Reducing renal failure: how low do glucose levels need to go?

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1 maagemet perspective Reducig real failure: how low do glucose levels eed to go? Practice Poits Clemet Lo1 & Sophia Zougas,3* Diabetic kidey disease is the commoest cause of ed-stage kidey disease worldwide ad leads to sigificat morbidity ad mortality, icreased cardiovascular risk ad icreased ecoomic health costs due to the eed for dialysis. Major risk factors for diabetic ephropathy iclude hyperglycemia, hypertesio, dyslipidemia ad duratio of diabetes. There are both albumiuric ad oalbumiuric pathogeetic pathways to real dysfuctio i diabetic ephropathy. Studies i both Type 1 ad Type diabetes show a relatioship betwee tighter glucose cotrol ad a lower risk of the developmet ad progressio of albumiuria ad diabetic ephropathy. While older trials such as the UKPDS ad DCCT aimed for a glycated hemoglobi (HbA1c) approachig 7%, more cotemporary trials such as ACCORD, ADVANCE ad VADT lowered the HbA1c to less tha 7%. The major side effect of lowerig glucose levels is hypoglycemia. The real beefits of itesive blood glucose cotrol have to be balaced with the patiet s age, comorbidities ad the risk of hypoglycemia. A geeral glycemic target of HbA1c of 7% to prevet oset ad progressio of diabetic ephropathy is appropriate i most patiets. Other risk factor modificatio such as treatig hypertesio, the use of rei agiotesi system blockade ad treatig dyslipidemia are equally as importat as glycemic cotrol i the maagemet of the patiet with diabetic ephropathy. Diabetes & Edocrie Fellow, Moash Medical Cetre, Souther Health, VIC, Australia Associate Professor & Head, Cliical Research & Diabetes Program, School of Public Health & Prevetive Medicie, Moash Site, Moash Uiversity, VIC, Australia 3 The George Istitute for Global Health, NSW, Australia *Author for correspodece: sophia.zougas@med.moash.edu.au /DMT Future Medicie Ltd Diabetes Maage. (01) (1), 5 3 part of ISSN

2 maagemet perspective Lo & Zougas Summary Diabetic kidey disease is the commoest cause of ed-stage kidey disease worldwide. Oe strategy to prevet the developmet ad progressio of diabetic kidey disease is itesive blood glucose cotrol. Radomized cotrolled trials such as the UKPDS ad DCCT have demostrated that a target HbA1c level of 7% improves real outcomes. More recetly, ACCORD, ADVANCE ad VADT have explored the effects of targetig eve lower HbA1c levels of %. These cotemporary trials have uiversally reported improvemets i albumiuria but o clear effects o prevetig ed-stage kidey disease. Thus, the additioal ad likely log-term real beefits of itesive glucose lowerig to achieve HbA1c levels 7% eed to be balaced agaist the potetial risks of itesive therapy such as severe hypoglycemia. A idividualized approach is required with the uderstadig that the greatest real beefits are likely to be achieved at a HbA1c level of 7%. Other risk factors for real impairmet should also be addressed. Diabetes is ow the commoest cause of ed-stage kidey disease i both the developed ad developig world [1]. Chroic kidey disease causes sigificat morbidity ad mortality, ad further icreases cardiovascular risk i people with diabetes []. It also results i sigificat idividual ad ecoomic health costs due to the eed for real replacemet therapy. Measures to decrease the developmet ad progressio of chroic kidey disease i people with diabetes are thus urgetly eeded, particularly as the prevalece of Type diabetes cotiues to icrease globally. Pathophysiology Major risk factors for diabetic ephropathy iclude hyperglycemia, hypertesio, dyslipidemia ad duratio of diabetes. Classic diabetic ephropathy develops over 0 years. The oset of diabetic ephropathy is usually marked by glomerular hyperfiltratio, which is the followed by the developmet of worseig albumiuria progressig from ormo albumiuria (<30 mg/4 h) to microalbumiuria ( mg/4 h) ad the to proteiuria (>300 mg/4 h). The glomerular filtratio rate usually remais stable util the developmet of proteiuria, ad the progressively falls by a average of 10 1 ml/mi/1.73 m /year, ultimately leadig to real failure (Figure 1) [3 5]. This pathway is classically see i Type 1 diabetes ad i some patiets with Type diabetes, although there are exceptios. O kidey biopsy, some patiets with Type diabetes labeled as havig diabetic ephropathy do ot exhibit the classical pathological real fidigs or have mixed disease. Furthermore, micro a lbumiuria ca regress either as part of the atural history of the disease or with the use of rei agiotesi system blockade. Some patiets may also be observed to develop a declie i real fuctio without progressive albumiuria. Thus, 6 Diabetes Maage. (01) (1) it is believed that both classical albumiuric ad oclassical oalbumiuric pathways lead to declie of real fuctio i people with d iabetes [6,7]. Epidemiological studies have established a clear lik betwee glycemic cotrol ad the developmet ad progressio of diabetic kidey disease. The recet publicatio of three ladmark trials (ACCORD, ADVANCE ad VADT) [8 11] has added to our uderstadig of the relatioship betwee glycemic cotrol ad kidey disease. Here, we review these three trials, as well as other major studies that provide evidece for the importat role of glucose cotrol i the prevetio of diabetic kidey disease ad real failure. Studies of patiets with Type 1 diabetes The DCCT assessed the effect of itesive glucose cotrol o the developmet of diabetic ephropathy ad declie i real fuctio i youg patiets with Type 1 diabetes [1]. A total of 1441 patiets with Type 1 diabetes, a mea glycated hemoglobi (HbA1c) of 8.9% ad a mea age of 7 years were radomized. The cohort cosisted of two groups: a primary prevetio group with o retiopathy, mild microalbumiuria (<40 mg/day) ad a mea diabetes duratio of.6 years; ad a secodary prevetio group with mild-to-moderate oproliferative retiopathy or microalbumiuria (<00 mg/day) ad a mea diabetes duratio of 8.8 years. The effect of itesive isuli therapy (media HbA1c reached was approximately 7%) was compared with covetioal therapy (media HbA1c reached was approximately 9%). The primary outcome was the developmet ad progressio of retiopathy; other secodary outcomes icluded macrovascular ad real outcomes. After a mea follow-up of 6.5 years, itesive cotrol as compared with covetioal

3 Reducig real failure: how low do glucose levels eed to go? cotrol, led to a 39 ad 54% reductio i the occurrece of ew microalbumiuria ad ew macroalbumiuria, respectively (95% CI: 1 5 ad 19 74%, respectively).moreover, whe the patiets were followed for a further 8 years i the post trial, EDIC study, the effects of the former itesive cotrol compared with covetioal cotrol, further reduced the occurrece of ew microalbumiuria by 59% (despite the HbA1c levels covergig after 4 years) [13] cotributig to a decreased risk of ay cardiovascular disease by 4% (p = 0.0) [14]. There was a two- to three-fold icreased risk of major hypoglycemia i the itesive cotrol group compared with the covetioal group. Studies of patiets with Type diabetes The UKPDS [15], a ope label trial of 3867 ewly diagosed patiets with Type diabetes, compared the effects of itesive glycemic cotrol with either sulfoylurea, or isuli versus covetioal dietary therapy o the developmet of microvascular ad macrovascular complicatios. Primary aggregate ed poits were ay diabetes-related ed poit (icludig real failure defied as requiremet for dialysis or a plasma creatiie greater tha 50 µmol/l); diabetes-related death (icludig death from real disease) ad all-cause mortality. Subcliical real ed poits were also assessed every 3 years ad icluded microalbumiuria, proteiuria ad a twofold icrease i plasma creatiie. After 10 years, the mea HbA1c was 7% i the itesive therapy group compared with 7.9% i the covetioal therapy group. The risk of ay diabetes-related ed poit was 