In results of five trials, effects of antihyperglycemic drug found to occur during first few months or years.
What is so unique about this information is that there is minimal recognition of this phenomenon in the medical literature, that during the first months or years of treatment with an antihyperglycemic drug, patients may experience worsening of renal function regardless of the agent used to lower blood glucose. Sequential changes in estimated glomerular filtration rate (or in serum creatinine) have been reported in at least five large-scale trials, using different antihyperglycemic agents.
Primary care physicians and specialists alike should be aware that, although control of hyperglycemia reduces the risk of nephropathy in type 2 diabetes, treatment can cause an early reduction in glomerular filtration rate. It may take several years for the benefit of glycemic control on the course of nephropathy to improve. The most persuasive evidence supporting the occurrence of early worsening of renal function after initiation of treatment with antidiabetic drugs is derived from five randomized controlled clinical trials with different antihyperglycemic agents.
Prolonged hyperglycemia in type 2 diabetes exerts adverse structural and functional effects on the kidney, and sustained lowering of blood glucose for a decade or longer has been shown to reduce the risk of progression to end-stage renal disease.1 However, during the first months or years of treatment with an antihyperglycemic drug, patients may experience worsening of renal function regardless of the agent used to lower blood glucose.
In the ADVANCE trial, 3 11,140 patients with type 2 diabetes were randomly assigned to intensive or standard glycemic control for five years. The primary intervention used to achieve target levels of glycated hemoglobin in the intensive glycemia group was the sulfonylurea gliclazide. At the end of two years, the absolute incremental reduction in glycated hemoglobin between the two groups was 0.6%. Critical decreases in glomerular filtration rate (defined as a doubling of serum creatinine) were observed more frequently in the intensive control group than in the standard treatment group during the first two years. In contrast, after three to five years of follow-up, such critical declines in renal function were seen more commonly in the standard treatment group.
In the ACCORD trial,4 10,251 patients with type 2 diabetes were randomly assigned to intensive or conventional glycemic control and followed for a median of 3.7 years. Target levels of glycated hemoglobin in the intensive arm were generally achieved with insulin and rosiglitazone. At the end of two years, the absolute difference in glycated hemoglobin between the two groups was 1.2%. However, during the first three years of treatment, the patients receiving intensive therapy had higher serum creatinine concentrations than patients receiving standard treatment; this difference was observed as early as six months after randomization and persisted for 24 months. Intensive glycemic control was accompanied by lower concentrations of serum creatinine (when compared with standard treatment) after only three years of follow-up.
In the LEADER trial,7 9,340 patients were randomly assigned to placebo or liraglutide while 14,735 patients with type 2 diabetes in the TECOS trial5 were randomly assigned sitagliptin in the TECOS trial. They observed the same results that kidney function was reduced to start but after time, it improved along with better glucose control.
Finally, in the EMPA-REG trial,8 7,020 patients with type 2 diabetes were randomly assigned to placebo or the sodium-glucose cotransporter 2 inhibitor empagliflozin for a median of 2.6 years. After two years, the absolute difference between the two groups in glycated hemoglobin was 0.4%. Initiation of treatment with the sodium-glucose cotransporter 2 inhibitor was accompanied by a striking decline in glomerular filtration rate, which was apparent after only four weeks and persisted for one year. However, when treatment was maintained for 18 months or longer, the glomerular filtration rate was improved in the empagliflozin group (when compared with placebo), and progression to end-stage kidney disease was less common in patients treated with empagliflozin.
Early worsening of renal function is likely to be related to the lowering of blood glucose. Hyperglycemia causes an increase in the filtration of glucose, which (by activation of sodium-glucose cotransporter 2 in the proximal tubule) increases the proximal tubular reabsorption, thereby reducing the delivery of sodium to the macular densa and eliciting an increase in the glomerular filtration rate (via tubuloglomerular feedback).9 Hyperglycemia may also induce the release of vasoactive factors (nitric oxide and angiotensin) that may modulate afferent and efferent arteriolar tone so as to increase the glomerular filtration rate.10 Regardless of the mechanism, by lowering blood glucose, treatment with antihyperglycemic drugs would be expected to reduce the proximal tubular reabsorption of sodium, increase sodium delivery to distal segments, and reduce glomerular hyperfiltration.9, 10 This action likely accounts for the early decline in glomerular function observed in large-scale trials.
If glycemic control can be maintained for years, the amelioration of glomerular hyperfiltration might be expected to slow the progression of diabetic nephropathy.1 Such a mechanism explains why an improvement in renal function eventually emerges in the trials, typically after 2 years of follow-up. Late improvement in glomerular function was seen in every trial, except one with sitagliptin.5 This lack of late benefit with dipeptidyl peptidase-4 inhibitors is possibly explained by the fact that their long-term use was associated with the most modest between-group difference in glycated hemoglobin among the large-scale studies.
Physicians should be aware that treatment with glucose-lowering drugs can cause an early reduction in glomerular filtration rate and that it may take several years for the favorable effects of sustained glycemic control on the course of nephropathy to improve.
- Medical professionals in diabetes care need to be aware that it could take up to 2-3 years for the kidney function to begin to improve.
- It may take several years for the benefit of glycemic control on the course of nephropathy to improve.
- Glucose control is critical to prevent kidney disease and end-stage renal disease.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
US Department of Health and Human Services Food and Drug Administration. Guidance for Industry. Diabetes Mellitus. Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Silver Spring, MD: Center for Drug Evaluation and Research; 2008.
Perkovic V, Heerspink HL, Chalmers J, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013;83:517-523.
Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419- 430.
Cornel JH, Bakris GL, Stevens SR, et al. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS. Diabetes Care. 2016;39:2304- 2310.
Cooper ME, Perkovic V, McGill JB, et al. Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of the dipeptidyl peptidase 4 inhibitor linagliptin in type 2 diabetes. Am J Kidney Dis. 2015;66:441-449.
Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377:839-848.
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.
Pessoa TD, Campos LC, Carraro-Lacroix L, Girardi AC, Malnic G. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol. 2014;25:2028- 2039.
Hallow KM, Gebremichael Y, Helmlinger G, Vallon V. Primary proximal tubule hyperreabsorption and impaired tubular transport counterregulation determine glomerular hyperfiltration in diabetes: a modeling analysis. Am J Physiol Renal Physiol. 2017 May 1;312(5):F819-F835. doi: 10.1152/ajprenal.00497.2016. Epub 2017 Feb 1.