endogenously secreted insulin, which undergoes substantial degradation in the liver, exogenous insulin is to a larger degree eliminated by the kidneys.⁴² Insulin is filtered at the glomerulus followed by reabsorption in the proximal tubule. There is also uptake and degradation of insulin by peritubular endothelial cells.⁴³ Insulin clearance decreases in parallel with a decrease in GFR, leading to an overall decrease in exogenous insulin requirements.^44,45 Because specific insulin preparations have not been well studied in CKD and because individual patient needs vary substantially, no definitive guidelines exist for insulin dose adjustments on the basis of eGFR. Because of the lack of evidence for many of the oral and noninsulin injectable antihyperglycemic agents, however, insulin therapy is a mainstay of therapy in patients with CKD. It is essential that blood glucose levels be monitored closely and that insulin doses be individualized on the basis of each patient’s glycemic response and patterns, with a mindful approach to titration to minimize the risk of hypoglycemic events in this high-risk population.

Sulfonylureas and Meglitinides

Hypoglycemia is consistently a primary treatment concern with the sulfonylurea and meglitinide classes of medications but assumes particular importance in the setting of CKD.¹⁹ Glyburide is extensively metabolized in the liver into several active metabolites that are excreted by the kidney and is not recommended for use in DKD.^33,46 Glimepiride is associated with less hypoglycemia when compared with glyburide and should be initiated at a low dose and titrated conservatively if used (refer to Table 2).⁴⁷ Glipizide, in contrast, is metabolized by the liver into several inactive metabolites, and its clearance and elimination half-life are not affected by a reduction in eGFR.⁴⁸ Accordingly, dose adjustments in patients with CKD are not necessary with glipizide, making it the sulfonylurea of choice in this population.¹⁹

Similarly, the main concern with meglitinide use in the setting of CKD is increased risk of hypoglycemia due to decreased renal clearance of the parent drugs and metabolites.¹⁹ Lower doses of meglitinides are required in CKD, with initial conservative dosing (Table 2).

Thiazolidinediones

Both pioglitazone and rosiglitazone are nearly completely metabolized by the liver.^49–51 Despite the lack of a need for dosage adjustments in patients with DKD (Table 2), thiazolidinedione use is generally avoided in the setting of DKD due to concerns of refractory fluid retention, higher BP, congestive heart failure, and increased fracture risk that have been observed with this medication class.^33,52

Considerations for Use of Newer Antihyperglycemic Agents in CKD

In the year 2008, the US FDA issued guidance for industry outlining expectations for evaluating CV risk in new antihyperglycemic therapies seeking approval for the treatment of T2DM.⁵³ Accordingly, several agents in the following antihyperglycemic classes have pending and/or available data pertaining to CV and kidney outcomes from dedicated CVOTs.

Dipeptidyl Peptidase-4 Inhibitors

All of the currently available dipeptidyl peptidase-4 (DPP-4) inhibitors are labeled for use in CKD, but sitagliptin, saxagliptin, and alogliptin require downward dose titration on the basis of eGFR.⁵⁴ Linagliptin, in contrast, does not require dose adjustment on the basis of kidney function.⁵⁵ DPP-4 inhibitors have been shown to lower HbA1C by approximately 0.5% in patients with CKD stages 3 and 4 (−0.52%; 95% confidence interval [95% CI], −0.64 to −0.39).⁵⁶ A potential renal sparing effect, as noted by a reduction in albuminuria with treatment, has been seen with all of the currently available DPP-4 inhibitors.^57–60 Whether effects on albuminuria are independent of changes in BP or glycemic changes is unknown.

Data from several CVOTs involving DPP-4 inhibitors have been reported (Table 4).^61–67 The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) showed that sitagliptin was noninferior to placebo for the primary composite CV outcome of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina (hazard ratio [HR], 0.98; 95% CI, 0.88 to 1.09; P<0.001).⁶¹ Sitagliptin was additionally shown to have no clinically significant effect on CV or CKD outcomes, irrespective of baseline eGFR, in another TECOS analysis.⁶²

Table 4.