1% lower i the itesive therapy group compared with the covetioal therapy group. This was primarily drive by a 5% reductio i risk of micro vascular complicatios (defied as vitreous hemorrhage, retial photocoagulatio or real failure). After 9 years, fewer patiets i the itesive group compared with the covetioal group developed microalbumiuria (19. vs 5.4%; relative risk [RR]: 0.76; p = ), proteiuria (4.4 vs 6.5%; RR: 0.67; p = 0.06) ad doublig i serum creatiie (0.71 vs 1.76%; RR: 0.4; p = 0.07). However, more weight gai ad a greater umber of total ad major hypoglycemic episodes were reported i the itesive versus the covetioal group, especially i those patiets receivig isuli (3% of patiets o isuli had a major hypoglycemic episode, ad 40% had either a major or mior maagemet perspective Urie albumi excretio Blood pressure Normal rage Glomerular filtratio Normo- Micro- Proteiuria Diabetes duratio Figure 1. Natural history of classical diabetic ephropathy. Reproduced with permissio from [3]. episode). The 10 year post-trial follow-up has subsequetly reported maitaied beefits o microvascular complicatios (vitreous hemorrhage, retial photocoagulatio or real failure) i the itesive group, despite early loss of the glycemic differece betwee the two treatmet groups [16]. The Kumamoto trial [17], studied the effect of itesive glucose cotrol with isuli therapy o the developmet of microvascular complicatios i 110 Japaese patiets with Type diabetes (55 patiets who had diabetes without microvascular complicatios i the primary prevetio cohort ad 55 patiets who had mild retiopathy ad microalbumiuria i the secodary itervetio cohort). Patiets were radomized to either a itesive regime of rapid-actig isuli with meals ad basal itermediate isuli at ight, or a covetioal regime of a itermediate actig isuli oce or twice daily. The primary prevetio group had a mea age of 40 years, average duratio of diabetes of 6.5 years ad mea HbA1c of 9%. The secodary itervetio group had a mea age of 50.5 years, average duratio of diabetes of 10.3 years ad mea HbA1c of 9.%. After 6 years, a mea HbA1c of 7.1% was achieved i the itesive group versus 9.4% i the covetioal group. Compared to the covetioal group, the itesive group had a sigificatly lower rate of developmet of ephropathy. I particular, i the primary prevetio group, 7.7% of those receivig itesive therapy developed albumiuria compared with 8% of those receivig covetioal therapy 7

4 maagemet perspective Lo & Zougas (p = 0.03). Ulike the UKPDS ad DCCT, this study oly reported a icreased risk of mild hypoglycemia i the itesive versus the c ovetioal therapy groups. The Vetera Affairs Cooperative Study o Glycemic Cotrol ad Complicatios i Type diabetes [18] was of similar size to the Kumamoto study, ad examied the effects of itesive glucose cotrol o microalbumiuria ad creatiie clearace. Ivestigators assiged 153 male patiets of mea age 60 years, with diabetes of mea duratio 7.8 years ad with a mea HbA1c of 9.8%, to either itesive cotrol (mea achieved HbA1c was 7.1%) or stadard cotrol (mea HbA1c achieved was 9.1%). Of the cohort 38% had microalbumiuria, ad were evely assiged to both groups. Both groups received isuli, however while patiets i the stadard group could oly receive a maximum of two ijectios of isuli, the itesive group could be o a multidose regime. At years of follow-up, itesive therapy slowed the progressio of microalbumiuria sigificatly with the chages i the albumi:creatiie ratio from baselie to years beig i the itesive group compared with i the stadard group (p = 0.046). This effect was demostrated most i patiets with evidet microalbumiuria at study etry. The itesive group also had a slower declie i creatiie clearace compared with the stadard cotrol. For patiets without baselie microalbumiuria, the declie was osigificat i both the itesive ad stadard groups. I patiets with microalbumiuria, the itesive group showed a sigificat 1% reductio i creatiie