Medical therapies to reduce chronic kidney disease progression and cardiovascular risk: glycaemic control

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1 Medical therapies to reduce chronic kidney disease progression and cardiovascular risk: glycaemic control Date written: July 2012 Author: Richard Phoon, David Johnson GUIDELINES a. We recommend that patients with early (stage 1-3) CKD due to type 1 or type 2 diabetes mellitus aim to achieve a HbA1c target of approximately 7.0% or 53 mmol/mol* (1B). b. We recommend caution against intensively lowering HbA1c levels appreciably below 7.0% in view of demonstrated increased risks of hypoglycaemia (1B) and possibly death (1C). c. We recommend that multifactorial interventions targeting cholesterol and blood pressure as well as glycaemic control should be instituted to improve renal and cardiovascular outcomes in patients with early (stage 1-3) CKD due to diabetes mellitus, particularly type 2 diabetes mellitus (1B). * SI units recommended as per The International HbA1c Consensus [1, 2] UNGRADED SUGGESTIONS FOR CLINICAL CARE There are no ungraded statements. IMPLEMENTATION AND AUDIT Kidney Check Australia Taskforce (KCAT) education programs should incorporate these updated guidelines. Audits of primary health care providers, similar to the BEACH study, should be commissioned to evaluate awareness of these guidelines. Relevant education programs (KCAT) and guidelines (Heart Foundation) should incorporate these recommendations. Audits of primary health care providers should be commissioned to evaluate awareness of these guidelines. Relevant education programs (KCAT) and guidelines (Diabetes Australia) should incorporate these recommendations. Audits of primary health care providers should be commissioned to evaluate awareness of these guidelines and to monitor relevant key performance indicators, including HbA1c, and cardiovascular and renal outcomes. BACKGROUND Chronic kidney disease (CKD) represents a major, rapidly growing, public health burden worldwide. In Australia, CKD affects approximately 1 in 7 (or more than 2 million) adults over the age of 25, and contributes to nearly 10% of all deaths and over 1.1 million hospitalisations annually. [3, 4] Several studies, in various populations [5-24], have demonstrated that: CKD is a potent, independent cardiovascular (CV) risk factor, with CV events occurring between 10 to 100 times more frequently in the CKD population, and CKD has a multiplicative impact on other chronic diseases. CKD is expensive. In , the estimated total recurrent health expenditure on CKD in Australia was $647 million. [25] A recent analysis of the health economic impact of end-stage kidney disease (ESKD) in Australia estimated that, at the end of 2007, hospital dialysis cost around $189 million per year. [26] Early Chronic Kidney Disease July 2012 Page 1 of 9

2 Taken together, CKD is a significant contributor of morbidity and mortality, and represents a major expense to the health care system. Early intervention with appropriate medical therapies is essential to address this public health burden and may reduce the progression of CKD and CV risk by up to 50%. [27] The objective of this guideline is to review currently available evidence in this regard and provide appropriate clinical recommendations. Recommendations in other guidelines, and the evidence underpinning these recommendations, have also been reviewed. Diabetes mellitus, particularly type 2, is increasing in prevalence and associated with significant cardiovascular morbidity and mortality. It also represents the leading cause of chronic kidney disease worldwide. The role of glycaemic control in retarding CKD progression has been discussed in detail in the CARI guideline, [28]. In brief, evidence from large, prospective trials indicates that tight glycaemic control in type 1 [29] and, to a lesser extent, type 2 [30, 31]diabetic patients results in clinically significant preservation of renal function. Less consistent evidence exists for a benefit with intensiveglucose lowering therapy in reducing cardiovascular disease. The optimal level to which glycosylated haemoglobin (HbA1c) should be targeted (< 7.0%) is largely based on the DCCT and UKPDS trials [29-31] but the threshold below which the benefit is lost or at which the incidence of side-effects becomes unacceptable is not clear. The objective of this