M ore than 25% of the U.S. population

C O N S E N S U S R E P O R T Diabetes in Older Adults M. SUE KIRKMAN, MD 1 VANESSA JONES BRISCOE, PHD, NP, CDE 2 NATHANIEL CLARK, MD, MS, RD 3 HERMES FLOREZ, MD, MPH, PHD 4 LINDA B. HAAS, PHC, RN, CDE 5 JEFFREY B. HALTER, MD 6 M ore than 25% of the U.S. population aged $65 years has diabetes (1), and the aging of the overall population is a signifiant driver of the diabetes epidemi. Although the burden of diabetes is often desribed in terms of its impat on working-age adults, diabetes in older adults is linked to higher mortality, redued funtional status, and inreased risk of institutionalization (2). Older adults with diabetes are at substantial risk for both aute and hroni mirovasular and ardiovasular ompliations of the disease. Despite having the highest prevalene of diabetes of any age-group, older persons and/or those with multiple omorbidities have often been exluded from randomized ontrolled trials of treatmentsdand treatment targetsdfor diabetes and its assoiated onditions. Heterogeneity of health status of older adults (even within an age range) and the dearth of evidene from linial trials present hallenges to determining standard intervention strategies that fit allolder adults. To address these issues, the Amerian Diabetes Assoiation (ADA) onvened a Consensus Development Conferene on Diabetes and Older Adults (defined as those aged $65 years) in February 2012. Following a series of sientifipresentations by experts in the field, the writing group independently developed ELBERT S. HUANG, MD, MPH 7 MARY T. KORYTKOWSKI, MD 8 MEDHA N. MUNSHI, MD 9 PEGGY SOULE ODEGARD, BS, PHARMD, CDE 10 RICHARD E. PRATLEY, MD 11 CARRIE S. SWIFT, MS, RD, BC-ADM, CDE 12 this onsensus report to address the following questions: 1. What is the epidemiology and pathogenesis of diabetes in older adults? 2. What is the evidene for preventing and treating diabetes and its ommon omorbidities in older adults? 3. What urrent guidelines exist for treating diabetes in older adults? 4. What issues need to be onsidered in individualizing treatment reommendations for older adults? 5. What are onsensus reommendations for treating older adults with or at risk for diabetes? 6. How an gaps in the evidene best be filled? What is the epidemiology and pathogenesis of diabetes in older adults?daording to the most reent surveillane data, the prevalene of diabetes among U.S. adults aged $65 years varies from 22 to 33%, depending on the diagnosti riteria used. Postprandial hyperglyemia is a prominent harateristi of type 2 diabetes in older adults (3,4), ontributing to observed differenes in prevalene depending on whih diagnosti test is used (5). Using the A1C or From 1 Medial Affairs and Community Information, Amerian Diabetes Assoiation, Alexandria, Virginia; the 2 Department of Mediine, Vanderbilt University, Nashville, Tennessee; the 3 Diabetes Center of Cape Cod, Emerald Physiians, Hyannis, Massahusetts; the 4 Miami Veterans Affairs Healthare System, Geriatri Researh, Eduation and Clinial Center, and the University of Miami, Miami, Florida; the 5 Veterans Affairs Puget Sound Health Care System, Seattle, Washington; the 6 Division of Geriatri Mediine, University of Mihigan, Ann Arbor, Mihigan; the 7 Setion of General Internal Mediine, The University of Chiago, Chiago, Illinois; the 8 Division of Endorinology, University of Pittsburgh, Pittsburgh, Pennsylvania; 9 Beth Israel Deaoness Medial Center and the Joslin Diabetes Center, Harvard Medial Shool, Boston, Massahusetts; the 10 Department of Pharmay, University of Washington, Seattle, Washington; the 11 Florida Hospital Diabetes Institute, Orlando, Florida; and 12 Kadle Medial Center, Rihland, Washington. Corresponding author: M. Sue Kirkman, skirkman@diabetes.org. DOI: 10.2337/d12-1801 The linial reommendations and reommendations for a researh agenda in this artile are solely the opinion of the authors and do not represent the offiial position of the Amerian Diabetes Assoiation. This artile has been opublished in the Journal of the Amerian Geriatris Soiety. 2012 by the Amerian Diabetes Assoiation and the Amerian Geriatris Soiety. Readers may use this artile as long as the work is properly ited, the use is eduational and not for profit, and the work is not altered. See http://reativeommons.org/lienses/by-n-nd/3.0/ for details. fasting plasma gluose (FPG) diagnosti riteria, as is urrently done for national surveillane, one-third of older adults with diabetes are undiagnosed (1). The epidemi of type 2 diabetes is learly linked to inreasing rates of overweight and obesity in the U.S. population, but projetions by the Centers for Disease Control and Prevention (CDC) suggest that even if diabetes inidene rates level off, the prevalene of diabetes will double in the next 20 years, in part due to the aging of the population (6). Other projetions suggest that the number of ases of diagnosed diabetes in those aged $65 years will inrease by 4.5-fold (ompared to 3-fold in the total population) between 2005 and 2050 (7). The inidene of diabetes inreases with age until about age 65 years, after whih both inidene and prevalene seem to level off (www.d.gov/diabetes/statistis). As a result, older adults with diabetes may either have inident disease (diagnosed after age 65 years) or long-standing diabetes with onset in middle age or earlier. Demographi and linial harateristis of these two groups differ in a number of ways, adding to the omplexity of making generalized treatment reommendations for older patients with diabetes. Older-age onset diabetes is more ommon in non-hispani whites and is haraterized by lower mean A1C and lower likelihood of insulin use than is middle-age onset diabetes. Although a history of retinopathy is signifiantly more ommon in older adults with middle-age onset diabetes than those with older-age onset, there is, interestingly, no differene in prevalene of ardiovasular disease (CVD) or peripheral neuropathy by age of onset (8). Older adults with diabetes have the highest rates of major lower-extremity amputation (9), myoardial infartion (MI), visual impairment, and end-stage renal disease of any age-group. Those aged $75 years have higher rates than those aged 65 74 years for most ompliations. Deaths from hyperglyemi rises also are signifiantly higher in older adults (although rates have delined markedly in the past 2 deades). Those aged $75 years also have double the rate of emergeny department visits for hypoglyemia than the general population with diabetes (10). Although inreasing numbers of individuals with type 1 diabetes are living into 2650 DIABETES CARE, VOLUME 35, DECEMBER 2012 are.diabetesjournals.org

