Primary prevention of chronic kidney disease: managing diabetes mellitus to reduce the risk of progression to CKD

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1 Primary prevention of chronic kidney disease: managing diabetes mellitus to reduce the risk of progression to CKD Date written: July 2012 Author: Kate Wiggins, Graeme Turner, David Johnson GUIDELINES We suggest that patients with diabetes mellitus aim to achieve an HbA1c <7.0% or <53 mmol/mol* (2B). * SI units recommended as per The International HbA1c Consensus Committee [1, 2] UNGRADED SUGGESTIONS FOR CLINICAL CARE There are no ungraded statements IMPLEMENTATION AND AUDIT KCAT education programs for primary health care providers should incorporate the CARI Early CKD Diabetes Mellitus recommendations. Primary health care practitioners should regularly audit their practices to ascertain the proportion of their diabetic patient population that meets the KHA-CARI Early CKD Guideline HbA1c targets for primary prevention of CKD. BACKGROUND Diabetes mellitus (DM) is well-recognised as a risk factor for development of chronic kidney disease (CKD). Furthermore, amongst patients with DM glycaemic control, most commonly assessed by measurement of the glycosylated haemoglobin (HbA1c) modulates the risk of developing diabetic nephropathy. In particular, elevated HbA1c levels increase the likelihood of renal disease. Several treatments for DM are available. These include oral hypoglycaemic agents (sulfonylureas, glitinides, metformin, glitazones, α-glucosidase inhibitors), incretin enhancers and mimetics, and insulin. Available insulin preparations include very short-, short-, intermediate- and long-acting agents. While all diabetic treatments aim to reduce blood glucose levels they have a diverse range of mechanisms of action with potential benefits and harms that extend beyond their glucose lowering activity. These differences may translate into variable effects on clinical outcomes. In this Guideline the currently available evidence regarding the role of treatment of DM in primary prevention of CKD is evaluated. Particular emphasis is placed on the relationship between glycaemic control and development of CKD, and on benefits of specific treatment regimens. SEARCH STRATEGY Databases searched: Text words for chronic kidney disease were combined with MeSH terms and text words for diabetes mellitus. The search was carried out in Medline (1966 August 2009). No language restrictions were placed on the search. The conference proceedings of the American Society of Early Chronic Kidney Disease July 2012 Page 1 of 9