guideline is to review currently available evidence with regards to targets for glucose-lowering therapy in patients with early CKD due to diabetes mellitus. SEARCH STRATEGY Databases searched: Text words for chronic kidney disease were combined with MeSH terms and text words for hypoglycaemic agents and diabetes mellitus. The search was carried out in Medline (1994 October 2009). No language restrictions were placed on the search. The conference proceedings of the American Society of Nephrology from were also searched for trials. A search update was conducted in Medline (2009 May 2012) using the same MeSH terms and text words Date of search/es: October 2009 and May WHAT IS THE EVIDENCE? The Effect of Intensive Glycaemic Control in Type 1 Diabetes The Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study group previously demonstrated a consistent salutary effect of intensive therapy on the progression of nephropathy [32] More recent follow-up data [33] (from 93% of the original cohort of 1441 patients) indicated that this effect also extends to cardiovascular risk. Despite convergence of HbA1c at year 11 of EDIC (7.9±1.3% vs 7.8±1.3%, NS), intensive treatment was associated with a reduction in risk of cardiovascular events (RRR 42%, 95% CI, 9-63%, P = 0.02). The Role of Multifactorial Intervention in Type 2 Diabetes In the Steno-2 study [34], 160 Danish patients with type 2 diabetes and persistent microalbuminuria were randomised to intensified, target-driven therapy (HbA1c < 6.5%, blood pressure < 130/80 mmhg, total cholesterol < 4.5 mmol/l, triglycerides < 1.7mmol/l) or conventional therapy, with a mean follow-up intensive and conventional therapy groups, respectively). The intensive therapy group had a lower blood pressure (SBP: 131±13 vs 146±18 mmhg, P < 0.01; DBP 73±11 vs 78±10 mmhg, P < 0.01) and total cholesterol (159±34 vs 216±50 mg/dl, P < 0.01), and better glycaemic control (HbA1c: 7.9±1.2 vs 9.0± 1.8, P < 0.01) and was associated with increased use of combination ACEI / ARB therapy, statins and aspirin. Intensive therapy led to an approximately 50% reduction in the incidence of cardiovascular and microvascular events (cardiovascular disease: HR 0.47; 95% CI, , P < 0.01); nephropathy [defined as a urinary albumin excretion rate > 300 mg/24hrs in two of three consecutive urine specimens]: HR 0.39; 95% CI, , P < 0.01). In the follow-up (mean 5.5 years) to the Steno-2 study [35], blood pressure, cholesterol and glycaemic control were not significantly different between groups (although more patients in the intensive therapy group were on metformin, sulfonylureas and/or -blocker therapy). Despite the similarities in clinical parameters, Early Chronic Kidney Disease July 2012 Page 2 of 9

3 intensive therapy was associated with a lower risk of total mortality (HR 0.54; 95% CI, , P < 0.05) and there was a continued reduction in incidence of cardiovascular events (HR 0.41; 95% CI, ; P < 0.001) and nephropathy (RR 0.44; 95% CI, ; P < 0.01). Although the duration of the study was reasonable, study numbers were small and in a select population which may not easily extrapolate to an Australian population. The study supports the benefits of multifactorial intervention in type 2 diabetes but is unable to identify the specific contribution of intensive glycaemic control. The Effect of Intensive Glycaemic Control on Cardiovascular Risk in Type 2 Diabetes The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial [36] was an RCT of patients with type 2 diabetes, randomised to standard (local guidelines) vs intensive glycaemic control (gliclazide plus other drugs as required to achieve HbA1c < 6.5%). After a median follow-up of 5 years, the intensive-control group achieved better glycaemic control (6.5 vs 7.3%, P < 0.001) and a lower risk of nephropathy (4.1% vs 5.2%; HR, 0.79; 95% CI , P < 0.01), but not retinopathy. Intensive-control had no significant effect on major cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke: HR 0.94, 95% CI, , NS) or all-cause mortality (HR 0.93, 95% CI, , NS). Overall, intensive-control was associated with a lower incidence of major microvascular events (new / worsening nephropathy or retinopathy: HR 0.86, 95% CI, , P = 0.01) and the composite primary endpoint of major macro-vascular events (and major microvascular events (HR 0.90; 95% CI, , P = 0.01). This study confirms the renoprotective effect of intensive glycaemic control in type 2 diabetes. It suggests that this benefit is continuous, at least to a target HbA1c of 6.5% (compared to 7.0% in most local guidelines), albeit with an increased risk severe hypoglycaemia. Severe hypoglycemia (defined as patients with transient dysfunction of the central nervous system who were unable to treat themselves and required help from another person) occurred more frequently in the intensive-control group (2.7%) than in the standard-control group (1.5%) (HR 1.86, 95% CI , p<0.001) as did minor hypoglycaemia (120 vs 90 events per 100 patients per year, respectively). 