old age (11), this disussion of pathophysiology onerns type 2 diabetesd overwhelmingly the most ommon inident and prevalent type in older age-groups. Older adults are at high risk for the development of type 2 diabetes due to the ombined effets of inreasing insulin resistane and impaired panreati islet funtion with aging. Age-related insulin resistane appears to be primarily assoiated with adiposity, saropenia, and physial inativity (12), whih may partially explain the disproportionate suess of the intensive lifestyle intervention in older partiipants in the Diabetes Prevention Program (DPP) (13). However, age-related delines of panreati islet funtion (4,14) and islet proliferative apaity (15,16) have previously been desribed. What is the evidene for preventing and treating diabetes and its ommon omorbidities in older adults? Sreening for diabetes and prediabetes Older adults are at high risk for both diabetes and prediabetes, with surveillane data suggesting that half of older adults have the latter (1). The ADA reommends that overweight adults with risk fatorsd and all adults aged $45 yearsdbe sreened in the linial setting every 1 3 years using either an FPG test, A1C, or oral gluose tolerane test. The reommendations are based on substantial indiret evidene for the benefits of early treatment of type 2 diabetes, the fat that type 2 diabetes is typially present for years before linial diagnosis, and the evidene that signs of ompliations are prevalent in newly diagnosed patients (17). The benefits of identifiation of prediabetes and asymptomati type 2 diabetes in older adults depend on whether primary or seondary preventive interventions would likely be effetive and on the antiipated timeframe of the benefit of interventions versus the patient s life expetany. Most would agree that a funtional and generally healthy 66-year-old individual should be offered diabetes sreening sine interventions to prevent type 2 diabetes or the ompliations of type 2 diabetes would likely be benefiial given the presumption of deades of remaining life. Most would also agree that finding prediabetes or early type 2 diabetes in a 95-year-old individual with advaned dementia would be unlikely to provide benefit. Prevention or delay of type 2 diabetes Numerous linial trials have shown that in high-risk subjets (partiularly those with impaired gluose tolerane), type 2 diabetes an be prevented or delayed by lifestyle interventions or by various lasses of mediations. These trials primarily enrolled middle-aged partiipants. In the DPP, whih is the largest trial to date, ;20% of partiipants were aged $60 years at enrollment. These partiipants seemed to have more effiay from the lifestyle intervention than younger partiipants, but did not appear to benefit from metformin (13,18). Follow-up of the DPP ohort for 10 years after randomization showed ongoing greater impat of the original lifestyle intervention in older partiipants (49% risk redution in those aged $60 years at randomization vs. 34% for the total ohort) (19) and additional benefits of the lifestyle intervention that might impat older adults, suh as redution in urinary inontinene (20), improvement in several quality-of-life domains (21), and improvements in ardiovasular risk fators (22). Although these results suggest that diabetes prevention through lifestyle intervention be pursued in relatively healthy older adults, the DPP did not enroll signifiant numbers over the age of 70 years or those with funtional or ognitive impairments. Preventive strategies that an be effiiently implemented in linial settings and in the ommunity have been developed and evaluated (23), but as yet there has been little fous on older adults in these translational studies. Interventions to treat diabetes Glyemi ontrol. A limited number of randomized linial trials in type 2 diabetes form the basis of our urrent understanding of the effets of gluose lowering on mirovasular ompliations, ardiovasular ompliations, and mortality. While these trials have provided invaluable data and insights, they were not designed to evaluate the health effets of gluose ontrol in patients aged $75 years or in older adults with poor health status. There are essentially no diretly appliable linial trial data on gluose ontrol for large segments of the older diabeti patient population. The UK Prospetive Diabetes Study (UKPDS), whih provided valuable evidene of the benefits of glyemi ontrol on mirovasular ompliations, enrolled middle-aged patients with newly diagnosed type 2 diabetes, exluding those Kirkman and Assoiates aged $65 years at the time of enrollment (24,25). Mirovasular benefits persisted during the post-trial follow-up period, and statistially signifiant redutions in both mortality and MIs emerged, referred to as the legay effet of early glyemi ontrol (26). After the publiation of the main UKPDS results, three major randomized ontrolled trials (the Ation to Control Cardiovasular Risk in Diabetes [ACCORD] trial, the Ation in Diabetes and Vasular Disease: Preterax and Diamiron MR Controlled Evaluation [ADVANCE] trial, and the Veterans Affairs Diabetes Trial [VADT]) were designed to speifially examine the role of glyemi ontrol in preventing CVD events in middle-aged and older patients with type 2 diabetes. The trials enrolled patients at signifiantly higher ardiovasular risk than did the UKPDS, with eah having a substantial proportion of partiipants with a prior ardiovasular event, mean age at enrollment in the 60s, and established diabetes (8 11 years). Eah of these trials aimed, in the intensive glyemi ontrol arm, to redue gluose levels to near-normal levels (A1C,6.0 or,6.5%). The gluose ontrol portion of the ACCORD trial was terminated after approximately 3 years beause of exessive deaths in the intensive gluose ontrol arm (27). The primary ombined outome of MI, stroke, and ardiovasular death was not signifiantly redued. Prespeified subgroup analyses suggested that the disproportionate ardiovasular mortality risk in the intensive glyemi ontrol group was in partiipants under the age of 65 years as opposed to older partiipants. However, hypoglyemia and other adverse effets of treatment were more ommon in older partiipants (28). The ADVANCE trial did not demonstrate exessive deaths attributable to intensive gluose ontrol during a median follow-up of 5 years. While there were no statistially signifiant ardiovasular benefits, there was a signifiant redution in the inidene of nephropathy. In prespeified subgroup analysis of age, or $65 years, there was no differene between age-groups for the primary outome (29). Over 5 years of follow-up, the VADT found no statistially signifiant effet of intensive gluose ontrol on major ardiovasular events or death, but it did find signifiant redutions in onset and progression of albuminuria (30). The trial did not have prespeified subgroup analyses by age. Post ho analyses suggested that mortality in the intensive versus standard are.diabetesjournals.org DIABETES CARE, VOLUME 35, DECEMBER 2012 2651

