Glucose lowering and kidney protection: can we hit 2 birds with 1 stone?






Mark E. COOPER
MBBS, PhD, FRACP
Baker IDI Heart & Diabetes Institute,
Melbourne AUSTRALIA

Glucose lowering and kidney protection: can we hit
2 birds with 1 stone?


by M. E. Cooper, Australia



Epidemiological as well as clinical trial data have emphasized the central role of glucose in promoting microvascular complications, including diabetic nephropathy. Over the last 20 years, the mechanisms for such glucose-promoted development of renal complications have been extensively investigated and well described. Recent data from the ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) demonstrates powerful effects of improving glycemic control with a gliclazide MR–based regimen on a range of renal end points, including urinary albumin excretion and the development of end-stage renal disease. It is likely that the best approach to retard or reverse diabetic nephropathy will involve a multifactorial approach which includes not only glucose-lowering agents, but also therapies that address other risk factors such as hypertension. These studies emphasize not only the importance of glycemic control in the development and progression of diabetic complications, including nephropathy, but also highlight the role of therapies that improve glycemic control in retarding diabetic kidney disease.

Medicographia. 2013;35:48-52 (see French abstract on page 52)



Historically, the diagnosis of diabetes has been based on the level of hyperglycemia that is associated with the development of microvascular complications, including nephropathy.1 Thus, there has been a long-standing view that hyperglycemia per se is directly linked to the pathogenesis and progression of diabetic nephropathy. Initial observational studies, including the seminal findings by Pirart, clearly demonstrated that elevated glucose levels were associated with an increased prevalence of a range of diabetic complications.2 Subsequent studies, such as the landmark trial DCCT (Diabetes Control and Complications Trial) and its follow up study EDIC (Epidemiology of Diabetes Interventions and Complications), clearly showed that intensified glycemic control had a sustained beneficial effect on the development of diabetic nephropathy.3-5 These findings were observed in cohorts of type 1 diabetic subjects with or without microvascular complications at the time of randomization.

A more recent analysis of the EDIC cohort confirms long-term renal benefits of prior intensification of glycemic control with a lower glomerular filtration rate in those subjects in the conventionally treated groups.6 However, that study was underpowered to determine if this improvement in renal end points would ultimately lead to less end-stage kidney disease.

Nevertheless, there has always been a need for significant caution in extrapolating findings from type 1 diabetic subjects to the much larger clinical group, those with type 2 diabetes.

The UKPDS (United Kingdom Prospective Diabetes Study) clearly showed that in a group of newly diagnosed type 2 diabetic subjects there were significant benefits to optimizing glycemic control with sulfonylurea- and insulin-based regimens on various microvascular complications, including nephropathy.7 However, the appropriate thresholds for instituting intensification of glycemic control and the appropriate contemporary glycemic targets, specifically in terms of glycated hemoglobin (HbA1c), that clinicians should achieve to reduce the development and progression of nephropathy were not known. Thus, studies such as the ADVANCE trial (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation),8 as outlined below, were instituted to address these questions.

Over the last 20 years, there has been a significant advance in our understanding of how glucose itself promotes renal damage (Figure 1).9 It is clear that not only does hyperglycemia play a key role in promoting renal injury, but glucose appears to interact with other stimuli, such as hemodynamic factors clinically manifesting as systemic hypertension, to enhance damage of the various heterogeneous cell populations within the kidney.9,10

Glucose promotes the generation of reactive oxygen species which activate intracellular signaling molecules and enhance expression of growth factors and cytokines leading to increased extracellular matrix accumulation, albumin leakage, and inflammation in the diabetic kidney.11,12 Additional glucose-dependent pathways have been identified during the last 2 decades, including the generation of advanced glycation end products as a result of chronic hyperglycemia, and activation of intracellular signaling molecules such as protein kinase C and nuclear factor κB (NF-κB). These pathways are also activated by glucose-related stimuli such as angiotensin II, inducing a perpetuating cycle of progressive kidney injury. Thus, one can speculate that control of hyperglycemia should attenuate the deleterious impact of activation of these prosclerotic and pro-inflammatory pathways within the kidney, reducing the functional and structural manifestations of diabetic nephropathy, including albuminuria, declining renal function, glomerulosclerosis, and tubulointerstitial fibrosis.





Figure 1
Figure 1. Schema outlining interactions among hemodynamic
factors, metabolic pathways, intracellular signaling molecules,
and cytokines in mediating diabetic complications.