47% of patients in the intensive-control group and 62% of those in the standard-control group remained free of any hypoglycemic event during the follow-up period. The trial highlights the importance of multifactorial intervention (e.g. blood pressure, lipid-lowering and anti-platelet therapy) in reducing CV risk and allcause mortality, as suggested by the Steno-2 follow-up study. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study [37] was an RCT of patients with type 2 diabetes, randomised to intensive therapy (target HbA1c < 6.0%) or standard therapy (target HbA1c %). Stable median HbA1c levels were achieved in the intensive (6.4%) and standard therapy (7.5%) groups at 1 year and throughout the follow-up period. However, the trial was discontinued prematurely after a mean of 3.5 years follow-up due to the finding of higher all-cause mortality in the intensive-therapy group (5.0% vs 4.0%; HR 1.22, 95% CI, , P = 0.04). There were no differences in the primary composite outcome of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death (HR 0.90, 95% CI , NS). Intensive therapy was associated with an increased incidence of hypoglycaemia requiring medical assistance (10.5% vs 3.5%, P < 0.001) and weight gain > 10 kg since baseline (27.8% vs 14.1%, P < 0.001). Similar to the ADVANCE trial, this study did not show a benefit of intensive glycaemic control on cardiovascular risk. It raises concerns with using a target HbA1c of 6.0% which, in this trial, was associated with increased all-cause mortality and more hypoglycaemic episodes. Limitations of the study are that, in the intensive therapy group, more patients received thiazolidinediones (91.7% vs 58.3%) and fewer patients received ACEI therapy (69.7% vs 71.9%, P < 0.05). SUMMARY OF EVIDENCE There is strong evidence that intensive glycaemic control reduces CV risk in type 1, but not type 2, diabetes. A multifactorial interventional approach to patients with diabetes, particularly type 2, is beneficial in reducing all-cause mortality and CV risk. Strong evidence supports the role of intensive glycaemic control (perhaps to a target HbA1c of 6.5%) in retarding the progression of CKD in type 1 and type 2 diabetes. Balanced against this is the risk of complications (severe hypoglycaemia and perhaps also increased mortality) that may be associated with lowering of glucose to near-normal levels. Early Chronic Kidney Disease July 2012 Page 3 of 9

4 WHAT DO THE OTHER GUIDELINES SAY? Kidney Disease Outcomes Quality Initiative: No recommendation. UK Renal Association: No recommendation. Canadian Society of Nephrology: [38] Targets for glycaemic control, where they can be achieved safely should follow standard Canadian Diabetes Association Guidelines (hemoglobin A1c < 7.0%, fasting glucose 4-7 mmol/l) 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 Metformin is recommended for most type 2 diabetic patients with stage 1 and 2 CKD who have stable renal function unchanged over the prior 3 months Metformin may be continued in individuals with stable stage 3 CKD Tailor the choice of other glucose-lowering agent(s) (including insulin) to the individual, the level of renal function, and comorbidity Risk of hypoglycaemia should be assessed regularly in individuals taking insulin or insulin secretagogues, and these patients should be taught how to recognize, detect, and treat hypoglycemia. Clinical practice recommendation Short-acting sulfonylureas (e.g. gliclazide) are preferred over long-acting agents in CKD. European Best Practice Guidelines: No recommendation. International Guidelines: Kidney Check Australia Taskforce:[39] Intensive blood glucose control significantly reduces the risk of developing microalbuminuria, macroalbuminuria and/or overt nephropathy in people with Type 1 and Type 2 diabetes. Management - Lifestyle modification - Oral hypoglycaemics - Insulin Target - Pre-prandial BSL mmol/l - HbA1c < 7.0% SUGGESTIONS FOR FUTURE RESEARCH Long-term follow-up of renal function (in addition to albuminuria) in the ADVANCE and ACCORD trials should be performed. CONFLICT OF INTEREST Richard Phoon has a level II b. conflict of interest for receiving speaker fees and honoraria from several companies related to anaemia, CKD-MBD and cardiovascular disease between 2008 and 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. Pediatric Diabetes. 