Consensus Report glyemi ontrol arm was related to duration of diabetes at the time of study enrollment. Those with diabetes duration less than 15 years had a mortality benefit in the intensive arm, while those with duration of 20 years or more had higher mortality in the intensive arm (31). These three trials add to the unertainty regarding the benefits and risks of more intensive treatment of hyperglyemia in older adults. An ADA position statement surmised that the ombination of the UKPDS follow-up study and subset analyses of the later trials... suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atheroslerosis might reap ardiovasular benefit from intensive glyemi ontrol, [while]... potential risks of intensive glyemi ontrol may outweigh its benefits in other patients, suh as those with a very long duration of diabetes, known history of severe hypoglyemia, advaned atheroslerosis, and advaned age/frailty (32). Reently, a Japanese trial reported results of a multifatorial intervention versus standard are in about 1,000 patients aged $65 years (mean age 72 years). After 6 years, no differenes in mortality or ardiovasular events were found, but the intervention s effet on glyemia was minimal and the number of events was low (33). Sine randomized ontrolled trials have not inluded many older patients typial of those in general pratie, it is instrutive to observe the relationship between glyemi ontrol and ompliations in general populations of older diabeti patients. A study from the U.K. General Pratie Researh Database showed that for type 2 diabeti patients aged $50 years (mean age 64 years) whose treatment was intensified from oral monotherapy to addition of other oral agents or insulin, there was a U-shaped assoiation between A1C and mortality, with the lowest hazard ratio for death at an A1C of about 7.5%. Low and high mean A1C values were assoiated with inreased allause mortality and ardia events (34). A retrospetive ohort study of 71,092 patients with type 2 diabetes aged $60 years evaluated the relationships between baseline A1C and subsequent outomes (aute nonfatal metaboli, mirovasular, and ardiovasular events and mortality). As in the prior study, mortality had a U-shaped relationship with A1C. Compared to risk with A1C,6.0%, mortality risk was lower for A1C between 6.0 and 9.0% and higher at A1C $11.0%. Risk of any end point (ompliation or death) beame signifiantly higher at A1C $8.0%. Patterns were generally onsistent aross age-groups (60 69, 70 79, and $80 years) (35). Diabetes is assoiated with inreased risk of multiple oexisting medial onditions in older adults ranging from CVD to aner and potentially impating treatment deisions, suh as whether stringent glyemi ontrol would be of net benefit (36,37). A 5-year longitudinal, observational study of Italian patients with type 2 diabetes ategorized patients into subgroups of high (mean age 64.3 years [SD 9.5]) and lowto-moderate omorbidity (mean age 61.7 years [SD 10.5]) using a validated patientreported measure of omorbidity. Having an A1C of #6.5 or,7% at baseline was assoiated with lower 5-year inidene of ardiovasular events in the low-tomoderate omorbidity subgroup, but not in the high omorbidity subgroup, suggesting that patients with high levels of omorbidity may not reeive ardiovasular benefit from intensive blood gluose ontrol (38). Lipid lowering. There are no large trials of lipid-lowering interventions speifially in older adults with diabetes. Benefits have been extrapolated from trials of older adults that inlude but are not limited to those with diabetes and trials of people with diabetes inluding but not limited to older adults. A statin study in older adults (partiipants aged 70 82 years) found a 15% redution in oronary artery disease events with pravastatin (39,40). A meta-analysis of 18,686 people with diabetes in 14 trials of statin therapy for primary prevention showed similar 20% relative redutions in major adverse vasular outomes in those under ompared with those over age 65 years (41). Statin trials for seondary prevention of CVD in adults with diabetes have also demonstrated omparable relative redutions in reurrent ardiovasular events and mortality by age-group (42). Sine older patients are at higher risk, absolute risk redutions with statin therapy would be greater in older patients. Cardiovasular prevention with statins, espeially seondary benefit, emerges fairly quikly (within 1 2 years), suggesting that statins may be indiated in nearly all older adults with diabetes exept those with very limited life expetany. The evidene for redution in major ardiovasular end points with drugs other than statins is limited in any agegroup. The ACCORD lipid trial found no benefit of adding fenofibrate to statin therapy (43), and post ho analyses suggested that the negative results applied to both those under and those over age 65 years (M. Miller, personal ommuniation). Subgroup analyses of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, whih suggested some benefit of fenofibrate in people with type 2 diabetes, suggested no benefit in those aged $65 years (44). Blood pressure ontrol. Multiple trials have investigated the role of treatment of hypertension to redue the risk of ardiovasular events (17). Benefit forolder adults with diabetes has been inferred from the trials of older adults inluding but not limited to those with diabetes and from the trials of middle- and older-aged adults with diabetes (42). There is onsistent evidene that lowering blood pressure from very high levels (e.g., systoli blood pressure [SBP] 170 mmhg) to moderate targets (e.g., SBP 150 mmhg) redues ardiovasular risk in older adults with diabetes. Seleted trials have shown benefit with targets progressively lower, down to SBP,140 mmhg and diastoli blood pressure (DBP),80 mmhg (45). The ACCORD-BP trial showed no benefit on the primary outome (major adverse ardiovasular events) of SBP targets,120 mmhg ompared with,140 mmhg, but found a signifiant redution in stroke, a seondary outome (46). Subgroup analyses of those aged, versus $65 years suggested that the stroke benefit may have been limited to the older ohort (M. Miller, personal ommuniation). Observational analyses of other trial ohorts suggest no benefit to SBP targets more aggressive than,140 mmhg and thatlowdbpmaybeariskfatorformortality in older adults. A post ho analysis of the ohort of partiipants with diabetes in the International Verapamil SR- Trandolapril Study (INVEST), whose mean age was ;65 years, showed that ahieved SBP under 130 mmhg was not assoiated with improved ardiovasular outomes ompared with SBP under 140 mmhg (47). This report validated SBP ontrol under 140 mmhg, as death and ardiovasular events were more likely in subjets whose SBP was over 140 mmhg. A post ho analysis of the VADT (in whih the goal blood pressure was,130/80 mmhg) similarly showed that those whose SBP was $140 mmhg had inreased mortality, while those at,105 mmhg, 105 129 mmhg, and 130 139 mmhg had equally low mortality rates. For DBP, ahieved values,70mmhgwereassoiatedwithhigher mortality, while those of 70 79 mmhg or.80 mmhg were equally low (48). 2652 DIABETES CARE, VOLUME 35, DECEMBER 2012 are.diabetesjournals.org