2 Nephrology from were also searched for trials. Search update was carried out in Medline ( ). Text words and MeSH terms for kidney disease and renal insufficiency were combined with text words and MeSH terms for diabetes mellitus and glycosylated haemoglobin. Date of search/es: August 2009; February 2012 WHAT IS THE EVIDENCE? Trial (DCCT) was a multicentre, randomised trial comparing intensive versus conventional insulin therapy in 1441 patients with Type I DM (Insulin-requiring diabetes mellitus; IDDM) [3]. The study population was divided into 2 cohorts, primary prevention and secondary intervention. Inclusion criteria for the primary prevention cohort were urinary albumin excretion (UAE) less than 40mg per 24 hours, IDDM for 1 to 5 years, and absence of retinopathy. A total of 726 patients met the inclusion criteria for primary prevention, of which 378 were randomised to conventional therapy and 348 to intensive therapy. Baseline creatinine clearance was 127±28 vs 128±30 ml/min in the conventional and intensive therapy groups, respectively, and UAE 12±8 vs12±9 mg/24 hours. Patients in the primary prevention cohort had a significantly lower HbA1c beyond baseline. The mean follow-up was 6.5 years (range 3-9). The number of patients who developed microalbuminuria (defined by the authors as UAE 40mg/ 24 hours, measured annually) was less in the intensive therapy group (P<0.001); the mean adjusted risk of microalbuminuria was reduced by 34% (P=0.04). Amongst the secondary intervention cohort who had baseline AER <40mg/ 24 hours, intensive therapy reduced the adjusted mean risk of developing microalbuminuria by 43% (P=0.001). In the entire study population advanced nephropathy (UAE 300mg/24 hours, creatinine clearance <70mL/min/1.73m 2 ) developed in 7 patients (2 in the intensive therapy and 5 in the conventional therapy group). Severe hypoglycaemic episodes were more common in the intensive therapy group. The Epidemiology of Diabetes Interventions and (EDIC) was a long-term follow-up study of a subgroup of participants in the DCCT [4]. The 1349 patients (688 and 687 in the former conventional and intensive treatment cohorts respectively) were followed for a further 7 or 8 years at completion of the DCCT. During the course of the EDIC study the mean HbA1c levels in the two cohorts approached each other but remained statistically different (8.0 vs 8.2% for the intensive and conventional groups respectively, P=0.002). In patients who had normoalbuminuria (AER <28 µg/min or 40 mg/24 hours) at DCCT commencement and completion, 6.8% of the former intensive therapy group developed microalbuminuria (AER >40mg/24 hours) compared to 15.8% of the former conventional therapy group. Albuminuria (AER >300mg/24 hours) developed in 1.4% and 9.4% of atrisk patients in the former intensive and conventional treatment cohorts by EDIC completion. An increase in the serum creatinine to above 2 mg/dl (176.8 µmol/l) occurred in 0.7% of the intensive group and 2.8% of the conventional group (P=0.004). Statistically significant differences in the mean serum creatinine throughout the EDIC study were also observed (0.89 vs 0.92 mg/dl (78.7 vs 8.13 µmol/l), P<0.001). Despite more frequent hypoglycaemic episodes in the intensive treatment group there was no long-term effect on cognition [5]. The United Kingdom Prospective (UKPDS) was a randomised controlled trial conducted between 1977 and 1997 that compared conventional therapy (diet alone) with intensive therapy (insulin, glibenclamide, glipizide, metformin or chlorpropamide as monotherapy or combination therapy) in 3,867 patients with newly diagnosed type 2 diabetes [6, 7]. Median follow-up was 10.0 years. Data was presented separately for intensive therapy with insulin, sulfonylureas or chlorpropamide versus conventional therapy, and metformin versus conventional therapy. The median HbA1c was 7.0% for intensive therapy with insulin, chlorpropamide and sulfonylureas versus 7.9% conventional therapy, and 7.4% for metformin vs 8.0% for the conventional group. Amongst a subgroup of patients treated with chlorpropamide, glibenclamide or insulin, (and conventional therapy controls) microalbuminuria was consistently more common in the conventional therapy group from 9 years onwards. No difference in microalbuminuria was seen between metformin and conventional therapy. There was no difference in the number of patients developing renal failure (dialysis or plasma creatinine > 250 mol/l) or dying from renal disease either between conventional Early Chronic Kidney Disease July 2012 Page 2 of 9