clearace (p = ) compared with a sigificat 17% declie (p = 0.009) i the stadard cotrol. The majority of older trials have studied the effects of targetig a HbA1c level of close to 7% compared with levels of 8% or greater. More recetly, three major radomized trials, the ACCORD, the ADVANCE ad the VADT, have examied the effects of targetig a HbA1c level less tha 7%, compared with levels of greater tha 7% o the developmet of both macrovascular ad microvascular c omplicatios, icludig real outcomes (Table 1). The ACCORD [8] glycemic cotrol arm radomized 10,51 North America patiets with Type diabetes of media duratio 10 years, average HbA1c of 8.1%, mea age 6 years, ad either with prevalet cardiovascular disease or at high risk of cardiovascular disease, to either 8 Diabetes Maage. (01) (1) itesive glycemic cotrol (media achieved HbA1c was 6.4%) or stadard glycemic cotrol (media achieved HbA1c was 7.5%). The primary outcome was a composite of major cardiovascular evets, defied as ofatal myocardial ifarctio, o fatal stroke ad death from cardiovascular causes. Secodary outcomes icluded two prespecified composite microvascular ed poits. The first composite ed poit was the developmet of real failure (defied as iitiatio of dialysis or ed-stage real disease, real trasplatatio, or rise of serum creatiie >91.7 µmol/l) or retiopathy (requirig retial photocoagulatio or vitrectomy). The secod composite ed poit added peripheral europathy to the first composite outcome. I the itesive cotrol group, therapy was titrated mothly for 4 moths, ad moths thereafter, to achieve ad maitai the proposed glycemic target. I the stadard cotrol group, therapy ad targets were reviewed every 4 moths. HbA1c was rapidly reduced withi the first 6 moths with combiatios of isuli ad other oral glucose-lowerig agets. After a average 3.5 years of follow-up, the trial was termiated prematurely due to a icreased risk of all-cause ad cardiovascular mortality i the itesive cotrol group. At this time, there was o sigificat differece betwee the groups for either the first composite micro vascular (HR: 1.00; 95% CI: ; p = 1) or the secod composite outcome (HR: 0.95; 95% CI: ; p = 0.19) or the rate of overt real failure (HR: 0.95; 95% CI: ; p = 0.713). Compared with the covetioal group, the itesive group had a 1% reductio i risk of microalbumiuria (p = ), 31% reductio i risk of macro albumiuria (p = ) but a 7% icrease i the risk of doublig of serum creatiie or decrease i estimated glomerular filtratio rate (egfr; p = 0.016) ad a threefold icreased risk of severe hypoglycemia. This differece i the risk of doublig of serum creatiie was abset after a media follow-up of 5 years postcessatio of itesive glycemic cotrol. The iitial declie i egfr was thought to be due to a decrease i glomerular hyperfiltratio associated with improved glycemic cotrol [9]. ADVANCE [10] was a multiatioal trial that radomized 11,140 patiets with Type diabetes of media duratio of 7 years, mea HbA1c of 7.5%, mea age of 66 years ad with major macrovascular or microvascular complicatios or at least oe other risk factor, to either stadard or itesive glucose cotrol. The composite primary

5 Alb: Albumi; Cr: Creatiie; HbA1c: Glycated hemoglobi VADT 10,51 ACCORD glycemic arm 11, (male oly) VA Cooperative Study ADVANCE glycemic arm Kumamoto 110 Study UKPDS DCCT 1 Sample Type of Duratio of Study size () diabetes diabetes at duratio baselie (years) (years) Trial HbA1c achieved i itesive group (%) HbA1c achieved i covetioal or stadard group (%) Lower progressio of m icroalbumiuria Chages i Alb:Cr ratio from baselie were vs 0.141; p = % reductio i developmet of microalbumiuria 31% reductio i the developmet of macroalbumiuria 1% reductio i the developmet of macroalbumiuria, doublig of Cr, eed for real replacemet therapy or real death Reductio i albumiuria progressio 9.1 vs 13.8% Developmet of microalbumiuria decreased by 4% ad doublig of Cr decreased by 60% at 9 years