Aspirin. In populations without diabetes, the greatest absolute benefitofaspirin therapy (75 162 mg) is for individuals with a 10-year risk of oronary heart disease of 10% or greater (49). The inreased ardiovasular risk posed by diabetes and aging and the known benefits of aspirin for seondary prevention suggest that, in the absene of ontraindiations, this therapy should be offered to virtually all older adults with diabetes and known CVD. However, the benefits of aspirin for primary prevention of CVD events have not been thoroughly eluidated in older adults with diabetes and must be balaned against risk of adverse events suh as bleeding. A randomized study of Japanese individuals with diabetes but no CVD history demonstrated no signifiant benefit of aspirin on the omposite primary outome, but a subgroup analysis of subjets aged $65 years demonstrated a signifiantly lower risk of the primary end point with aspirin (50). The inidene of gastrointestinal bleeding with the use of aspirin has not been diretly ompared in older- versus middleaged adults, but in separate studies the rates were higher (1 10 per 1,000 annually) for older adults (51) than those for middleaged adults (3 per 10,000 annually) (49). More reently, the greater risk of major gastrointestinal or intraerebral bleeding in older adults who use aspirin was suggested by an observational analysis, but diabetes per se was not assoiated with inreased bleeding with aspirin (52). In light of the probable higher risk of bleeding with age, the benefit of aspirin therapy in older adults with diabetes is likely strongest for those with high ardiovasular risk and low risk of bleeding. Unfortunately, the risk fators for these outomes tend to overlap. When aspirin is initiated, the use of agents suh as proton pump inhibitors to protet against gastrointestinal bleeding may be warranted (53). Further evidene is needed to onfirm a lear role of aspirin for primary prevention of ardiovasular events in older adults with diabetes. Sreening for hroni diabetes ompliations The sreening and interventions for hroni diabetes ompliations reommended by the ADA have a strong evidene base and are ost-effetive (54). However, as is the ase for many diabetes interventions, the underlying evidene generally omes from studies of younger adults. When onsidering hroni ompliations, the issues of inident versus prevalent diabetes and diabetes heterogeneity again need to be raised. Some older adults have long-standing diabetes with assoiated mirovasular and marovasular ompliations. Others have newly diagnosed diabetes with evidene of ompliations (on sreening tests) at initial presentation, while still others have newly diagnosed diabetes without evidene of ompliations. For relatively healthy older adults with long life expetany, following the sreening reommendations for all adults with diabetes is reasonable. For very old patients and/or those with multiple omorbidities and short life expetany, it is prudent to weigh the expeted benefit time frame of identifying early signs of ompliations and intervening to prevent worsening to end-stage disease. For the latter group, partiular attention shouldbepaidto sreening for risk fators of ompliations that might further impair funtional status or quality of life over a relatively short period of time, suh as foot ulers/ amputations and visual impairment. Considerations in linial deision making should also inlude prior test results. For example, there is evidene, inluding in the older adult population, that dilated eye examinations that are initially normal an safely be repeated every 2 3 years instead of yearly (55). What urrent guidelines exist for treating diabetes in older adults?dseveral organizations have developed diabetes guidelines speifi to, or inluding, older adults. The ADA inludes a setion on older adults in its annual Standards of Medial Care in Diabetes (17). The setion disusses the heterogeneity of persons aged $65 years and the lak of high-level evidene. The overall reommendations, all based on expert opinion, inlude the following: Older adults who are funtional, are ognitively intat, and have signifiant life expetany should reeive diabetes are using goals developed for younger adults. Glyemi goals for older adults not meeting the above riteria may be relaxed using individualized riteria, but hyperglyemia leading to symptoms or risk of aute hyperglyemi ompliations should be avoided in all patients. Other ardiovasular risk fators should be treated in older adults with onsideration of the timeframe of benefit andthe individual patient. Treatment of hypertension is indiated in virtually all older adults, and lipid and aspirin therapy may benefit those with life expetany at least equal to the timeframe of primary or seondary prevention trials. Sreening for diabetes ompliations should be individualized in older adults, but partiular attention should be paid to ompliations that would lead to funtional impairment. The ADA goals for glyemi ontrol do not speifially mention age. The reommendation for many adults is an A1C,7%, but less stringent goals are reommended for those with limited life expetany, advaned diabetes ompliations, or extensive omorbid onditions (17). In ollaboration with the ADA and other medial organizations, the California HealthCare Foundation/Amerian Geriatris Soiety panel published guidelines for improving the are of older adults with diabetes in 2003. A signifiant proportion of the reommendations onerns geriatri syndromes. Highlights of diabetes-speifi reommendations inlude A1C targets of #7.0% in relatively healthy adults, while for those who are frail or with life expetany less than 5 years, a less stringent target, suh as 8%, was onsidered appropriate. The guidelines also suggested that the timeline of benefits was estimated to be at least 8 years for glyemi ontrol and 2 3 years for blood pressure and lipid ontrol (2). The U.S. Department of Veterans Affairs and the U.S. Department of Defense (VA/DOD) diabetes guidelines were updated in 2010. As with other guidelines, the VA/DOD guidelines do not distinguish by age-group. They highlight the frequeny of omorbid onditions in patients with diabetes and stratify glyemi goals based on omorbidity and life expetany. For glyemi goals, for example, the guidelines have three ategories: Kirkman and Assoiates The patient with either none or very mild mirovasular ompliations of diabetes, who is free of major onurrent illnesses and who has a life expetany of at least 10 15 years, should have an A1C target of,7%, if it an be ahieved without risk. The patient with longer-duration diabetes (more than 10 years) or with omorbid onditions and who requires a ombination mediation regimen inluding insulin should have an A1C target of,8%. The patient with advaned mirovasular ompliations and/or major omorbid are.diabetesjournals.org DIABETES CARE, VOLUME 35, DECEMBER 2012 2653