Abbreviations: CTGF, connective tissue growth factor; NF-κ B, nuclear factor
κ B; TGF-, transforming growth factor β.
Adapted from reference 9: Cooper. Diabetologia. 2001;44(11):1957-1972.
© 2001, Springer-Verlag.



The ADVANCE study has been able to directly address the relative roles of blood pressure and glucose-lowering therapies in retarding and potentially reversing complications as a result of type 2 diabetes. This multinational, multiethnic study of over 11 000 type 2 diabetic subjects included a glucose control arm which involved a stepped-care approach based on first-line antidiabetic therapy with the sulfonylurea gliclazide MR.13 In this study using conventional approaches to optimize glycemic control, which was able to achieve over several years a net reduction in HbA1c of approximately 0.7%, it was possible to specifically test if a reduction in HbA1c would translate to a reduction in renal end points.13

In the initial analysis, microvascular end points including nephropathy were included as a component of the primary end point of the study, which was a composite end point of both microvascular and macrovascular complications. Further analysis revealed that the major effect of improved glycemic control was on microvascular end points with additional exploration of the major findings of the study emphasizing benefits on renal rather than retinal outcomes.13 Specifically, there was a 21% decrease in new-onset nephropathy, defined as a composite of the development of macroalbuminuria, doubling of serum creatinine to equal or greater than 200 μM, the need for renal replacement therapy, and death due to renal disease (Figure 2).13 The major effect appeared to be the 30% decrease in development of macroalbuminuria. Furthermore, an additional renal secondary end point was the 9% decrease in development of microalbuminuria. This effect on microalbuminuria was further examined, and, indeed, not only was there a 10% reduction in progression of albuminuria, but also a 15% increase in regression, as defined by a reduction in albuminuria from the microalbuminuric to the normoalbuminuric range. Furthermore, detailed analyses are currently being performed with preliminary results indicating a >50% decrease in end stage kidney disease. Thus, it is clear that improvements in glycemic control have effects on prevention of early renal disease, as reflected by a reduction in microalbuminuria and a retardation in the progression from early to advanced renal disease, as defined by a decrease in progression to macroalbuminuria and/or end-stage kidney disease.


Figure 2
Figure 2. Effects of blood glucose lowering (ΔHbA1c). Hazard ratios and relative risk reductions are given for intensive glucose control
vs standard glucose control.

Adapted from reference 13: Patel et al. New Engl J Med. 2008;358:2560-2572. © 2008, Massachusetts Medical Society.



In the ADVANCE study, a close relationship between albuminuria and cardiovascular disease was identified.14 Not only an increase in baseline, but also an elevation in achieved urinary albumin excretion was associated with a higher risk of cardiovascular disease. Thus, it is possible that the renoprotective effects seen with intensified glycemic control will ultimately translate to cardiovascular protection. This link between impaired renal function and cardiovascular disease has been previously identified in various epidemiological studies and clinical trials.15,16 At this stage, no such benefit on macrovascular end points has been detected at the termination of the ADVANCE study, but it is postulated that such benefits of prior improvements in glycemic control on cardiovascular end points may become apparent during the follow-up study, known as ADVANCE- ON (ADVANCE post trial ObservatioNal study). The likelihood that benefits on renal end points may precede effects on cardiovascular disease is supported by the findings from the Steno-2 study where microvascular protection was seen after 4 years of multifactorial intervention,17 but cardiovascular benefits were only seen at the 8-year time point.18 Indeed, these benefits were sustained during follow-up after 13 years despite a 5-year return to less intensified conventional therapies associated with not only reduced cardiovascular events, but a decrease in overall mortality.19

The positive effects on microvascular complications seen in the ADVANCE study have also been seen in other clinical trials performed concurrently involving intensification of glycemic control. In the VADT (Veterans Affairs Diabetes Trial), optimization of glycemic control led to a reduction in urinary albumin excretion.20 Similar positive effects were seen in the ACCORD study (Action to Control CardiOvascular Risk in Diabetes) with intensified glycemic control leading to a delay in the onset of microalbuminuria.21 A recent meta-analysis has summarized the effects of improved glycemic control on renal end points.22 Indeed, these studies have emphasized the greater than 25% reduction in development of macroalbuminuria when one pools data not only from the VADT,20 ACCORD,21 and ADVANCE13 trials, but includes data from the Kumamoto23 and UKPDS7 trials. There was also a 30% decrease in end-stage renal disease (ESRD), but this did not reach statistical significance (except in ADVANCE; -65% ESRD; P=0.0224), probably because of the low rate of events in both the conventionally and intensively treated groups.