Summary of CVOT data for DPP-4 inhibitors currently marketed in the United States

Agent	Trial Name (clinicaltrials.gov Identifier)	Summary of Key Findings
Sitagliptin61,62	TECOS (NCT00790205)	Sitagliptin was noninferior to placebo for the primary composite CV outcome (HR, 0.98; 95% CI, 0.88 to 1.09; P<0.001)
		Sitagliptin did not increase rates of hospitalization for heart failure compared with placebo (HR, 1.00; 95% CI, 0.83 to 1.20; P=0.98)
		Four-point major adverse CV event rates increase with lower baseline eGFR (3.52, 3.55, 5.74, and 7.34 events per patient-yr for stages 1–3b, respectively)
		Sitagliptin had no clinically significant effect on CV or CKD outcomes, irrespective of baseline eGFR
Saxagliptin63,64	SAVOR-TIMI 53 Trial (NCT01107886)	Saxagliptin was noninferior to placebo for the primary composite CV outcome (HR, 1.00; 95% CI, 0.89 to 1.12; P<0.001)
		More participants in the saxagliptin group were hospitalized for heart failure (HR, 1.27; 95% CI, 1.07 to 1.51; P<0.01)
		Saxagliptin treatment was associated with improvement and/or less deterioration in ACR categories from baseline to end of trial (P=0.02, P<0.001, and P=0.05 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively)
		Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR
Alogliptin65,66	EXAMINE (NCT00968708)	Alogliptin was noninferior to placebo for the primary composite CV outcome (HR, 0.96; upper boundary of the one-sided 95% CI, 1.16; P<0.001)
		Hospital admission for heart failure was the first event in 85 (3.1%) patients taking alogliptin compared with 79 (2.9%) taking placebo (HR, 1.07; 95% CI, 0.79 to 1.46)
Linagliptin67	CARMELINA (NCT01897532)	Trial in progress; estimated completion in January of 2018

ACR, albumin-to-creatinine ratio; EXAMINE, Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome; CARMELINA, Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus.

Likewise, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) Trial showed noninferiority for saxagliptin when compared with placebo on the primary composite outcome (HR, 1.00; 95% CI, 0.89 to 1.12; P<0.001).⁶³ In an assessment of kidney outcomes from the SAVOR-TIMI 53 Trial cohort, treatment with saxagliptin was associated with an improvement or less deterioration in albumin-to-creatinine ratio categories from baseline to the end of the trial (for participants with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria).⁶⁴ Improvements in albumin-to-creatinine ratio were observed in the absence of an effect on eGFR and were not explained by improvements in glycemic parameters alone. The SAVOR-TIMI 53 Trial reported an increase in hospitalization for heart failure with saxagliptin when compared with placebo (HR, 1.27; 95% CI, 1.07 to 1.51; P=0.01).⁶³ In response to these findings, a meta-analysis of randomized clinical trials of DPP-4 inhibitors was conducted showing the overall risk of acute heart failure to be higher in patients treated with DPP-4 inhibitors versus those treated with placebo or an active comparator.⁶⁸ However, this observation was not externally validated by analysis of congestive heart failure admissions in clinical practice on the basis of “real world” large administrative datasets from Canada, the United Kingdom, and the United States.⁶⁹ Several ongoing DPP-4 inhibitor trials will soon provide additional data related to health outcomes with these agents in patients with DKD. The Efficacy, Safety and Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with Linagliptin Study and the Renal Effects of DPP-IV Inhibitor Linagliptin in Type 2 Diabetes Study are investigating potential for “renoprotective” effects of these agents.^70,71

Glucagon-Like Peptide-1 Receptor Agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) mimic the action of endogenous glucagon-like peptide-1, thus enhancing insulin secretion, inhibiting inappropriate glucagon secretion from pancreatic α-cells, delaying gastric emptying, and inducing satiety.⁷² The use of GLP-1 RAs, in general, has increased in recent years due to benefits of better glycemic control, low risk of hypoglycemia, and weight loss.⁷² Of importance in the setting of CKD, GLP-1 RA use has been associated with postmarketing reports of decreased kidney function, but such events have not been uniformly observed in clinical trials or population-based observational studies.^73–75 The majority of case reports of altered kidney function with exenatide have involved at least one contributory factor, such as congestive heart failure, pancreatitis, infection, volume depletion, and/or the use of concomitant medications, such as diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, and nonsteroidal anti-inflammatory drugs.⁷⁶ Additionally, patients who experience gastrointestinal adverse events (i.e., nausea, vomiting, and diarrhea) associated with GLP-1 RA treatment seem to be at greatest risk.