Consensus Report illness and/or a life expetany of less than 5 years is unlikely to benefit from aggressive gluose-lowering management and should have an A1C target of 8 9%. Lower targets (,8%) an be established on an individual basis (56). The European Diabetes Working Party for Older People reently published guidelines for treating people with diabetes aged $70 years. These extensive guidelines reommend that the deision to offer treatment should be based on the likely benefit/risk ratio of the intervention for the individual onerned, but fators suh as vulnerability to hypoglyemia, ability to self-manage, the presene or absene of other pathologies, the ognitive status, and life expetany must be onsidered (57). There are reommendations to arry out annual evaluations of funtional status (global/physial, ognitive, affetive) using validated instruments to avoid the use of glyburide due to its high risk of hypoglyemia in this population and to alulate ardiovasular risk in all patients less than 85 years of age. Suggested A1C targets are based on age and omorbidity. A range of 7 7.5% is suggested for older patients with type 2 diabetes without major omorbidities and 7.6 8.5% for frail patients (dependent, multisystem disease, home are resideny inluding those with dementia) where the hypoglyemia risk may be high and the likelihood of benefit relatively low. Extensive review of the guidelines is beyond the sope of this report, but there are similar themes, whih suggest pursuing an individualized approah with a fous on linial and funtional heterogeneity and omorbidities, and weighing the expeted time frame of benefit of interventions against life expetany. What issues need to be onsidered in individualizing treatment reommendations for older adults? Comorbidities and geriatri syndromes Diabetes is assoiated with inreased risk of multiple oexisting medial onditions in older adults. In addition to the lassi ardiovasular and mirovasular diseases, a group of onditions termed geriatri syndromes, desribed below, also our at higher frequeny in older adults with diabetes and may affet self-are abilities and health outomes inluding quality of life (58). Cognitive dysfuntion. Alzheimer s-type and multi-infart dementia are approximately twie as likely to our in those with diabetes ompared with age-mathed nondiabeti ontrol subjets (59). The presentation of ognitive dysfuntion an vary from subtle exeutive dysfuntion to overt dementia and memory loss. In the ACCORD trial, for whih referred partiipants were felt to be apable of adhering to a very omplex protool, 20% of those in the anillary trial of ognition were found to have undiagnosed ognitive dysfuntion at baseline ( J. Williamson, personal ommuniation) (60). In this trial, neither intensive glyemi ontrol nor blood pressure ontrol to a target SBP,120 mmhg was shown to prevent a deline in brain funtion (61). Cross-setional studies have shown an assoiation between hyperglyemia and ognitive dysfuntion (62). Hypoglyemia is linked to ognitive dysfuntion in a bidiretional fashion: ognitive impairment inreases the subsequent risk of hypoglyemia (60), and a history of severe hypoglyemia is linked to the inidene of dementia (63). High rates of unidentified ognitive defiits in older adults suggest that it is important to periodially sreen for ognitive dysfuntion. Simple assessment tools an be aessed at www.hospitalmediine.org/geriresoure/toolbox/howto. htm. Suh dysfuntion makes it diffiult for patients to perform omplex self-are tasks suh as gluose monitoring, hanging insulin doses, or appropriately maintaining timing and ontent of diet. In older patients with ognitive dysfuntion, regimens should be simplified, aregivers involved, and the ourrene of hypoglyemia arefully assessed. Funtional impairment. Aging and diabetes are both risk fators for funtional impairment. After ontrolling for age, people with diabetes are less physially ative and have more funtional impairment than those without diabetes (64,65). The etiology of funtional impairment in diabetes may inlude interation between oexisting medial onditions, peripheral neuropathy, vision and hearing diffiulty, and gait and balane problems. Peripheral neuropathy, present in 50 70% of older patients with diabetes, inreases the risk of postural instability, balane problems, and musle atrophy (66 68), limiting physial ativity and inreasing the risk of falls. Other medial onditions that ommonly aompany diabetes suh as oronary artery disease, obesity, degenerative joint disease, stroke, depression, and visual impairment also negatively impat physial ativity and funtionality (69). Falls and fratures. Normal aging and diabetes, and the onditions desribed above that impair funtionality, are assoiated with the higher risk of falls and fratures (70,71). Women with diabetes have a higher risk of hip and proximal humeral fratures after adjustment for age, BMI, and bone density (71). It is important to assess fall risks and perform funtional assessment periodially in older adults (72). Avoidane of severe hyperglyemia and hypoglyemia an derease the risk of falls. Physial therapy should be enouraged in patients who are at high risk or who have experiened a reent fall. Mediare may over physial therapy for a limited time in some of these situations. Polypharmay. Older adults with diabetes are at high risk of polypharmay, inreasing the risk of drug side effets and drug-to-drug interations. A hallenge in treating type 2 diabetes is that polypharmay may be intentional and neessary to ontrol related omorbidities and redue the risk of diabetes ompliations (73,74). In one study, polypharmay (defined as the use of six or more presription mediations) was assoiated with an inreased risk of falling in older people (75). The osts of multiple mediations an be substantial, espeially when older patients fall into the doughnut hole of Mediare Part D overage. Mediation reoniliation, ongoing assessment of the indiations for eah mediation, and the assessment of mediation adherene and barriers are needed at eah visit. Depression. Diabetes is assoiated with a high prevalene of depression (76). Untreated depression an lead to diffiulty with self-are and with implementing healthier lifestyle hoies (77) and is assoiated with a higher risk of mortality and dementia in patients with diabetes (78,79). In older adults, depression may remain undiagnosed if sreening is not performed. Clinial tools suh as the Geriatri Depression Sale (80) an be used to periodially sreen older patients with diabetes. Vision and hearing impairment. Sensory impairments should be onsidered when eduating older adults and supporting their self-are. Nearly one in five older U.S. adults with diabetes report visual impairment (81). Hearing impairment involving both high- and low/mid-frequeny sound is about twie as prevalent in people with diabetes, even after ontrolling for age (82) and may be linked to both vasular disease and neuropathy (83). 2654 DIABETES CARE, VOLUME 35, DECEMBER 2012 are.diabetesjournals.org