3 and intensive therapy groups, or agents used in intensive therapy. Hypoglycaemic episodes were more common in patients receiving intensive therapy. A cohort of 3227 patients entered a post-trial monitoring study. After 10 years of monitoring there was no difference in the urinary albumin: creatinine ratio between intensive and conventional treatment [8]. Plasma creatinine levels were 15% higher in patients treated with metformin than other groups. Sasaki and colleagues retrospectively evaluated risk factors for development of persistent microalbuminuria ( 2 consecutive positive tests for urine albumin ( 30 mg/dl) measured by Albustix in one year, in the absence of other renal disease) in patients with Type 2 diabetes mellitus [9]. Patients were first seen in a Japanese medical clinic between 1960 and 1979, and followed until 1984 (average follow-up 10 years). In total 1196 patients (740 males, 456 females) were evaluated. The mean annual incidence rate of persistent microalbuminuria differed significantly according to the type of treatment patients were on at baseline (10.74% vs 19.47% vs 40.78% for diet, oral hypoglycaemic agents and insulin respectively, P<0.01). Treatment with insulin was an independent predictor for development of microalbuminuria on logistic regression analysis. Limitations of this study include the retrospective nature, and absence of information about glycaemic control other than fasting glucose at baseline. The study does not establish whether insulin therapy is associated with an increased risk of developing microalbuminuria because it is a surrogate marker of poor glycaemic control and/ or duration of DM. Applicability to current practice may be limited because this study was conducted in a Japanese population. SUMMARY OF EVIDENCE Despite the high risk of developing CKD in patients with DM and recommendations for good glycaemic control there is very little evidence regarding treatment of DM and prevention of CKD. Three studies have evaluated the relationship between diabetes management and prevention of CKD. The DCCT was a well-designed RCT involving a large number of patients. It showed that intensive treatment with insulin reduced the risk of developing microalbuminuria, although the definition of microalbuminuria differed to the current NKF definition. This benefit was sustained in a further 7-8 years of follow-up despite convergence of HbA1c levels. The overall rate of microalbuminuria in the DCCT/ EDIC cohort was lower than in other reported series, possibly due to a Hawthorne effect. This may reduce the applicability of the results to other populations. The relationship between glycaemic control and patient outcomes in type 2 diabetics was studied in the UKPDS trial. Microalbuminuria was less common with intensive therapy with glibenclamide, chlorpropamide or insulin than with conventional therapy, but no difference was seen with metformin therapy. Although a sustained beneficial effect of intensive therapy on overall patient outcomes was seen with intensive therapy following trial completion, this was not the case with renal outcomes. There is only one study addressing management of diabetes in the primary prevention of CKD. This was a retrospective cohort study with multiple limiting factors as discussed above. All studies in this area were commenced over 30 years ago. In light of modern treatment targets and newer therapeutic agents, this limits their applicability to current practice. WHAT DO THE OTHER GUIDELINES SAY? Kidney Disease Outcomes Quality Initiative:[10] 2.1 Target HbA1c for people with diabetes should be <7.0%, irrespective of the presence or absence of CKD (A) UK Renal Association: No recommendations. Canadian Society of Nephrology (CSN): [11] Targets for glycemic control, where they can be achieved safely, should follow standard Canadian Diabetes Association Guidelines (hemoglobin A1c < 7.0%, fasting plasma glucose 4 7 mmol/l) (grade B). Early Chronic Kidney Disease July 2012 Page 3 of 9

4 Glycemic control should be part of a multifactorial intervention strategy addressing blood pressure control and cardiovascular risk and promoting the use of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers, statins, and aspirin (grade A) Metformin is recommended for most type 2 diabetic patients with stage 1 and 2 CKD who have stable renal function unchanged over the prior months (grade A) Metformin may be continued in individuals with stable stage 3 CKD (grade B) Tailor the choice of other glucose-lowering agent(s) (including insulin) to the individual, the level of renal function, and comorbidity (grade D, opinion) Risk of hypoglycemia should be assessed regularly in individuals taking insulin or insulin secretagogues, and these patients should be taught how to recognize, detect, and treat hypoglycemia (grade D, opinion). European Best Practice Guidelines (EBPG): No recommendations. International Guidelines: No recommendations. SUGGESTIONS FOR FUTURE RESEARCH 1. Future research should focus on different treatment goals and development of CKD, particularly in patients with type 2 DM. 2. Studies of different therapeutic agents should be performed with a view to assessing whether nonglucose lowering effects of agents impact on the risk of developing CKD. 3. Studies should have long-term follow-up (many years) in light of the natural history of diabetic nephropathy. CONFLICT OF INTEREST Graeme Turner and Kate Wiggins have no relevant financial affiliations that would cause a conflict of interest according to the conflict of interest statement set down by CARI. David Johnson has a level II b. conflict of interest for receiving speaker honoraria and advisor s fees from several companies related to anaemia, CKD-MBD, hypertension and cardiovascular disease between 2008 and Early Chronic Kidney Disease July 2012 Page 4 of 9

5 REFERENCES 1. Hanas R and John G, on behalf of the International HbA 1c Consensus Committee, Consensus Statement on the Worldwide Standardization of the Hemoglobin A1c Measurement. Pediatr Diabetes. 2010; 11: Jones GRD, Barker G, Goodall I et al. Change of HbA1c reporting to the new SI units. Med J Aust. 2011; 195: DCCT. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Trial Research Group. N Engl J Med. 1993; 329: EDIC, Writing Team for the Diabetes C, Trial/Epidemiology of Diabetes I et al. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and (EDIC) study. J Am Med Assoc. 2003; 290: Jacobson AM, Musen G, Ryan CM et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med. 2007; 356: UKPDS. 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: UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).. Lancet. 1998; 352: Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359: Sasaki A, Horiuchi N, Hasagawa K et al. Persistent albuminuria as an index of diabetic nephropathy in type 2 diabetic patients in Osaka, Japan-incidence, risk factors, prognosis and causes of death. Diabetes Res Clin Pract. 1989; 7: National Kidney Foundation. K/DOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007; 49 (suppl 2): S1-S Levin A, Hemmelgarn B, Culleton B et al. Guidelines for the management of chronic kidney disease. Can Med Assoc J. 2008; 179: Early Chronic Kidney Disease July 2012 Page 5 of 9

