Standards of Care for Diabetes - Diabetes Care

C A L R E V I E W

Standards of Care forDiabetesGORDON C. WEIR, MDDAVID M. NATHAN, MD

DANIEL E. SINGER, MD

Proper treatment of diabetes will pre-vent, delay, or ameliorate many ofits chronic complications. More-

over, timely detection of the early stagesof complications is necessary to initiateefficacious treatment. Caring for diabetesis a special medical challenge because thedisorder is chronic, and the improvementin outcomes is largely dependent on long-term preventive care delivered by a coor-dinated team of health care providers.There is an extraordinary need for activepatient participation in this care. Diabetescare is provided in a wide variety of set-tings, but in all situations patients shouldbe provided with help for the manage-ment of metabolic control, attention tospecific diabetes-related problems, accessto appropriate specialists for specificcomplications, and assurance that generalmedical care is also being provided. Thistechnical review will focus on the generalaspects of diabetes care provided by a co-ordinated group of health care providerswho have specific expertise, but not withmany of the more specialized issues ofmanagement and policy covered else-where in the literature.

Three major aspects of treatmentwill be discussed:

• Glycemic control.

• Treatment of other conditions that mayhave a profound influence on the de-velopment of chronic complications,such as dyslipidemia and hyperten-sion.

• Identification of risk factors for, andearly evidence of, the complications ofretinopathy, nephropathy, and footproblems, to institute specific preven-tion and treatment approaches.

METABOLIC CONTROL ANDDIABETES COMPLICATIONS —The major chronic complications of dia-betes include retinopathy, nephropathy,neuropathy, and large vessel disease (pe-ripheral, cerebral, and coronary). Thesecomplications have devastating conse-quences including visual impairment,blindness, renal failure, amputation,stroke, myocardial infarction, and short-ened life span.

From the Joslin Diabetes Center (G.C.W.); the Diabetes Unit (D.M.N.); and the General InternalMedicine Unit (D.E.S.), Department of Medicine, Massachusetts General Hospital and HarvardMedical School, Boston, MA.

Address correspondence and reprint requests to Gordon C. Weir, MD, Joslin Diabetes Center,One Joslin Place, Boston, MA, 02215.

DCCT, Diabetes Control and Complications Trial; IDDM, insulin-dependent diabetes melli-tus; NIDDM, non-insulin-dependent diabetes mellitus; UGDP, University Group DiabetesProject; ADA, American Diabetes Association; SHEP, Systolic Hypertension in the Elderly Pro-gram; DRS, Diabetic Retinopathy Study; ETDRS, Early Treatment of Diabetic Retinopathy Study;PDR, proliferative diabetic retinopathy; ACE, angiotensin-converting enzyme.

For decades, a consuming debateover the benefits of glycemic control hasraged (1-15). Studies focusing on glyce-mic control and complications includedepidemiological surveys, experimentalwork in animals, many retrospectivestudies, and a few small randomized clin-ical trials. Although the weight of evi-dence provided a rationale for control ofblood glucose levels, conclusive evidencewas finally provided by the Diabetes Con-trol and Complications Trial (DCCT),which demonstrated that intensive treat-ment of diabetes, aimed at achieving gly-cemic control as close to the normal rangeas possible, delayed the onset and slowedthe progression of diabetic retinopathy,nephropathy, and neuropathy (16).

The DCCT, which ended in June1993, was prospective, randomized, andcarried out at 29 centers and included1,441 patients with insulin-dependentdiabetes mellitus (IDDM) recruited from1983 through 1989. One treatment groupreceived conventional therapy that wasjudged to be current state-of-the-art careand consisted of one or two daily injec-tions of insulin. The intensive therapygroup received insulin injections three ormore times per day or used an externalinsulin pump. In addition, these patientswere aggressively managed by the healthcare team with intensive attention to dietand frequent visits and phone calls. Theywere expected to test their glucose valuesat least four times a day and come forclinic visits once a month. There were twoarms of the DCCT, a primary preventionstudy that included patients with no com-plications, and a secondary interventionstudy that included patients with "verymild to moderate" nonproliferative reti-nopathy at baseline. The patients werefollowed for a mean of 6.5 years with atotal of 9,300 patient-years; 99% of thepatients completed the study.