2010; 11: Jones GRD, Barker G, Goodall I et al. Change of HbA1c reporting to the new SI units. The Medical journal of Australia. 2011; 195: Green F and C R, An Overview of Chronic Kidney Disease in Australia. 2009, Australian Institute of Health and Welfare: Canberra. 4. National Chronic Kidney Disease Strategy. 2006, Kidney Health Australia. 5. Anavekar NS, McMurray JJ, Velazquez EJ et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. New England Journal of Medicine. 2004; 351: Brantsma AH, Bakker SJL, Hillege HL et al. Cardiovascular and renal outcome in subjects with K/DOQI stage 1-3 chronic kidney disease: the importance of urinary albumin excretion. Nephrology Dialysis Transplantation. 2008; 23: Chien K-L, Hsu H-C, Lee Y-T et al. Renal function and metabolic syndrome components on cardiovascular and all-cause mortality. Atherosclerosis. 2008; 197: Farbom P, Wahlstrand B, Almgren P et al. Interaction between renal function and microalbuminuria for cardiovascular risk in hypertension: the nordic diltiazem study. Hypertension. 2008; 52: Foley RN, Parfrey PS, and Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. American Journal of Kidney Diseases. 1998; 32: S Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. New England Journal of Medicine. 2004; 351: Keith DS, Nichols GA, Gullion CM et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Archives of Internal Medicine. 2004; 164: Kurth T, de Jong PE, Cook NR et al. Kidney function and risk of cardiovascular disease and mortality in women: a prospective cohort study. BMJ. 2009; 338: b Luthi J-C, Flanders WD, Burnier M et al. Anemia and chronic kidney disease are associated with poor outcomes in heart failure patients. BMC Nephrology. 2006; 7: Manjunath G, Tighiouart H, Coresh J et al. Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney International. 2003; 63: McCullough PA, Li S, Jurkovitz CT et al. CKD and cardiovascular disease in screened highrisk volunteer and general populations: the Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) American Journal of Kidney Diseases. 2008; 51: S McDonald SP, Maguire GP, and Hoy WE. Renal function and cardiovascular risk markers in a remote Australian Aboriginal community. Nephrology Dialysis Transplantation. 2003; 18: Nakamura K, Okamura T, Hayakawa T et al. Chronic kidney disease is a risk factor for cardiovascular death in a community-based population in Japan: NIPPON DATA90. Circulation Journal. 2006; 70: Nickolas TL, Khatri M, Boden-Albala B et al. The association between kidney disease and cardiovascular risk in a multiethnic cohort: findings from the Northern Manhattan Study (NOMAS). Stroke. 2008; 39: Parikh NI, Hwang S-J, Larson MG et al. Chronic kidney disease as a predictor of cardiovascular disease (from the Framingham Heart Study). American Journal of Cardiology. 2008; 102: Rashidi A, Sehgal AR, Rahman M et al. The case for chronic kidney disease, diabetes mellitus, and myocardial infarction being equivalent risk factors for cardiovascular mortality in patients older than 65 years. American Journal of Cardiology. 2008; 102: Remuzzi G and Remuzzi A. Is regression of chronic nephropathies a therapeutic target? Journal of the American Society of Nephrology. 2005; 16: Early Chronic Kidney Disease July 2012 Page 5 of 9