Although this report has focused on the glucose arm of the ADVANCE study, it needs to be appreciated that the development of diabetic complications is multifactorial in origin with blood pressure also playing a key role in the susceptibility to and rate of progression of diabetic complications including nephropathy.10 Indeed, blood pressure reduction using a perindopril/ indapamide-based regimen was very effective at reducing renal events.25 Furthermore, subsequent analysis revealed a close correlation between renal events and achieved systolic blood pressure.26 Recent analyses have been performed to assess the relative contributions of improvements in glycemic control and blood pressure on mortality and diabetic complications in the ADVANCE trial. Indeed, particularly with respect to nephropathy, both interventions had similar beneficial effects on renal end points with the combination of intensified glycemic control and antihypertensive therapy having additive effects on diabetic renal disease (Figure 3).27 This concept of multifactorial intervention has been previously demonstrated in the Steno-2 study where a regimen involving lipid-, glucose-, and blood pressure–lowering therapies was particularly effective at retarding microvascular and macrovascular complications, ultimately translating to a >50% decrease in mortality.19


Figure 3
Figure 3. Joint effects of blood pressure and glucose lowering in
ADVANCE.

Abbreviations: ADVANCE, Action in Diabetes and Vascular disease: PreterAx
and DiamicroN MR Controlled Evaluation; RRR, relative risk reduction.
Based on data from reference 27: Zoungas et al. Diabetes care. 2009;32:
2068-2074.



References
1. Tong PC, Kong AP, So WY, et al. The usefulness of the International Diabetes Federation and the National Cholesterol Education Program’s Adult Treatment Panel III definitions of the metabolic syndrome in predicting coronary heart disease in subjects with type 2 diabetes. Diabetes care. 2007;30:1206-1211.
2. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and last part) (author’s transl) [article in French]. Diabete Metab. 1977;3:245-256.
3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New Engl J Med. 1993; 329:977-986.
4. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. New Engl J Med. 2000;342:381-389.
5. The Epidemiology of Diabetes Interventions and Complications (EDIC) study group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy. JAMA. 2003;290:2159- 2167.
6. de Boer IH, Sun W, Cleary PA, et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. New Engl J Med. 2011;365:2366-2376.
7. 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.
8. ADVANCE Management Committee. Study rationale and design of ADVANCE: action in diabetes and vascular disease—Preterax and Diamicron MR controlled evaluation. Diabetologia. 2001;44:1118-1120.
9. Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia. 2001;44:1957-1972.
10. Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet. 1998;352:213-219.
11. Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes. 2008;57:1446-1454.
12. Thallas-Bonke V, Thorpe SR, Coughlan MT, et al. Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C--dependent pathway. Diabetes. 2008; 57:460-469.
13. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med. 2008; 358:2560-2572.
14. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813-1821.
15. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. New Engl J Med. 2004;351:1285-1295.
16. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. New Engl J Med. 2004;351:1296-1305.
17. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial interven tion in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet. 1999;353:617-622.
18. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. New Engl J Med. 2003;348:383-393.
19. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention onmortality in type 2 diabetes. New Engl J Med. 2008;358:580-591.
20. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. New Engl J Med. 2009;360:129-139.
21. 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.
22. Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med. 2012;172:761-769.
23. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23(suppl 2):B21-B29.
24. Zoungas S, Lambers Heerspink HJ, Chalmers J, et al. Intensive glucose lowering and end stage kidney disease: new data from the ADVANCE trial. Diabetologia. 2011;54(suppl 1):S23.
25. Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
26. de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol. 2009;20:883-892.
27. Zoungas S, de Galan BE, Ninomiya T, et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: new results from the ADVANCE trial. Diabetes Care. 2009;32:2068-2074.
28. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782-787.
29. Thomas MC, Cooper ME, Shahinfar S, Brenner BM. Dialysis delayed is death prevented: a clinical perspective on the RENAAL study. Kidney Int. 2003;63: 1577-1579.


Keywords: end-stage renal disease; glycemic control; diabetic nephropathy; HbA1c; type 2 diabetes