The adherence of the intensivetherapy group was striking, with the 711patients maintaining a mean HbAlc of~7.0% (the normal range was <6.05%),which was clearly lower than the mean

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value of ~9.0% in the conventional treat-ment group of 730 patients. The meancapillary glucose value for the intensivegroup was 155 ± 30 mg/dl (mean ± SD),and for the conventional group it was 231± 55 mg/dl.

The efficacy of intensive treatmentwas dramatic. Intensive therapy reducedthe average risk of development of a sus-tained change in retinopathy in the pri-mary-prevention cohort by 76%. In thesecondary intervention, cohort intensivetreatment led to a 54% reduction in therisk of progression of retinopathy. For ne-phropathy, in the primary-prevention co-hort, intensive treatment reduced the riskof developing microalbuminuria by 34%(>40 mg/24 h), and, in the secondary-intervention group, the risk was reducedby 56%. The development of neuropathy(assessed by neurological examinations,autonomic nerve testing, and nerve con-duction studies), was reduced by 69%with intensive therapy in the primary-prevention cohort, and by 57% in the sec-ondary-intervention group. Macro vascu-lar disease was difficult to assess becauseof the low frequency in this young popu-lation, but in the combined cohort, inten-sive therapy reduced the presence ofhypercholesterolemia (low-density li-poprotein cholesterol >160 mg/dl) by34%. The number of major cardiovascu-lar and peripheral vascular events waslower in the intensive treatment groupthan in the conventionally treated group,but the number of events was small anddid not achieve a statistically significantdifference (P = 0.06).

In evaluating adverse events andsafety, mortality did not differ betweenthe two treatment groups. However, inthe intensive therapy group, the inci-dence of severe hypoglycemia was threetimes higher. This is a matter of concern,particularly because episodes of comaand seizures were also increased by two-to threefold. Although there were nodeaths definitely attributable to hypogly-cemia, the potential risk for motor vehicleand other accidents is of great concern.Intensive therapy was also associated

with weight gain, with a mean increase of4.6 kg more than the conventional groupafter 5 years.

An important question is whetherthere is a threshold effect such that bene-fits will only accrue if a certain level ofglycemic control is achieved. A definitiveanswer is not available, but analysis of theresults in the intensive treatment groupsuggests that risk of worsening retinopa-thy increases gradually along with risingglycohemoglobin values, suggesting thatany improvement in control could bebeneficial. Because of the success foundwith intensive treatment in the DCCT,this approach to achieving glycemic con-trol must be considered the new standardof care for IDDM. However, the methodsused in the study were demanding andexpensive; in the future, efforts will bemade to reach this standard with simplertechniques. For example, the DCCTschedule of clinic visits at least once amonth may not be necessary; little isknown about the optimal frequency ofsuch visits. The requirements for frequentself-glucose monitoring should probablycontinue. The relative popularity of mul-tiple injections versus external pumps re-mains to be determined; both providedsimilarly good results. The need for a co-ordinated approach among physicians,nurses, dietitians, mental health workers,or their equivalents, with a heavy empha-sis on training in self-management is nowstrongly supported by the DCCT results.Indeed, national standards for diabetespatient education programs already exist(17). Until studies demonstrate that sim-pler approaches provide equivalent con-trol with equal or fewer adverse events,the DCCT intensive treatment strategyshould be adopted. Some caveats raisedby the DCCT study group (16) were thatcaution should be used in applying theseresults to children <13 years of age, andpatients with advanced complications orrecurrent hypoglycemia, where the risk-to-benefit ratio may not be the same as inthe DCCT study population.

A critical question is whether theDCCT results apply to non-insulin-de-

pendent diabetes mellitus (NIDDM),which accounts for the vast majority ofcases of diabetes. At the onset, it is worth-while to acknowledge that, currently,there is no definitive evidence to resolvethis controversial issue. At best we canshape the competing concerns from indi-rect evidence. The etiologies of IDDM andNIDDM are different. IDDM results fromautoimmune destruction of islets, whileNIDDM has a complex etiology of relative)3-cell failure and insulin resistance. Mi-crovascular complications are more fre-quent in IDDM than in NIDDM, wheremacrovascular disease dominates. None-theless, microvascular and neurologicalcomplications in NIDDM are clinicallyand pathologically similar to those ofIDDM, and they are similarly associatedwith duration of diabetes and degree ofhyperglycemia (2,18-21). It is reasonableto suggest that the beneficial effect of gly-cemic control on forestalling microvascu-lar complications in IDDM demonstratedby the DCCT may also apply to NIDDM.The major controversy concerns themeans for achieving glycemic control andtheir relative risks and benefits.