Other ommonly ourring medial onditions. Persistent pain from neuropathy or other auses or its inadequate treatment is assoiated with adverse outomes in older adults inluding funtional impairment, falls, slow rehabilitation, depression and anxiety, dereased soialization, sleep and appetite disturbanes, and higher health are osts and utilization (2). Pain should be assessed at every visit in older patients with the implementation of strategies for amelioration of pain. Urinary inontinene is ommon in older patients, espeially women, with diabetes. In addition to standard assessments and treatments for inontinene, liniians should remember that unontrolled hyperglyemia an inrease the amount and frequeny of urination. Unique nutrition issues Nutrition is an integral part of diabetes are for all ages, but there are additional onsiderations for older adults with diabetes. Though energy needs deline with age, maronutrient needs are similar throughout adulthood. Meeting mironutrient needs with lower alori intake is hallenging; therefore older adults with diabetes are at higher risk for defiienies. Older adults may be at risk for undernutrition due to anorexia, altered taste and smell, swallowing diffiulties, oral/dental issues, and funtional impairments leading to diffiulties in preparing or onsuming food. Overly restritive eating patterns, either self-imposed or provider-direted, may ontribute additional risk for older adults with diabetes. The Mini-Nutritional Assessment, speifially designed for older adults, is simple to perform and may help determine whether referral to a registered dietitian for medial nutrition therapy (MNT) is needed (http:// www.mna-elderly.om/). MNT has proven to be benefiial in older adults with diabetes (84). Reommendations should take into aount the patient s ulture, preferenes, and personal goals and abilities. When nutrition needs are not being met with usual intake, additional interventions may inlude enouraging smaller more frequent meals, fortifying usual foods, hanging food texture, or adding liquid nutrition supplements (either regular or diabetesspeifi formulas) between meals. For nutritionally vulnerable older adults, identifying ommunity resoures suh as Meals on Wheels, senior enters, and the U.S. Department of Agriulture s Older Amerians Nutrition Program may help maintain independent living status. Overweight and obesity are prevalent among older adults. BMI may not be an aurate preditor of the degree of adiposity in some older adults due to hanges in body omposition with aging (85). Saropenia may our in both over- and underweight older adults. Obesity exaerbates deline in physial funtion due to aging and inreases the risk of frailty (86). While unintentional weight loss is a known nutrition onern, intentional weight loss in overweight and obese older adults ould potentially worsen saropenia, bone mineral density, and nutrition defiits (87,88). Strategies that ombine physial ativity with nutrition therapy to promote weight loss may result in improved physial performane and funtion and redued ardiometaboli risk in older adults (86,87). Unique needs in diabetes selfmanagement eduation/training and support As with all persons with diabetes, diabetes selfmanagement eduation/training (DSME/T) for older adults should be individualized and tailored to the individual s unique medial, ultural, and soial situation. Additionally, for older adults, DSME/T may need to aount for possible impairments in sensation (vision, hearing), ognition, and funtional/physial status. Care partnersdfamily, friends, or other aregiversdshould be involved in DSME/T to inrease the likelihood of suessful selfare behaviors (89). When ommuniating with ognitively impaired patients, eduators should address the patient by name (even when a aregiver will provide most are), speak in simple terms, use signals (ues) that aid memory (verbal analogies, hands-on experiene, demonstrations and models), and utilize strategies suh as sequened visits to build on information. Other tatis inlude summarizing important points frequently, fousing on one skill at a time, teahing tasks from simple to omplex, and providing easy-to-read handouts. Even in the absene of ognitive impairment, eduators should onsider that many patients may have low health literay and numeray skills or may be overwhelmed by the presene of multiple omorbidities. Physial ativity and fitness Musle mass and strength deline with age, and these derements may be exaerbated by diabetes ompliations, omorbidities, and periods of hospitalization in older adults with diabetes. People with diabetes of longer duration and those with higher Kirkman and Assoiates A1C have lower musle strength per unit of musle mass than BMI- and age-mathed people without diabetes and than those whose disease is of shorter duration or under better glyemi ontrol (90). Although age and diabetes onspire to redue fitness and strength, physial ativity interventions improve funtional status in older adults (91) with and without diabetes. In the Look AHEAD (Ation for Health in Diabetes) study, partiipants aged 65 76 years had lower gains in fitness with the intensive lifestyle intervention than younger patients, but still improved their measures of fitness by a mean of over 15% (92). In older adults, even light-intensity physial ativity is assoiated with higher selfrated physial health and psyhosoial well-being (93). Older adults with diabetes who are otherwise healthy and funtional should be enouraged to exerise to targets reommended for all adults with diabetes (17). Even patients with poorer health status benefit from modest inreases in physial ativity. Tatis to failitate ativity for older adults may inlude referring to supervised group exerise and ommunity resoures suh as senior enters, YMCAs, the EnhaneFitness program, and the resoures of the Arthritis Foundation. Age-speifi aspets of pharmaotherapy Older patients are at inreased risk for adverse drug events from most mediations due to age-related hanges in pharmaokinetis (in partiular redued renal elimination) and pharmaodynamis (inreased sensitivity to ertain mediations) affeting drug disposition. These hanges may translate into inreased risk for hypoglyemia, the potential need for redued doses of ertain mediations, and attention to renal funtion to minimize side effets (94,95). The risk for mediationrelated problems is ompounded by the use of omplex regimens, high-ost therapies, and polypharmay or mediation burden. Colletively, these fators should be onsidered and weighed against the expeted benefits of a therapy before inorporating it into any therapeuti plan. Attention to the seletion of mediations with a strong benefit-to-risk ratio is essential to promote effiay, persistene on therapy, and safety. Antihyperglyemi mediation use in older adults. Comparative effetiveness studies of mediations to treat diabetes in older adult populations are laking. Type 2 diabetes with onset later in life is are.diabetesjournals.org DIABETES CARE, VOLUME 35, DECEMBER 2012 2655