of follow-up Lower progressio of albumiuria 7.7 vs 8% 39% lower rate of m icroalbumiuria 54% reductio i the occurrece of albumiuria More weight gai ad icreased risk of severe h ypoglycemia i the i tesive vs stadard group Sigificatly icreased risk of mortality causig p remature termiatio of study at 3.5 years Icreased risk of severe h ypoglycemia i the i tesive vs stadard group Icreased risk of major hypoglycemia ad mea 4.6 kg more weight gai at 5 years i itesive vs covetioal group More weight gai ad icreased risk of m ajor h ypoglycemia i the i tesive vs covetioal group No sigificat icrease i weight gai or severe h ypoglycemia i the i tesive isuli vs c ovetioal isuli group Weight gai ad h ypoglycemia risks were ot reported Differece Real outcomes i itesive group vs Complicatios i HbA1c covetioal group betwee groups (%) Table 1. Summary of major radomized cotrolled trials i patiets with diabetes pertaiig to glycemic lowerig ad real outcomes. [11] [10] [8,9] [18] [17] [15] [1] Ref. Reducig real failure: how low do glucose levels eed to go? maagemet perspective 9

6 maagemet perspective Lo & Zougas outcome was major macrovascular evets (cardiovascular death, ofatal myocardial ifarctio or ofatal stroke) ad major microvascular evets (ew or worseig ephropathy or retiopathy) assessed both together ad separately. The itesive group received gliclazide modified release plus other glucose lowerig agets as required, to achieve a target HbA1c of 6.5%. The stadard therapy group received sulfoylureas other tha gliclazide, plus other drugs ad isuli as required, as per local guidelies. I compariso to ACCORD, the HbA1c level was gradually reduced over 3 years to a mea of 6.5% i the itesive group compared with 7.3% i the stadard group. After a media 5-years follow-up, the icidece of the combied major macrovascular ad microvascular outcome was reduced by 10% (95% CI: 18%; p = 0.01). Similarly to the UKPDS, most of this effect was due to a reductio i microvascular complicatios, particularly a sigificat 1% reductio i the icidece of ew or worseig ephropathy defied as the developmet of macroalbumiuria (urie albumi:creatiie ratio >33.9 mg/mmol), doublig of serum creatiie 00 µmol/l, eed for real replacemet therapy or death due to real disease. Itesive glycemic cotrol was associated with a modestly icreased rate of severe hypoglycemia. The VADT was a smaller radomized cotrol trial that studied the effect of itesive versus stadard glucose cotrol o 1791 USA military veteras with a mea age of 60 years, Type diabetes of mea duratio of 11.5 years, ad mea HbA1c of 9.4% [11]. The primary outcome was the time to first occurrece of a major cardio vascular evet. Secodary outcomes icluded microvascular complicatios such as ephropathy, retiopathy ad europathy. Glucose-lowerig strategies icluded the use of oral glucose lowerig agets ad isuli. After a media follow-up of 5.6 years, the itesive group achieved a HbA1c of 6.9% compared with 8.4% i the stadard group. This did ot result i a sigificat differece i the primary composite major cardiovascular evet ed poit. However, a sigificat reductio i albumiuria progressio was observed (9.1 vs 13.8%; p < 0.01). No other reoprotective effects of itesive therapy were reported. Similar to the ACCORD trial, severe hypoglycemia was icreased fourfold with i tesive glucose lowerig. Coclusio While differig i desig, as well as extet ad itesity of glucose cotrol, the available 30 Diabetes Maage. (01) (1) evidece from trials would suggest that over several years, more itesive glucose cotrol will improve a rage of real outcomes i particular the developmet ad progressio of albumiuria ad thus future developmet of diabetic ephropathy ad ed-stage kidey disease i patiets with Type 1 ad diabetes. The optimal HbA1c target for prevetig kidey disease is likely to be less tha 7% based o curret trial evidece. The beefits of aimig for such itesive glucose cotrol must be weighed up agaist the