6 APPENDICES Table 1. Characteristics of included studies Study ID N Study design Participants Follow up Comments and results Trial Research Group (1993) [DCCT] [3] RCT 6.5 years (average) 726 = primaryprevention cohort 715 = secondaryintervention cohort Patients with insulin dependent diabetes mellitus (IDDM), 13 to 39 years old, 726 had no retinopathy at baseline (the primary prevention cohort) and 715 had mild retinopathy (the secondary intervention cohort) In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for retinopathy development by 76% (95% CI: 62 to 85%; P<0.001) as compared to conventional therapy. In the secondary-prevention cohort, intensive therapy: Slowed the progression of retinopathy by 54% (95% CI: 39 to 66%; P<0.001) Reduced the development of proliferative or severe non-proliferative retinopathy by 47% (95% CI: 14 to 67%; P= 0.011) In the two cohorts combined, intensive therapy reduced the occurrence of: Microalbuminuria by 39% (95% CI: 21 to 52%) Albuminuria by 54% (95% CI: 19 to 74%) Clinical neuropathy by 60% (95% CI: 38 to 74%) Intensive therapy delays the onset and slows the progression of diabetic retinopathy, nephropathy and neuropathy in patients with IDDM. Two-to-three fold increase in severe hypoglycaemia was the main adverse event. Trial / Epidemiology of Diabetes Interventions and Research Group (2003) [EDIC] [4] Observational cohort Follow-up of the same cohort from the DCCT study in 28 medical centres USA and Canada (1993) 687 in the former intensive - treatment group 688 in the former conventional - treatment group 7 to 8 years Outcome measures for the follow-up comparison between the former intensive-treatment group and the former conventional-treatment group respectively. HbA1c level: 8% compared to 8.2% (P=0.002) Microalbuminuria: 6.8% compared to 15.8% Clinical albuminuria: new cases 1.4% compared to 9.4% Hypertension: 29.9% compared to 40.3% (P<0.001) Serum creatinine level of 2mg/dL or greater: 5 participants compared to 9 (P = 0.004) Conclusion: previous intensive treatment of diabetes with near-normal glycaemia during the DCCT study has an extended benefit in delaying progression of diabetic nephropathy. Early Chronic Kidney Disease July 2012 Page 6 of 9