Consensus Report haraterized by prominent defets in b-ell funtion, suggesting therapeuti attention to b-ell funtion and suffiieny of insulin release, as well as the traditional fous on hepati gluose overprodution and insulin resistane. Understanding the advantages and disadvantages of eah antihyperglyemi drug lass helps liniians individualize therapy for patients with type 2 diabetes (96). Issues partiularly relevant to older patients are desribed for eah drug lass. Metformin is often onsidered the first-line therapy in type 2 diabetes. Its low risk for hypoglyemia may be benefiial in older adults, but gastrointestinal intolerane and weight loss from the drug may be detrimental in frail patients. Despite early onerns, the evidene for an inrease in the risk of lati aidosis with metformin is minimal. The dose should be redued if estimated glomerular filtration rate (egfr) is 30 60 ml/min, and the drug should not be used if egfr is,30 ml/min (94,97). Metformin s low ost may be a benefitinthoseonmultiple mediations or who are subjet to the Mediare Part D doughnut hole. Sulfonylureas are also a low-ost lass of mediations, but the risk of hypoglyemia with these agents may be problemati for older patients. Glyburide has the highest hypoglyemia risk and should not be presribed for older adults (98). Glinides are dosed prior to meals, and their short half-life may be useful for postprandial hyperglyemia. They impart a lower risk for hypoglyemia than sulfonylureas, espeially in patients who eat irregularly, but their dosing frequeny and high ost may be barriers. a-gluosidase inhibitors speifially target postprandial hyperglyemia and have low hypoglyemia risk, making them theoretially attrative for older patients. However, gastrointestinal intolerane may be limiting, frequent dosing adds to regimen omplexity, and this lass of mediations is ostly. Thiazolidinediones have assoiated risks of weight gain, edema, heart failure, bone fratures, and possibly bladder aner, whih may argue against their use in older adults. The use of rosiglitazone is now highly restrited. The lass has traditionally been expensive, although the approval of generi pioglitazone may redue its ost. Dipeptidyl peptidase-4 inhibitors are useful for postprandial hyperglyemia, impart little risk for hypoglyemia, and are well tolerated, suggesting potential benefits for older patients. However, their high ost may be limiting. Gluagon-like peptide-1 agonists also target postprandial hyperglyemia and impart low risk of hypoglyemia, but their assoiated nausea and weight loss may be problemati in frail older patients. Injetion therapy may add to regimen omplexity, and its very high ost may be problemati. For some agents, dose redution is required for renal dysfuntion. Insulin therapy an be used to ahieve glyemi goals in seleted older adults with type 2 diabetes with similar effiay and hypoglyemia risk as in younger patients. However, given the heterogeneity of the older adult population, the risk of hypoglyemia must be arefully onsidered before using an insulin regimen to ahieve an aggressive target for hyperglyemia ontrol. A mean A1C of 7% was ahieved and maintained for 12 months with either an insulin pump regimen or multiple daily insulin injetions in otherwise healthy and funtional older adults (mean age 66 years), with low rates of hypoglyemia (99). The addition of longating insulin was similarly effetive in ahieving A1C goals for older patients with type 2 diabetes (mean age 69 years) in a series of trials with no greater rates of hypoglyemia than in younger patients (mean age 53 years) (100). However, there are few data on suh regimens in people over age 75 years or in older adults with multiple omorbidities and/or limited funtional status who were exluded from these trials. Problems with vision or manual dexterity may be barriers to insulin therapy for some older adults. Pen devies improve ease of use but are more ostly than the use of vials and syringes. Hypoglyemia risk (espeially noturnal) is somewhat lower with analog ompared with human insulins, but the former are more expensive. Insulinindued weight gain is a onern for some patients, and the need for more blood gluose monitoring may inrease treatment burden. Other approved therapies for whih there is little evidene in older patients inlude olesevelam, bromoriptine, and pramlintide. An emerging drug lass, sodium-gluose otransporter-2 inhibitors, may require additional study in older adults to assess whether drug-assoiated genital infetions or urinary inontinene is problemati in this population. Vulnerability to hypoglyemia. Age appears to affet ounter-regulatory responses to hypoglyemia in nondiabeti individuals. During hypoglyemi lamp studies, symptoms begin at higher gluose levels and have greater intensity in younger men (aged 22 26 years), while measures of psyhomotor oordination deteriorate earlier and to a greater degree in the older subjets (aged 60 70 years), erasing the usual 10 20 mg/dl plasma gluose differene between subjetive awareness of hypoglyemia and onset of ognitive dysfuntion (101). Studies in older individuals with diabetes are limited. One small study ompared responses to hypoglyemi lamps in older (mean age 70 years) versus middle-aged (mean age 51 years) people with type 2 diabetes. Hormonal ounter-regulatory responses to hypoglyemia did not differ between agegroups, but middle-aged partiipants had a signifiant inrease in autonomi and neuroglyopeni symptoms at the end of the hypoglyemi period, while older partiipants did not. Half of the middle-aged partiipants, but only 1 out of 13 older partiipants, orretly reported that their blood gluose was low during hypoglyemia (102). The prevalene of any hypoglyemia (measured blood gluose below 70 mg/dl) or severe hypoglyemia (requiring thirdparty