There is agreement about the ben-eficial effects of diet, exercise, and weightloss as a means to glycemic control. Un-fortunately, such approaches are notsufficient for many patients. Concernsemerge with the use of oral agents andintensive insulin therapy to achieve nearnormal glucose levels in NIDDM. Theonly completed trial of glycemic controlin NIDDM, the University Group Diabe-tes Project (UGDP) study, did not observea benefit of insulin therapy in preventingvascular complications, and did observean unexpected increase in cardiovascularmortality with tolbutamide (22,23).These decades-old results of the UGDPhave been widely debated but cannot beentirely dismissed. Probably of greaterconcern is the evidence suggesting thathyperinsulinemia leads to increased riskof cardiovascular disease. This evidencecomes from observational epidemiologi -cal studies of predominantly nondiabeticpopulations, and is not completely con-

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sistent across studies (24-28). Nonethe-less, it is possible that intensive use of ex-ogenous insulin may lead to an increasedrisk of macro vascular disease. A recent2-year pilot study of intensive therapy inNIDDM, the Veterans Cooperative Study,observed a trend toward an increased riskfor cardiovascular events, but this was notstatistically significant when adjusted forbaseline status (29). Intensive regimenswith insulin, and even sulfonylurea com-pounds, can lead to weight gain, and raisethe risk of hypoglycemic episodes thatwill be particularly poorly tolerated in theolder NIDDM patient with vascular dis-ease.

As a result of these considerations,it seems premature to advocate the use ofintensive pharmacological regimens toachieve near-normal glucose control in allpatients with NIDDM. Physicians shouldrecognize the likely benefits of improvedglycemic control on preventing microvas-cular complications, and should encour-age diet and exercise to achieve glycemictargets. Use of intensive pharmacologicalregimens should be based on the clinicalstatus of individual patients. In contrastto IDDM, many patients with NIDDMwho require insulin therapy to achieveglycemic targets can be managed satisfac-torily on one or two injections per day,and they need not perform self-bloodglucose monitoring as frequently. Pa-tients who are relatively younger andlikely to have greater tolerance of hypo-glycemia would seem to be good candi-dates for more aggressive regimens. Ef-forts to achieve weight loss and reduceother recognized cardiovascular risk fac-tors must continue when diabetes man-agement is intensified. Patients whoseshorter life expectancies would preventtheir realizing the benefits of better glyce-mic control, those with serious cardiovas-cular disease, and those for whom hypo-glycemic episodes would be particularlydangerous would appear to be poor can-didates for intensive regimens. Physiciansand patients should be aware of the un-certainties in the clinical evidence bearingon their decision. A randomized trial of

improving glycemic control in NIDDMwith insulin and sulfonylurea agents isunderway in the U.K., and will hopefullyprovide some clarification of these issues(30,31).

MANAGEMENT OFDYSLIPIDEMIA ANDHYPERTENSION— Dyslipidemiaand hypertension are known to be impor-tant risk factors for the macrovascular dis-ease of people with diabetes, with most ofthe data generated in NIDDM popula-tions (32-34). In addition, hypertensionis known to have an adverse influence onthe progression of nephropathy and per-haps on retinopathy (21,35-38). There-fore, vigilant screening for hypertensionat regular intervals and appropriate treat-ment are an important part of diabetescare. These issues are not discussed indepth in this technical review because theAmerican Diabetes Association (ADA) hasalready developed Consensus Statementsabout both hypertension and dyslipi-demia (39,40). A limitation in creatingscreening and treatment recommenda-tions is that the vast majority of clinicalstudies dealing with the effects of treat-ment of hypertension and dyslipidemiaeither exclude or fail to separately analyzesubjects with diabetes. Thus, there is littledirect information about the influence ofantihypertensive or lipid-lowering treat-ment on stroke, ischemic heart disease, ormortality in diabetes. A Norwegian studyfound a major decrease in mortality withbeta blockade in diabetic patients aftermyocardial infarction (42). In the SystolicHypertension in the Elderly Program(SHEP), the use of chlorthalidone wasfound to have a significant benefit for pa-tients with diabetes and coronary arterydisease (43,44). Nonetheless, because ofthe limited clinical trial data, treatmentrecommendations are mostly based onepidemiological observations and extrap-olation from randomized trials carriedout in nondiabetic patients. It must beemphasized that decisions about drug