Two agents within the GLP-1 RA class of medications, liraglutide and lixisenatide, currently have CVOT data available as summarized in Table 5.^77–81 The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) Trial showed that the addition of lixisenatide to usual care did not significantly alter the rate of major CV events or other serious adverse events.⁷⁸ The primary composite end point of CV-related death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 13.4% of the lixisenatide group compared with 13.2% of those receiving placebo (HR, 1.02; 95% CI, 0.89 to 1.17; P<0.001 for noninferiority). In contrast, in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) Study, fewer patients experienced the primary composite CV outcome in the liraglutide group when compared with those receiving placebo (HR, 0.87; 95% CI, 0.78 to 0.97; P=0.01 for superiority).⁷⁷ Why the ELIXA Trial and the LEADER Study showed different outcomes in terms of the primary composite CV outcome is unknown. Pending CVOTs from other agents in the GLP-1 RA class should shed additional light on these differences.

Table 5.

Summary of CVOT data for GLP-1 RAs currently marketed in the United States

Agent	Trial Name (clinicaltrials.gov Identifier)	Summary of Key Findings
Liraglutide77	LEADER Study (NCT01179048)	The primary composite CV outcome occurred in significantly fewer patients in the liraglutide group (13.0%) than the placebo group (14.9%; HR, 0.87; 95% CI, 0.78 to 0.97; P=0.01 for superiority)
		Fewer patients died from CV causes in the liraglutide group (4.7%) than the placebo group (6.0%; HR, 0.78; 95% CI, 0.66 to 0.93; P<0.01)
		Death from any cause was lower in the liraglutide group (8.2%) than the placebo group (9.6%; HR, 0.85; 95% CI, 0.74 to 0.97; P=0.02)
Lixisenatide78	ELIXA Trial (NCT01147250)	Lixisenatide was noninferior to placebo for the primary composite CV outcome (HR, 1.02; 95% CI, 0.89 to 1.17; P<0.001)
		No significant between-group differences in the rate of hospitalization for heart failure (HR, 0.96; 95% CI, 0.75 to 1.23)
Exenatide79	EXSCEL (NCT01144338)	Trial in progress; estimated completion in April of 2018
Dulaglutide80	REWIND (NCT01394952)	Trial in progress; estimated completion in July of 2018
Albiglutide81	HARMONY Outcomes (NCT02465515)	Trial in progress; estimated completion in May of 2019

EXSCEL, Exenatide Study of Cardiovascular Event Lowering Trial; REWIND, Researching Cardiovascular Events with a Weekly Incretin in Diabetes; HARMONY Outcomes, A Long Term, Randomised, Double Blind, Placebo-controlled Study to Determine the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus.

Studies in patients with DKD have additionally shown that liraglutide lowered albuminuria levels in patients with normal kidney function or early-stage CKD⁸² and that liraglutide treatment did not adversely affect eGFR and showed improved glycemic control in patients with T2DM and CKD stage 3.⁸³ Recently released data from the LEADER Study as well as clinical trials of semaglutide and dulaglutide consistently show reduced risk of albuminuria onset and progression.^77,84,85 The consistency of these data across GLP-1 RA class strongly suggests a class effect toward protection against DKD. The mechanisms of action may be multifactorial from lower levels of glycemia and body weight to direct effects on the kidney.

Additional data-pending trials involving GLP-1 RA in the setting of DKD include the Effect of LIXIsenatide on the Renal System (ELIXIRS) Study and the Assessment of Weekly Administration of Dulaglutide in Diabetes-7 (AWARD-7) Study.^86,87 The ELIXIRS Study will explore the effects of lixisenatide treatment on kidney function and biomarkers in participants with T2DM. The AWARD-7 Study will soon report findings related to the efficacy and safety of dulaglutide for glycemic management as well as DKD progression in patients with T2DM and CKD stages 3 and 4. Importantly, the AWARD-7 Study also has a nested validation study of HbA1C that will inform modification and use of this glycemic biomarker in patients with low eGFR.