assistane) in older populations is not known. In the ACCORD trial, older partiipants in both glyemi intervention arms had ;50% higher rates of severe hypoglyemia (hypoglyemia requiring thirdparty assistane) than partiipants under age 65 years (M. Miller, personal ommuniation). In a population analysis of Mediaid enrollees treated with insulin or sulfonylureas, the inidene of serious hypoglyemia (defined as that leading to emergeny department visit, hospitalization, or death) was approximately 2 per 100 person-years (103), but learly studies based on administrative databases miss less atastrophi hypoglyemia. The risk fators for hypoglyemia in diabetes in general (use of insulin or insulin seretagogues, duration of diabetes, anteedent hypoglyemia, errati meals, exerise, renal insuffiieny) (104) presumably apply to older patients as well. In the Mediaid study ited above, independent risk fators inluded hospital disharge within the prior 30 days, advaned age, blak rae, and use of five or more onomitant mediations (103). Assessment of risk fators for hypoglyemia is an important part of the linial are of older adults with hypoglyemia. Eduation of both patient and aregiver on the prevention, detetion, and treatment of hypoglyemia is paramount. Risks of undertreatment of hyperglyemia. Although attention has rightly been paid to the risks of overtreatment of hyperglyemia in older adults (hypoglyemia, treatment burden, possibly inreased 2656 DIABETES CARE, VOLUME 35, DECEMBER 2012 are.diabetesjournals.org

mortality), untreated or undertreated hyperglyemia also has risks, even in patients with life expetany too short to be impated by the development of hroni ompliations. Blood gluose levels onsistently over the renal threshold for glyosuria (;180 200 mg/dl, but an vary) inrease the risks for dehydration, eletrolyte abnormalities, urinary inontinene, dizziness, and falls. Hyperglyemi hyperosmolar syndrome is a partiularly severe ompliation of unreognized or undertreated hyperglyemia in older adults. Although it is appropriate to relax glyemi targets for older patients with a history of hypoglyemia, a high burden of omorbidities, and limited life expetany, goals that minimize severe hyperglyemia are indiated for almost all patients. Life expetany A entral onept in geriatri diabetes are guidelines is that providers should base deisions regarding treatment targets or interventions on life expetany (2,17,56,57). Patients whose life expetany is limited (e.g.,,5 years,,10 years) are onsidered unlikely to benefit from intensive gluose ontrol, for example, whereas those with longer life expetany may be appropriate andidates for this intervention. An observation supporting this onept is that umulative event urves for the intensive and onventional glyemi ontrol arms of the UKPDS separated after the 9-year mark. National Vital Statistis life table estimates of average life expetany for adults of speifi ages, sexes, and raes (105) may not apply to older adults with diabetes, who have shorter life expetanies than the average older adult. Mortality predition models that aount for variables suh as omorbidities and funtional status an serve as the basis for making more refined life expetany estimates (106 108). Mortality predition models speifi to diabetes exist but were not Kirkman and Assoiates designed to inform treatment deisions (109,110). A limitation of existing mortality models is that they an help to rank patients by probability of death, but these probabilities must still be transformed into a life expetany for a partiular older diabeti patient. Simulation models an help transform mortality predition into a usable life expetany. One suh model estimated the benefits of lowering A1C from 8.0 to 7.0% for hypothetial older diabeti patients with varying levels of age, omorbidity, and funtional status (111). A ombination of multiple omorbid illnesses and funtional impairments was a better preditor of limited life expetany and diminished benefits of intensive gluose ontrol than age alone. This model suggests that life expetany averages less than 5 years for patients aged 60 64 years with seven additional index points (points due to omorbid onditions and funtional impairments), aged 65 69 Table 1dA framework for onsidering treatment goals for glyemia, blood pressure, and dyslipidemia in older adults with diabetes Patient harateristis/ health status Healthy (Few oexisting hroni illnesses, intat ognitive and funtional status) Complex/intermediate (Multiple oexisting hroni illnesses* or 21 instrumental ADL impairments or mild to moderate ognitive impairment) Very omplex/poor health (Long-term are or end-stage hroni illnesses** or moderate to severe ognitive impairment or 21 ADL dependenies) Rationale Longer remaining life expetany Intermediate remaining life expetany, high treatment burden, hypoglyemia vulnerability, fall risk Limited remaining life expetany makes benefit unertain Reasonable A1C goal (A lower goal may be set for an individual if ahievable without reurrent or severe hypoglyemia or undue treatment burden) Fasting or preprandial gluose (mg/dl) Bedtime gluose (mg/dl) Blood pressure (mmhg) Lipids,7.5% 90 130 90 150,140/80 Statin unless ontraindiated or not tolerated,8.0% 90 150 100 180,140/80 Statin unless ontraindiated or not tolerated,8.5% 100 180 110 200,150/90 Consider likelihood of benefitwith statin (seondary prevention moreso than primary) This represents a onsensus framework for onsidering treatment goals for glyemia, blood pressure, and dyslipidemia in older adults with diabetes. The patient harateristi ategories are general onepts. Not every patient will learly fall into a partiular ategory. Consideration of patient/aregiver preferenes is an important aspet of treatment individualization. Additionally, a patient s health status and preferenes may hange over time. ADL, ativities of daily living. *Coexisting hroni illnesses are onditions serious enough to require mediations or lifestyle management and may inlude arthritis, aner, ongestive heart failure, depression, emphysema, falls, hypertension, inontinene, stage III or worse hroni kidney disease, MI, and stroke. By multiple we mean at least three, but many patients may have five or more (132). **The presene of a single end-stage hroni illness suh as stage III IV ongestive heart failure or oxygen-dependent lung disease, hroni kidney disease requiring dialysis, or unontrolled metastati aner may ause signifiant symptoms or impairment of funtional status and signifiantly redue life expetany. A1C of 8.5% equates to an estimated average gluose of ;200 mg/dl. Looser glyemi targets than this may expose patients to aute risks from glyosuria, dehydration, hyperglyemi hyperosmolar syndrome, and poor wound healing. are.diabetesjournals.org DIABETES CARE, VOLUME 35, DECEMBER 2012 2657