7 Study ID N Study design Participants Follow up Comments and results 3,867 RCT Adult participants newly diagnosed with Type 2 Diabetes from 23 UK hospitals between 1977 and years HbA1c was 7.0% in the intensive group compared to 7.9% in the conventional group. Compared to the conventional group the risk in the intensive group was: - 12% lower for any diabetes-related end-point (95% CI: 1 to 21; P=0.029) - 10% lower for any diabetes-related death (95% CI: -11 to 27; P= 0.34) - 6% lower for all-cause mortality (95% CI: -10 to 20; P=0.44) There was a 25% risk reduction in microvascular endpoints (95% CI: 7 to 40; P=0.0099) Hypoglycaemic episodes: 0.7% in conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide and 1.8% with insulin. (1998)[7] Holman et al (2008) [8] 2,241 RCT Overweight participants recruited to UKPDS in 15 centres, with newly diagnosed Type 2 diabetes. 3,227 RCT Follow-up of UKPDS patients with Type 2 diabetes 10.7 years HbA1c was 7.4% in the metformin group compared to 8.0% in the conventional group. Compared to the conventional group the patients in the metformin group, had a risk reduction of: - 32% for any diabetes-related end-point (95% CI: 13 to 47; P=0.002) - 42% for diabetes-related death (95% CI: 9 to 63; P= ) - 36% for all-cause mortality (95% CI: 9 to 55; P=0.011) Metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint (P=0.0034); all-cause mortality (P=0.021); and stroke (P=0.032). 10 years In the sulfonylurea-insulin group, relative reductions in risk persisted for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001). Risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) also emerged over time. The metformin group also showed significant risk reductions for any diabetesrelated end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002). Plasma creatinine levels in the metformin group were 15% higher on average than those in the conventional-therapy group (P<0.04) Sasaki et al (1989)[9] 1,196 Retrospective Cohort Type 2 diabetic patients from the Osaka Medical Centre for Adult Diseases, Japan ( ) 740 males, 456 females 10 years Of the193 patients who developed persistent albuminuria, 66 (34%) died, before the end of the observation period, with a mean survival period of years after the onset of persistent albuminuria. Mean annual incidence rates of persistent albuminuria differed considerably depending on the type of treatment patients were on at baseline (10.74% for diet versus 19.47% oral hypoglycaemic versus 40.78% for insulin). Renal disease was the predominant cause of death in patients who developed persistent albuminuria, followed by heart disease and cerebrovascular disease. Early Chronic Kidney Disease July 2012 Page 7 of 9

8 Table 1a. Characteristics of included randomised controlled trials Study ID (author, year) Trial Research Group (1993) [DCCT] [3] N Study Design Setting Participants Intervention (experimental group) 1,441 Randomised controlled clinical trial 3,867 Randomised controlled clinical trial 29 centres, US Patients with IDDM +/- retinopathy 23 centres UK Participants newly diagnosed with Type 2 Diabetes Mellitus Intensive insulin therapy (insulin pump or >3 daily injections & glucose monitoring) Sulphonylurea, or insulin Intervention (control group) Conventional therapy (1 to 2 daily insulin injections) Conventional therapy with diet Follow up (months) Comments 78 Two study cohorts, randomised to intervention and control groups. Total of 4 treatment arms 120 A sub-study was conducted in overweight patients with type 2 diabetes, treated with intensive glucose control and metformin vs conventional treatment. Table 2. Methodological quality of randomised trials Study ID (author, year) Trial Research Group (1993) [DCCT][3] Method of Blinding Intention-totreat Loss to Comments allocation concealment * (participants) (investigators) (outcome assessors) analysis follow up (%) Not specified No No No No 3.0 _ Central and sealed, opaque envelopes which were opened in sequence No No No Yes Not specified Ø * Choose between: central; third party (e.g. pharmacy); sequentially labelled opaque sealed envelopes; alternation; not specified. Choose between: yes; no; unclear. Quality score How successfully do you think the study minimised bias? Choose between: very well (+); okay (Ø); poorly ( ). Early Chronic Kidney Disease July 2012 Page 8 of 9

9 Table 3a Results and quality rating for dichotomous outcomes Outcomes Study ID (author, year) Intervention group (no. of patients with events/no. of patients exposed) Control group (no. of patients with events/no. of patients exposed) Relative risk (RR) [95% CI] Risk difference (RD) [95% CI] Importance** Nephropathy Urinary albumin excretion (UAE) 40 mg/24hr Trial Research Group (1993) [DCCT][3] 2.2 rate/100 patient-yr (Primary prevention group) 3.6 rate/100 patient-yr (Secondary intervention group) 3.4 rate/100 patient-yr Risk reduction 34% (2 56) 5.7 rate/100 patient-yr Risk reduction 43% (21 58) Not provided Not provided Important All-cause mortality 489/ / (0.83, 1.11) (-0.03, 0.02) Critical Death from renal disease 8/2729 2/ (0.35, 7.84) 0.00 (-0.00, 0.00) Critical Renal Failure 16/2729 9/ (0.33, 1.67) * Methodological quality, consistency across studies and directness of the evidence (generalisability/applicability). ** The GRADE system uses the following 3 categories to rank the importance of end points: critical for decision making important but not critical for decision making not important for decision making (of lower importance to patients) (-0.01, 0/00) Critical Early Chronic Kidney Disease July 2012 Page 9 of 9