6 22. Shara NM, Resnick HE, Lu L et al. Decreased GFR estimated by MDRD or Cockcroft-Gault equation predicts incident CVD: the strong heart study. Journal of Nephrology. 2009; 22: Tsagalis G, Akrivos T, Alevizaki M et al. Renal dysfunction in acute stroke: an independent predictor of long-term all combined vascular events and overall mortality. Nephrology Dialysis Transplantation. 2009; 24: Weiner DE, Tighiouart H, Stark PC et al. Kidney disease as a risk factor for recurrent cardiovascular disease and mortality. American Journal of Kidney Diseases. 2004; 44: AIHW, Chronic Kidney Disease in Australia, in Cat.No. PHE , Australian Institute of Health and Welfare: Canberra. 26. Cass A, Craig J, Howard H et al, The Economic Impact of End-Stage Kidney Disease in Australia Johnson DW. Evidence-based guide to slowing the progression of early renal insufficiency. Internal Medicine Journal. 2004; 34: Chadban S, Howell M, Twigg S et al. Prevention and management of chronic kidney disease in type 2 diabetes. Nephrology. 2010; 15: S162-S Reichard P, Nilsson BY, and Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. New England Journal of Medicine. 1993; 329: UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352: 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). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352: DCCT. 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.[Erratum appears in N Engl J Med 2000 May 4;342(18):1376]. New England Journal of Medicine. 2000; 342: Nathan DM, Cleary PA, Backlund JY et al. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. New England Journal of Medicine. 2005; 353: Gæde P, Vedel P, Larsen N et al. Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. New England Journal of Medicine. 2003; 348: Gaede P, Lund-Andersen H, Parving HH et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. New England Journal of Medicine. 2008; Patel A, MacMahon S, Chalmers J et al. Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2008; 358: Gerstein HC, Miller ME, Byington RP et al. Effects of Intensive Glucose Lowering in Type 2 Diabetes. New England Journal of Medicine. 2008; 358: Levin A, Hemmelgarn B, Culleton B et al. Guidelines for the management of chronic kidney disease. CMAJ Canadian Medical Association Journal. 2008; 179: Chronic Kidney Disease (CKD) Management in General Practice (2nd edition) , Melbourne: Kidney Health Australia. Early Chronic Kidney Disease July 2012 Page 6 of 9

7 APPENDICES Table 1. Characteristics of included studies Study ID N Study design Nathan et al (2005) 1,340 RCT follow [33] (93% of up original 1,441 RCT cohort) Gaede et al (2003) [34] Gaede et al (2008) [Sterno-2 Study] [35] Patel et al (2008) [ADVANCE Trial] [36] Participants Follow up Comments and results Participants 13 to 40 years old with type 1 diabetes were randomised to intensive or conventional treatment 160 RCT Participants with type 2 diabetes and microalbuminuria were randomised to conventional or intensive treatment 160 RCT Participants with type 2 diabetes and microalbuminuria were randomised to conventional or intensive treatment (renin-angiotensin system blockers, aspirin and lipid-lowering agents) 11,140 RCT Participants 55 years old with type 2 diabetes and history of macro- or microvascular disease. Participants were randomly assigned to standard or intensive glucose control RCT 6.5 years (mean) followup 17 years (mean) 46 cardiovascular disease events occurred in 31 patients from the intensive treatment group, compared with 98 events in 52 patients from the conventional treatment. Intensive treatment reduced the risk of: - any cardiovascular disease event by 42% (95% CI: 9-63%, P = 0.02) - non-fatal myocardial infarction, stroke, or death from cardiovascular disease by 57% (95% CI: 12-79%, P = 0.02) 7.8 years Patients in the intensive therapy group had a significantly lower risk of: - cardiovascular disease (HR 0.47; 95% CI: , P < 0/01) - nephropathy (HR 0.39; 95% CI: ) - retinopathy (HR 0.42; 95% CI: ) - autonomic neuropathy (HR 0.37; 95% CI: ) 13.3 years 24 patients in the intensive-therapy group died compared with 40 in the conventional-therapy group (HR 0.54; 95% CI: , P = 0.02) Intensive therapy was associated with lower risk of: - death from cardiovascular causes (HR 0.43; 95% CI: , P = 0.04) - cardiovascular events (HR 0.41; 95% CI: , P < 0.001) - diabetic nephropathy (RR 0.44; 95% C: , P = 0.004) 5 years (median) At end of follow-up,, the mean-glycated haemoglobin was lower in the intense glucose control group (6.5% vs 7.3%; P <0.001) in the standardcontrol group Intensive-glucose control also reduced the incidence of nephropathy (4.1% vs 5.2%; hazard ratio 0.79; 95% CI: , P = 0.006), but had no significant effect on retinopathy (P = 0.50) Intensive control also reduced the incidence of combined major macrovascular and microvascular events (18.1% vs 20.0% with standard control, HR 0.90; 95% CI: , P = 0.01) Intensive therapy did not have a significant effect on major macro-vascular events (HR 0.94; 95% CI: , P = 0.32) or death from any cause (HR 0.93; 95% CI: , P = 0.28) Severe hypoglycaemia was more common in the intensive-control group (2.7% vs 1.5% in the standard-control group, HR 1.86; 95% CI: , P < 0.001) Early Chronic Kidney Disease July 2012 Page 7 of 9