treatment for these two conditions re-quire specific consideration in peoplewith diabetes. For example, some gener-ally useful drugs may have adverse effectson glycemic control, defense against insu-lin reactions, sexual function, or posturalhypotension (39,40). With regard to theuse of aspirin to prevent large vesselevents, available evidence indicates thatthe benefits for diabetic patients are sim-ilar for those without diabetes (41).

SCREENING FORRETINOPATHY — Some of the mostimportant advances in the treatment ofdiabetic retinopathy have been laser ther-apy and vitreous surgery. A PositionStatement by the ADA on screening fordiabetic retinopathy has been published(45). The benefits of laser therapy havebeen unequivocally demonstrated by twolarge multicentered trials: the DiabeticRetinopathy Study (DRS) and the EarlyTreatment of Diabetic Retinopathy Study(ETDRS). These studies were models ofclinical investigation because treatmentcould be randomized to one eye using theother as a control. Moreover, the endpoints of graded retinal photographs andvisual acuity allowed precise measure-ment of outcome. The DRS showed thattimely panretinal laser therapy could re-duce the risk of severe visual loss by al-most 60% (46,47). An even more strikingbenefit is shown in the ETDRS (48,49);data from several sources have estimatedthat untreated proliferative diabetic reti-nopathy (PDR) causes blindness in 50%of patients within 5 years (50-53), but inthe ETDRS, laser therapy resulted in only5% becoming blind in 5 years. In addi-tion, the ETDRS found that focal lasertherapy for macular edema could reducethe risk of moderate visual loss by 50%(49). Vitreous surgery provides a benefitfor a relatively small number of severelyaffected individuals, but can provide im-pressive improvement in vision (54,55).In addition to the obvious health benefitsto patients, economic analysis shows that


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important financial savings to society re-sult from this therapy (56,57).

Several organizations, includingthe ADA, have endorsed the recommen-dation that patients with IDDM have anannual dilated eye examination after 5years of diabetes and that patients withNIDDM have a dilated examination at thetime of diagnosis of diabetes and annuallythereafter (45,58-60). These examina-tions should be carried out by competenteye care professionals. It has been docu-mented that undilated examinations missa considerable amount of proliferativeretinopathy (61,62). There is debateabout whether primary care physiciansand diabetologists should perform fundo-scopic examinations. Some have shownthat these individuals can screen effec-tively (62), but it is generally felt that thescreening should be performed by onetrained in eye care. Unfortunately, ~50%of adults with diabetes in the UnitedStates are not receiving appropriatescreening for retinopathy, with the prob-lem being more severe in lower socioeco-nomic groups (63). Educating patientsabout the need for appropriate screeningis very important because it may help en-sure timely therapy.

PREVENTION OF LOWEREXTREMITY PROBLEMS —Ulceration and amputation of the lowerextremities are among the most importantcomplications of diabetes (64,65). About55,000 amputations are performed eachyear on people with diabetes, about halfof the total number of nontraumatic am-putations performed (66,67). Diabeticneuropathy is the major cause of limb-threatening ulceration, but macrovascu-lar disease also plays a major role; the twoare often found together (68,69). Unfor-tunately, physicians caring for peoplewith diabetes frequently fail to examinetheir patients' feet (70,71). Moreover, pa-tients with diabetes often do not take ap-propriate care of their feet (72). Problemscan be avoided if care providers examine