icreased risks of major hypoglycemia with agets i commo use at this time. I older patiets or those with other comorbidities, a low HbA1c target may be impractical ad usafe. Thus the cotrol of other risk factors for ephropathy such as hypertesio, ad dyslipidemia may be more critical for these patiets [19,0]. Limitatios of curret evidece There are several limitatios to the ifereces that ca be draw from available glucose l owerig trials. First, while itesive glucose cotrol results i better real outcomes, the lowest HbA1c achieved i trials was 6.4%. Whether further real beefits ca be safely achieved by lowerig the HbA1c to eve closer to 6% is curretly ukow. Secod, i most trials, the oly real outcome observed to sigificatly improve with itesive glucose cotrol was the developmet of albumiuria. This is because most of the trials were uderpowered ad too short to detect ay effects o the developmet of more advaced kidey disease such as ed-stage kidey disease requirig dialysis or trasplatatio. It is ot kow whether oalbumiuric pathogeetic pathways of diabetic ephropathy are modulated by strict glycemic cotrol. Log-term follow-up of the ACCORD, VADT ad ADVANCE cohorts will address the questio of legacy or metabolic memory i those with log stadig diabetes icludig the effects o more advaced kidey disease outcomes. Future perspective Curret strategies for glucose lowerig ofte iclude oral glucose lowerig agets ad isulis that icrease the risk of hypoglycemia. As a result, there is a trade-off betwee tight glucose cotrol ad the experiece of hypoglycemia. This is especially the case whe these agets are

7 maagemet perspective Reducig real failure: how low do glucose levels eed to go? used i the settig of impaired real fuctio. The exceptios are metformi, DPP4 ihibitors ad GLP1 agoists, which have a egligible risk of hypoglycemia whe used aloe or i combiatio with each other. However, these agets are cotraidicated (apart from some curretly available DPP4 ihibitors) oce the egfr declies to less tha 30 ml/mi or may require dose reductio oce the egfr is less tha 60 ml/mi. Furthermore, whe used aloe these agets are ulikely to achieve tight glucose cotrol i the majority of patiets [1]. Therefore, there is a eed for more physiological methods of isuli replacemet ad the developmet of ovel agets that target the differet pathologic pathways resultig i diabetes ad that ca be used i those with real impairmet Refereces Papers of special ote have bee highlighted as: of iterest of cosiderable iterest Atkis RC, Zimmet P. Diabetic kidey disease: act ow or pay later. Diab. Res. Cli. Pract. (90), e54 e56 (011). Hahr A, Molitch ME. Diabetes, cardiovascular risk ad ephropathy. Cardiol. Cli. (8), (010). 3 Marshall SM, Flyvbjerg A. Diabetic ephropathy. I: Textbook of Diabetes (4th Editio). Holt RIG, Cockram CS, Flyvbjerg A et al. (Eds). Blackwell Publishig Ltd., West Sussex, UK, (010). Zelmaovitz T, Gerchma F, Balthazar AP et al. Diabetic ephropathy. Diabetol. Metab. Sydr. 1(1), 10 (009). 5 Chadba S, Howell M, Twigg S et al. Natioal evidece based guidelies for diagosis, prevetio ad maagemet of chroic kidey disease i Type diabetes. Diabetes Australia ad the NHMRC. Caberra, Australia (009). 6 Good review article o the cocept of albumiuric ad oalbumiuric pathways of diabetic ephropathy. 8 Gerstei HC, Miller ME, Byigto RP et al.; ACCORD Study Group. Effects of itesive glucose lowerig i Type diabetes. N. Egl. J. Med. 358(4), (008) Excellet evidece-based guidelies o maagemet of chroic kidey disease i Type diabetes. Jerums G, Paagiotopoulos S, Premarate E, MacIsaac RJ. Itegratig albumiuria ad GFR i the assessmet of diabetic ephropathy. Nat. Rev. Nephrol. (5), (009). S Zougas has received speaker hooria ad travel grats from Servier, MSD, GSK, Novartis, Novo Nordisk, Boehriger Igleheim, AstraZeeca ad BMS. She has also served o exteral advisory boards for MSD, Novo Nordisk, ad Boehriger Igleheim. The authors have o other relevat affiliatios or fiacial ivolvemet with ay orgaizatio or etity with a fiacial iterest i or fiacial coflict with the subject matter or materials discussed i the mauscript apart from those disclosed. No writig assistace was utilized i the productio of this mauscript. Jerums G, Premarate E, Paagiotopoulos S, Clarke S, Power DA, MacIsaac RJ. New ad old markers of progressio of diabetic ephropathy. Diabetes Res. Cli. Pract. (8S), S30 S37 (008). Good review chapter o pathophysiology ad treatmet of diabetic ephropathy. 