SGLT-2 Inhibitors

SGLT-2 is overexpressed in hyperglycemic conditions and paradoxically, increases proximal tubular maximum capacity for glucose reabsorption.^13,14 By blocking SGLT-2, this class of medication reduces glucose and sodium reabsorption, resulting in decreased glomerular hyperfiltration and lessening of glomerular hypertension by reducing tubuloglomerular feedback (Figures 1 and 2).^88,89 At present, clinically available SGLT-2 inhibitors in the United States are canaglifozin, dapaglifozin, and empaglifozin. Several additional agents are in clinical development and/or available commercially outside of the United States. Placebo-controlled studies have shown adjusted mean treatment differences in HbA1C of approximately −0.5%–0.7% with SGLT-2 inhibitor use.^90–92 Among the patients with DKD, this effect on HbA1C was attenuated and dropped to approximately −0.40% in patients with eGFR=30–60 ml/min per 1.73 m² in studies involving canaglifozin and empaglifozin.^93,94 The BP-lowering effect of SGLT2 inhibition seems to be a class effect and has been reported for empaglifozin, dapaglifozin, and canaglifozin. Likewise, clinical trial data are available for each of the currently available SGLT-2 inhibitors showing a reduction in albuminuria with treatment.^94–97

The Empaglifozin Cardiovascular Outcomes, and Mortality in Type 2 Diabetes Clinical Trial recently showed that empaglifozin significantly lowered rates of death from CV causes (4% versus 6%; 38% relative risk reduction), hospitalization for heart failure (3% versus 4%; 35% relative risk reduction), and death from any cause (6% versus 8%; 32% relative risk reduction) in patients with T2DM and CV already receiving standard of care for treatment of BP and lipids.⁹⁸ Post hoc analyses of the same trial showed beneficial effects on the kidney, including reduction of albuminuria, slowing of eGFR decline, and a 50% reduction in risk of progressing to ESRD.⁹⁹ CVOT data for canagliflozin and dapagliflozin are currently pending as shown in Table 6.^98–101 An additional study, the Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy (CREDENCE) Trial, is underway to assess whether treatment with canagliflozin can reduce DKD progression. The CREDENCE Trial is anticipated to be completed in approximately the year 2019.¹⁰²

Table 6.

Summary of CVOT data for SGLT-2 inhibitors currently marketed in the United States

Agent	Trial Name (clinicaltrials.gov Identifier)	Summary of Key Findings
Empagliflozin98,99	EMPA-REG Outcome Trial (NCT01131676)	The primary composite CV outcome occurred in significantly fewer patients in the empagliflozin group (10.5%) than the placebo group (12.1%; HR, 0.86; 95% CI, 0.74 to 0.99; P=0.04 for superiority)
		The empagliflozin group had significantly lower rates of death from CV causes (3.7% versus 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction)
		Doubling of SCr occurred in 1.5% of the empagliflozin group and 2.6% of the placebo group (44% relative risk reduction)
		Progression to macroalbuminuria occurred in 11.2% of the empagliflozin group and 16.2% of the placebo group (38% relative risk reduction)
		RRT was initiated in 0.3% of the empagliflozin group and 0.6% of the placebo group (55% relative risk reduction)
Canagliflozin100	CANVAS (NCT01032629)	Trial completed in February 2017; results pending
Dapagliflozin101	DECLARE-TIMI-58 (NCT01730534)	Trial in progress; estimated completion in April of 2019

SCr, serum creatinine; CANVAS, Canagliflozin Cardiovascular Assessment Study; DECLARE-TIMI-58, Dapagliflozin Effect on Cardiovascular Events.

Glycemic management in patients with DM and CKD is complicated by many factors, including imprecision of HbA1C measurement and altered pharmacokinetics of antihyperglycemic agents. Appropriate glycemic goal setting and use of SMBG are critical to meet individualized glycemic goals and avoid hypoglycemic events in this at-risk population. A growing body of literature is providing insight into the CV and kidney safety of antihyperglycemic agents with the DPP-4 inhibitor, GLP-1 RA, and SGLT-2 inhibitor classes of medications. Additional ongoing trials examining the use of these agents in the CKD population will further inform the use of antihyperglycemic medications in patients with DM and kidney disease.

Disclosures

J.J.N. has received consulting fees from Eli Lilly and Company, Indianapolis, IN, Sanofi, Paris, France, Novo Nordisk, Plainsboro, New Jersey, and Boehringer Ingelheim, Ridgefield, CT. R.Z.A. has no relevant conflicts to report. K.R.T. has received consulting fees from Eli Lilly and Company, Indianapolis, IN, Amgen, Thousand Oaks, CA, Noxxon Pharma, Berlin, Germany, and Boehringer Ingelheim, Ridgefield, CT.