Issues of renal dysfunction and impairment significantly affect the management of diabetes, both in terms of glycemic targets and agent selection. Tight glycemic control from the time of diabetes diagnosis reduces the risk of developing diabetic nephropathy.1,2 However, an analysis of the ACCORD trial demonstrated a higher risk of hypoglycemia and cardiovascular disease associated with tight glycemic control in patients with type 2 diabetes and chronic kidney disease (CKD), with elevated risk for morbidity and mortality.3,4Among patients who receive dialysis, more than 40% experience severe hypoglycemia.5 Advanced kidney disease increases both the risk for and severity of hypoglycemia.6
Improving glycemic control has been shown to reduce microvascular complications; however, no clear evidence suggests that it will slow the progression of established chronic kidney disease. Therefore, glycemic targets should be tailored to the individual, with a goal of balancing the risk of hypoglycemia with potential improvement in microvascular complications, particularly among those patients who have diabetes and significant CKD (eGFR <30 ml/min/1.73 m2). Patients who receive dialysis are at high risk of hypoglycemia. Tight glycemic control for patients with severe renal failure or those on dialysis confers an increased risk of mortality, with only marginal survival benefits. For these reasons, attainment of a modest glycemic target is generally recommended, with a glycated hemoglobin (HbA1c) between 7% and 8.5% (53 and 68 mmol/mol).7,8
The risk for hypoglycemia is highest in elderly patients with renal dysfunction, particularly after inadequate carbohydrate consumption, following strenuous exercise, or with excess alcohol intake.9
Importantly, dialysis affects glycemic control through mechanisms that include clearing glucoregulatory hormones and antidiabetic drugs; altering insulin metabolism, resulting in fluctuations in uremia, acidosis, and phosphate metabolism; and directly changing blood glucose concentration via the dialysate. These features make glycemic control both complex and unpredictable.8
Given the high prevalence of chronic kidney disease in patients with type 2 diabetes, current guideline recommendations suggest taking CKD into account when selecting a second-line agent after metformin. In patients with CKD, SGLT2 inhibitors are recommended to reduce further CKD progression. If SGLT2 inhibitors are not tolerated, contraindicated, or if eGFR is less than adequate, GLP-1 receptor agonists with proven CVD benefit are recommended. It is important to consider a patient’s eGFR when selecting an agent as renal impairment can affect the efficacy and safety of these drug classes.10
- In the EMPA-REG study, participants with type 2 diabetes, cardiovascular disease (CVD), and an eGFR of >30 mL/min per 1.73m2, were randomized to receive either empagliflozin or placebo. Prespecified kidney outcomes included incident or worsening nephropathy (macroalbuminuria, doubling of creatinine, initiation of renal replacement therapy (RRT), or death from kidney disease) or new-onset albuminuria. New or worsening kidney disease occurred less frequently with empagliflozin compared with placebo (12.7% vs 18.8%; HR, 0.61; p<0.001). Empagliflozin therapy was also associated with fewer reports of doubling of creatinine (1.5% vs 2.6%; HR, 0.56) or RRT initiation (0.3% vs 0.6%; HR, 0.45).11
- In a randomized, placebo-controlled trial, canagliflozin was associated with a lower risk of progression of albuminuria (HR, 0.73; 95% CI, 0.67-0.79) and a reduction in the composite outcome of sustained 40% reduction in eGFR, need for RRT, or death from kidney causes (HR, 0.60; 95% CI, 0.47-0.77).12
GLP-1 Receptor Agonists
- In the SUSTAIN-6 trial of 3297 patients with type 2 diabetes and CVD or significant CV risk factors, new or worsening nephropathy was assessed over a 2-year period in patients randomized to semaglutide or placebo. The primary kidney outcome was a composite of time to the development of new-onset persistent macroalbuminuria, persistent doubling of serum creatinine and eGFR <45 mL/min per 1.73m2, end-stage renal disease, and death due to CKD. Rates of new or worsening nephropathy were significantly lower with semaglutide (HR, 0.64; 95% CI, 0.46-0.88; P<0.01). This reduction was largely the result of a decrease in new-onset macroalbuminuria with semaglutide compared to placebo (2.5% vs 4.9%, respectively).13
- In the LEADER trial of 9340 patients with type 2 diabetes at high risk of CVD, participants receiving liraglutide experienced a 22% reduction (P=0.003) compared with placebo in the same prespecified kidney outcome used in the SUSTAIN-6 trial. This benefit was driven by a 26% reduction in new-onset macroalbuminuria (HR, 0.74; 95% CI, 0.60-0.91; P=0.004).14
- A significant reduction in albuminuria was also noted in clinical trials of other GLP-1 RAs. Exenatide was associated with a reduction in new-onset macroalbuminuria (2.8% vs 2.2%; P=0.03) in patient with type 2 diabetes, 70% of whom had preexisting CVD.15 A trial with lixisenatide reported a modest reduction in albuminuria in 6068 patients with type 2 diabetes and recent admission for acute coronary syndrome.16 In a comparison of once weekly dulaglutide with insulin glargine in 576 subjects with type 2 diabetes and stage 3 or 4 CKD, dulaglutide use was associated with a significant reduction in albuminuria and a slowing of GFR decline in patients with macroalbuminuria at baseline.17
- Molitch ME, Steffes MW, Cleary PA, Nathan DM; Diabetes Control and Complications Trial Research Group. Baseline analysis of renal function in the Diabetes Control and Complications Trial. Kidney Int.1993;43:668-674.
- Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. 2000;321:405-412.
- Papademetriou V, Lovato L, Doumas M, et al. Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int. 2015;87:649-659.
- Alsahli M, Gerich JE. Hypoglycemia, chronic kidney disease, and diabetes mellitus.Mayo Clin Proc.2014;89:1564-1571.
- Rhee CM, Leung AM, Kovesdy CP, et al. Updates on the management of diabetes in dialysis patients.Semin Dial.2014;27:135-145.
- Moen MF, Zhan M, Hsu VD, et al. Frequency of hypoglycemia and its significance in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:1121-1127.
- National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850-886.
- Joint British Diabetes Societies for Inpatient Care. Management of adults with diabetes on the haemodialysis unit. April 2016. Available at www.diabetologists-abcd.org.uk/JBDS/JBDS_RenalGuide_2016.pdf
- Summary of product characteristics. Gliclazide (Diamicron MR). Servier Laboratories Ireland Ltd. November 2016. Available at medicines.org.uk/emc/product/1150/smpc
- American Diabetes Association. Standards of Medical Care in Diabetes – 2019. Diabetes Care. 2019;42(suppl 1):S90-S102.
- Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323-334.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.
- Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and kidney outcomes in type 2 diabetes. N Engl J Med. 2017;377:839-848.
- Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228-1239.
- Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247-57.
- Tuttle KR, Lakshmanan MC, Gross JL, et al. Comparable glycaemic control with once weekly dulaglutide versus insulin glargine, both combined with lispro, in type 2 diabetes and chronic kidney disease (AWARD-7). Diabetologia. 2017;60(Suppl 1):S3.