4 Fiacial & competig iterests disclosure 7 1 with miimal risk of hypoglycemia [1, 3]. This will make the achievemet of a HbA1c level of less tha 7% ad closer to euglycemia, a reality for more patiets with diabetes. Ismail-Beigi F, Crave T, Baerji MA et al.; ACCORD Study Group. Effect of itesive treatmet of hyperglycemia o microvascular outcomes i Type diabetes: a aalysis of the ACCORD radomised trial. Lacet 376, (010). ADVANCE collaborative group. Itesive blood glucose cotrol ad vascular outcomes i patiets with Type diabetes. N. Egl. J. Med. 358(4), (008). Duckworth W, Abraira C, Moritz T et al. Glucose cotrol ad vascular complicatios i veteras with Type diabetes. N. Egl. J. Med. 360(), (009). The effect of itesive treatmet of diabetes o the developmet ad progressio of log-term complicatios i isulidepedet diabetes mellitus. The Diabetes Cotrol ad Complicatios Trial Research Group. N. Egl. J. Med. 39(14), (1993). Ladmark trial o the effects of glucose lowerig o real fuctio i Type 1 diabetes. 13 Writig Team for the Diabetes Cotrol ad Complicatios Trial/Epidemiology of Diabetes Itervetios ad Complicatios Research Group. Sustaied effect of itesive treatmet of Type 1 diabetes mellitus o the developmet ad progressio of diabetic ephropathy. Epidemiology of diabetes itervetios ad complicatios (EDIC) study. JAMA 90, (003). 14 Natha DM, Cleary PA, Backlud JY et al. Itesive diabetes treatmet ad cardiovascular disease i patiets with Type 1 diabetes. N. Egl. J. Med. 353, (005). 15 Itesive blood-glucose cotrol with sulfoylureas or isuli compared with covetioal treatmet ad risk of complicatios i patiets with Type diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lacet (35), (1998). Ladmark trial o the effects of glucose lowerig o real fuctio i Type diabetes. 16 Holma RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10 year follow-up of itesive glucose cotrol i Type diabetes. N. Egl. J. Med. 359(15), (008). 17 Ohkubo Y, Kishikawa H, Araki E et al. Itesive isuli therapy prevets the progressio of diabetic microvascular complicatios i Japaese patiets with o-isuli depedet diabetes mellitus: a radomised prospective 6 year study. Diabetes Res. Cli. Pract. (8), (1995). 31

8 maagemet perspective Lo & Zougas Levi SR, Cobur JW, Abraira C et al. Effect of itesive glycemic cotrol o microalbumiuria i Type diabetes. Veteras Affairs Cooperative Study o Glycemic Cotrol ad Complicatios i Type Diabetes Feasibility Trial Ivestigators. Diabetes Care 3(10), (000). Gaede P, Vedel P, Larse N et al. Multifactorial itervetio ad cardiovascular disease i patiets with Type diabetes. N. Egl. J. Med. 348, (003). 0 1 Also called the STENO study. Major study showig the effectiveess of multifactorial itervetio i decreasig progressio of real impairmet i Type diabetes. Gaede P, Lud-Aderse H, Parvig HH et al. Effect of multifactorial itervetio o mortality i Type diabetes. N. Egl. J. Med. 358(6), (008). Natha DM, Buse JB, Davidso MB et al. Medical maagemet of hyperglycemia i Type diabetes: a cosesus algorithm for Diabetes Maage. (01) (1) the iitiatio ad adjustmet of therapy. Diabetes Care 3(1), (009). Rossig P, de Zeeuw D. Need for better diabetes treatmet for improved real outcome. Kidey It. Suppl. (79), S8 S3 (011). 3 Seaquist ER, Ibrahim HN. Approach to the patiet with Type diabetes ad progressive kidey disease. J. Cli. Edocriol. Metab. 95(7), (010). Good review article o maagemet of diabetic ephropathy.