8 Study ID N Study design Gerstein et al 10, 251 RCT Participants 40 to 79 years old, (2008) [ACCORD with type 2 diabetes and Study] [37] glycated haemoglobin level of 7.5% who also had cardiovascular disease. Participants Follow up Comments and results 3.5 years (mean) 257 patients in the intensive-therapy group died compared with 203 in the standard-therapy group (HR, 1.22; 95%CI: , P = 0.04) There was no significant difference in the primary outcome of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (HR 0.90; 95% CI: , P = 0.16) Intensive therapy was also associated with increased hypoglycaemia requiring medical assistance (10.5% vs 3.5%; P < 0.001) and weight gain of more than 10 kg (27.8% vs 14.1%; P < 0.001) Table 1a. Characteristics of randomised trials Study ID (author, year) N Study Design Setting Participants Intervention (experimental group) Intervention (control group) Follow up (months) Nathan et al (2005) [33] 1,340 Randomised Multicentre, Participants with type 1 Intensive treatment Conventional 17 (yrs) controlled clinical trial US diabetes (13 40 years old) treatment Gaede et al (2003) [34] 160 Randomised Single centre, Participants with type 2 Intensive treatment Conventional 93.6 controlled clinical trial Denmark diabetes and microalbuminuria treatment Gaede et al (2008) [35] 160 Randomised Single centre, Participants with type 2 Intensive treatment Conventional controlled clinical trial Denmark diabetes and microalbuminuria treatment Patel et al (2008) [36] 11,140 Randomised controlled clinical trial Multicentre, multinational Participants with type 2 diabetes with macro- or Intensive treatment Standard treatment 60 Gerstein et al (2008) [37] 10,251 Randomised controlled clinical trial Multicentre, US & Canada microvascular disease Participants with type 2 diabetes (HbA1c 7.5%)and cardiovascular disease Intensive therapy Standard therapy 42 Table 2a. Methodological quality of randomised trials Study ID (author, year) Method of allocation Blinding Intention-to-treat Loss to follow Comments concealment * (participants) (investigators) (outcome assessors) analysis up (%) Nathan et al (2005) [33] Not specified No No No Yes Unclear - Gaede et al (2003) [34] Sealed envelopes No No No Yes Gaede et al (2008) [35] Sealed envelopes No No No Yes Unclear - Patel et al (2008) [36] Central No No No Yes Gerstein et al (2008) [37] Not specified No No No Yes Unclear - * 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** Death from cardiovascular disease Nathan et al (2005) [33] 3 / / (0.09, 1.26) (-0.02, 0.00) Critical Gaede et al (2008) [35] 9 / / (0.12, 0.43) (-0.52, -0.26) Patel et al (2008) [36] 253 / / (0.74, 1.03) (-0.01, 0.00) Gerstein et al (2008) [37] 135 / / (1.11, 1.86) 0.01 (0.00, 0.01) All cardiovascular disease events Nathan et al (2005) [33] 31 / / (0.4, 0.94) (-0.05, -0.00) Important Gaede et al (2003) [34] *NA NA NA NA Gaede et al (2008) [35]] 25 / / (0.36, 0.75) (-0.44, -0.14) Patel et al (2008) [36] 1232/ / (0.92, 1.06) (-0.02, 0.01) New or worsening nephropathy Patel et al (2008) [36] 230 / / (0.67, 0.93) (-0.02, -0.00) Important Death from any cause Patel et al (2008) [36] 498 / / (0.83, 1.05) (-0.02, 0.00) Critical Gerstein et al (2008) [37] 257 / / (1.06, 1.51) 0.01 (0.00, 0.02) Combined major macrovascular Patel et al (2008) [36] 1009 / / (0.84, 0.98) (-0.03, -0.00) Critical and microvascular events Nonfatal myocardial infarction Gerstein et al (2008) [37] 186 / / (0.65, 0.95) (-0.02, -0.00) Critical Nonfatal stroke Gerstein et al (2008) [37] 67 / / (0.78, 1.55) 0.00 (-0.00, 0.01) Critical 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) * NA not applicable Table 3b. Results and quality rating for continuous outcomes Outcomes Study ID (author, year) Intervention group (mean [SD]) Control group (mean [SD]) Difference in means (95% CI) Importance** Change in glomerular filtration rate (ml/min/1.73m 2 ) Gaede et al (2003) [34] -30 (25) -32 (24) 2.00 (-6.42, 10.42) Important 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) * NA not applicable Early Chronic Kidney Disease July 2012 Page 9 of 9