feet on a regular basis and if patients arebetter educated about proper foot care. Astrong case can be made that certain high-risk groups, particularly those with insen-sate feet, should receive especially vigor-ous education. Absent pedal pulses andan ankle-arm blood pressure index of<0.45 strongly suggest the presence ofsignificant vascular disease (68). At thepresent time, it is felt that all diabetic pa-tients should receive proper self-manage-ment training to perform necessary footcare and that health care providers shouldexamine feet on a regular basis to look forulcers, structural deformities, neuropa-thy, and vascular insufficiency. Althoughmost of the existing studies are uncon-trolled, they suggest that attention to footcare can lower the rate of lower extremityamputations by 44-85% (73-76). In a re-cent randomized control trial of 395 indi-viduals with diabetes in Indiana, patientswere educated about self-foot care, andhealth care providers were given practiceguidelines and informational flow sheets(77). These interventions led to improvedself-foot care behavior and less lower ex-tremity disease, but the study was notlarge enough to obtain meaningful infor-mation about amputation.

SCREENING FOR DIABETICNEPHROPATHY— Diabetic nephropathy is one of the most devastatingcomplications of diabetes, being associ-ated with a high mortality, which islargely due to a markedly increased prev-alence of cardiovascular disease (78). Ne-phropathy develops in ~35-45% of pa-tients with IDDM and perhaps 20% ofthose with NIDDM (79-82). A recent re-port from Sweden indicates that the riskof nephropathy for IDDM may have fallento 10% in a population with improvedglycemic control (83). Nonetheless, dia-betic nephropathy is now the leadingcause of end-stage renal failure in the U.S.In the past decade it has become clear thattreatment can slow the progression of ne-phropathy. The beneficial effects of glyce-

mic control are best demonstrated by theDCCT, which found a decrease in the de-velopment of microalbuminuria and clin-ical grade albuminuria (1). Two small anduncontrolled studies suggested that gly-cemic control provides little benefit onceheavy proteinuria is present (84,85).However, the use of protein-restricted di-ets has been found to slow progression ofestablished nephropathy (86-88). Thediet studies with the clearest results haveused very strict protein restriction of 0.6g • kg"1 • day"1. Unfortunately, thesestudies were only short-term, and thepossible benefits of more modest proteinrestriction have not yet been evaluated indiabetic subjects. Moreover, in a largeItalian study of nondiabetic renal insuffi-ciency and the recently reported Modifi-cation of Diet in Renal Disease Study, alsoin mostly nondiabetic patients, the effectsof protein restriction were unimpressive(89,90). Although questions remainabout potential benefit, such severe re-striction of protein intake in patients withestablished diabetic nephropathy cannotbe recommended at the present time.

Treatment of hypertension hasbeen found to have a clearly beneficialeffect. Although the current focus is onangiotensin-converting enzyme (ACF.) in-hibitors (35,36,91-94), other antihyper-tensive medications, including variouscombinations of metoprolol, hydrala;:ine,furosemide, thiazides, and calcium chan-nel blockers, have been shown to have abeneficial effect on the course of diabeticnephropathy (95-98). More recent dataindicate that ACE inhibitors may exert abeneficial influence independent of theireffect on blood pressure. The ACE inhib-itor captopril was studied in a trial involv-ing 30 clinical centers in which 409 pa-tients were randomly assigned to receiveeither captopril or a placebo (99). Patientsin both treatment groups were treatedwith antihypertensive drugs other thanACE inhibitors to control blood pressure.The criterion for entry was IDDM of s 7years duration with onset before the ageof 30. Urinary protein excretion was^500 mg/24 h, and serum creatinine


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^2.5 mg/dl (221 jLtmol/1). Therefore, thiswas a study on subjects with establisheddiabetic nephropathy, and not on IDDMpatients with microalbuminuria. Itshould be noted that this group was nottreated with severe restriction of dietaryprotein (recommendation was 1 g/kg ofbody weight/day). The median follow-upperiod was 3 years. The risk of doublingthe serum creatinine was reduced by 48%in the captopril group. There was also areduction in the rate of decline of creati-nine clearance, this being 11 ± 21%(mean ± SD) per year in the captoprilgroup and 23 ± 25% in the placebogroup. The risk of developing the com-bined end points of death, dialysis, andtransplantation was reduced by 50%. Thedifference in blood pressure between thecaptopril and placebo group was insignif-icant, so the most reasonable conclusionis that the beneficial result from captoprilwas from an effect independent of its an-tihypertensive effect.

The mechanisms responsible forthe beneficial effects of ACE inhibitors areuncertain, but work in diabetic rats hasshown that the tone of the glomerular ef-ferent arteriole is reduced, leading to areduction of intraglomerular hyperten-sion (100,101). This is associated with areduction in capillary permeability andsubsequent protein excretion (102,103).Many studies in humans have shown thatACE inhibitors reduce protein excretionin subjects with diabetic nephropathy.The increased protein excretion found indiabetic nephropathy may enhance accu-mulation of mesangial matrix materialand may be associated with the cardiovas-cular risk factors such as hypercholester-olemia, hyperfibrinogenemia, and in-creased platelet adhesiveness (104).Another benefit may come from a reduc-tion of the effects of angiotensin II to pro-mote cellular and glomerular hypertro-phy (105). The benefits found withcaptopril most likely occur with otherACE inhibitors, which have been found tohave similar effects in animal studies andseveral small clinical trials (35,36).

A detailed description of the treat-

ment of diabetic nephropathy is beyondthe scope of this review, but any stan-dards of care must emphasize the impor-tance of strategies to prevent or slow thecourse of diabetic nephropathy. Thetreatment team must therefore reduce therisk factors that lead to nephropathy andidentify the early appearance of kidneyproblems so that appropriate treatmentcan be instituted. Several treatment issueshave recently been clarified. In subjectswith IDDM, glycemic control reduces therisk of developing diabetic nephropathy.Also, treatment with captopril has beenshown to slow the rate of progression ofestablished diabetic nephropathy inIDDM. There are also limited data sug-gesting that protein restriction has a ben-eficial influence on the progression of re-nal disease, but these are not firm enoughto merit being a recommended therapy.

A major question is whether nor-motensive patients with microalbumin-uria should be treated with ACE inhibi-tors. A case can be made for such arecommendation. Microalbuminuria isan established risk factor for progressionto overt nephropathy in IDDM (106-108). There are theoretical reasons andexperimental data supporting the conceptthat ACE inhibitors should slow the pro-gression of nephropathy, although nostudies have been of sufficient duration todemonstrate a reduction in the progres-sion of microalbuminuria to severe ne-phropathy (35,36,100-105). In a recentmulticenter randomized trial with IDDMsubjects, captopril slowed the 2-year pro-gression of microalbuminuria to clinicalproteinuria, albeit with an accompanyingsmall reduction in mean blood pressure(109). In another trial involving NIDDMpatients, enalapril, another ACE inhibi-tor, has been shown to stabilize plasmacreatinine and 24-h urinary albumin ex-cretion over a 5-year period when com-pared with placebo treatment that re-sulted in further worsening of both renalparameters (110). Since the prognosis fordiabetic nephropathy is poor, as evi-denced by premature death (78) and con-siderable morbidity, the possibility of al-

tering this prognosis by using a drug withapparent minimal toxicity tilts the deci-sion in favor of using ACE inhibitors inIDDM patients with microalbuminuriawhether they have hypertension or not.Because of adverse effects of ACE inhibi-tors on the fetus during pregnancy, spe-cial precautions must be taken for womenof childbearingage. Nonetheless, becausethe presence of microalbuminuria willlead to a treatment decision, it is impor-tant to measure urinary microalbuminlevels at regular intervals, probably yearlyin all postpubertal patients with IDDM. Inpeople with NIDDM, microalbuminuriais not as reliable a predictor of progres-sion to severe nephropathy and probableend-stage renal disease as it is in IDDM.Therefore, by itself, this indication is aless compelling reason to screen for mi-croalbuminuria in NIDDM. However, inpeople with NIDDM, microalbuminuriadoes predict early mortality from cardio-vascular disease (108,111). Knowledge ofthe presence of microalbuminuria can re-inforce the stringency of efforts to reduceother risk factors for cardiovascular dis-ease such as hypertension and dyslipi-demia. Therefore, periodic surveillancefor microalbuminuria may also be war-ranted in NIDDM.

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