The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations Diabetes Care 2017;40:444–452 | DOI: 10.2337/Dc16-1732

444 Diabetes Care Volume 40, April 2017

Pearl G. Lee1,2 and Jeffrey B. Halter2

DIABETES AND AGING The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations Diabetes Care 2017;40:444–452 | DOI: 10.2337/dc16-1732

Nearly a quarter of older adults in the U.S. have type 2 diabetes, and this population is continuing to increase with the aging of the population. Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging inﬂuences. The usual defects contributing to type 2 diabetes are further complicated by the natural physiological changes associated with aging as well as the comorbidities and functional impairments that are often present in older people. This paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population.

Diabetes is one of the leading chronic medical conditions among older adults, with high risk for vascular comorbidities such as coronary artery disease, physical and cognitive function impairment, and mortality. Despite decades of effort to prevent diabetes, diabetes remains an epidemic condition with particularly high morbidity affecting older adults. In fact, nearly 11 million people in the U.S. aged 65 years or older (more than 26% of adults aged 65 years or older) meet current American Diabetes Association criteria for diabetes (diagnosed and undiagnosed), accounting for more than 37% of the adult population with diabetes (1). At the same time, adults 65 years or older are developing diabetes at a rate nearly three-times higher than younger adults: 11.5 per 1,000 people compared with 3.6 per 1,000 people among adults aged 20–44 years old (1). However, increasing research in diabetes and aging has improved our understanding of the pathophysiology of diabetes and its association with aging and led to the 1Geriatric Research Education and Clinical development of a number of antihyperglycemic medications. The mechanism of di- Center, VA Ann Arbor Healthcare System, Ann abetes complications has been previously reviewed (2). The current paper reviews the Arbor, MI 2 pathophysiology of type 2 diabetes among older adults and the implications for hy- Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of perglycemia management in this population. Michigan, Ann Arbor, MI Corresponding authors: Pearl G. Lee, pearllee@ PATHOPHYSIOLOGY OF TYPE 2 DIABETES med.umich.edu, and Jeffrey B. Halter, jhalter@ Type 2 diabetes is by far the most prevalent form of diabetes in older adults and is an med.umich.edu. age-related disorder. The criteria for diagnosing diabetes are the same for all age Received 10 August 2016 and accepted 20 groups because the risks of diabetes-related complications are associated with January 2017. hyperglycemia over time across all age groups (3). Older adults are at high risk for © 2017 by the American Diabetes Association. the development of type 2 diabetes due to the combined effects of genetic, lifestyle, Readers may use this article as long as the work is properly cited, the use is educational and not and aging inﬂuences. These factors contribute to hyperglycemia through effects on for proﬁt, and the work is not altered. More infor- both b-cell insulin secretory capacity and on tissue sensitivity to insulin. The occur- mation is available at http://www.diabetesjournals rence of type 2 diabetes in an older person is complicated by the comorbidities and .org/content/license. functional impairments associated with aging. See accompanying articles, pp. 440, Hyperglycemia develops in type 2 diabetes when there is an imbalance of glucose 453, 461, 468, 476, 485, 494, 502, production (i.e., hepatic glucose production during fasting) and glucose intake (i.e., 509, 518, and 526. care.diabetesjournals.org Lee and Halter 445

food ingestion) as opposed to insulin- Expression of p16INK4a was increased in the cells can undergo compensatory stimulated glucose uptake in target tis- aging mice (7), and an additional copy of changes to maintain euglycemia. Aging sues, mainly skeletal muscle. Multiple p16INK4a was associated with markedly is thought to be associated with reduced factors in an older person contribute reduced pancreatic islet cell prolifera- capacity to regenerate b-cells, as sug- to such an imbalance of glucose regulation (8). b-Cell proliferation was in- gested by studies involving rodents tion, as illustrated by Fig. 1. Although creasedinp16INK4a knockout mice. (13–15) and humans (16–18). On the resistance to peripheral insulin action Therefore, p16INK4a increases with age one hand, for example, the b-cell toxin contributes to altered glucose homeo- and appears to mediate an age-associated streptozotocin, partial pancreatectomy, stasis, current evidence has found that decline in the replicative capacity of or exendin-4 were more effective in the direct effect of aging on diabetes mouse islets; p16INK4a could be a poten- stimulating b-cell proliferation in youn- pathophysiology is through impairment tial link between aging, metabolic de- ger mice (younger than 12 months old) of b-cell function, resulting in a decline rangements, and b-cell failure in type 2 than in older mice (13–15,19). On the in insulin secretion. diabetes. other hand, the age-associated decline in b-cell function in older rats has been GENETICS EFFECTS OF AGING shown to be reversible with glucagon- like peptide 1 (GLP-1; exendin) treat- Impaired Insulin Secretion, Insulin There is a strong genetic predisposition ment (20), suggesting stimulation of Resistance, and Their Interaction to type 2 diabetes (4). The genetic sus- b-cell regeneration (21). In humans, ceptibility to type 2 diabetes is poly- In the setting of genetic and lifestyle- the baseline b-cell population and ap- genic, involving a number of variants, related risk factors, aging contributes propriate association with other islet where each allele has a modest effect to the development of type 2 diabetes cell types is established before 5 years b on the risk of disease in an individual through impaired -cell function and im- of age (22). Other studies using C14 or b person. Genome-wide association stud- paired -cell adaptation to insulin resis- Ki67 have found that human adult b-cell ies, linkage analysis, candidate gene ap- tance (9,10) leading to impaired insulin turnover is very low (16,17,22,23). Sim- proach, and large-scale association secretion (11,12), as illustrated in Fig. 1. ilarly among middle-aged and older ﬁ ; studies have identi ed 70 loci confer- Studies in rodents and humans have adults, minimal b-cell regeneration ring susceptibility to type 2 diabetes (5). found that aging may exert a distinct in- was observed after a mean follow-up ﬂ b These genetic alleles appear to affect uence on -cell turnover as well as period of 1.8 6 1.2 years after a 50% theriskoftype2diabetesprimarily function. partial pancreatectomy: b-cell mass b through impaired pancreatic -cell func- In older patients who have developed and new b-cell formation were not in- tion, reduced insulin action, or obesity diabetes, autoimmune destruction of creased, and b-cell turnover was un- risk. b-cells is rarely observed. Limited path- changed (18). The follow-up time of Genome-wide association studies ologic investigation suggests that total this study may have been too short for INK4a have consistently found that p16 , b-cell mass may be moderately reduced, human b-cells to replicate, but other a cyclin-dependent kinase inhibitor but severe loss of b-cell mass is uncom- studies have also found evidence of (CDKI), encoded by the Cdkn2a locus, is mon. Pancreatic b-cell mass in adult hu- slow b-cell proliferation in humans associated with type 2 diabetes risks (6). mans exists in a dynamic state such that with advancing age (24,25). The decline in b-cell replication was directly associated with a decrease in the expression of a transcription factor known as the pancreatic and duodenal homeobox 1 (pdx1) (26). Thus, the overall evidence suggests that human b-cells survive for a long time and are unlikely to be replenished by replications once adult- hood is reached (27). Several age-related potential molecular pathways have been found to restrict b-cell regeneration. For example, the replication refractory period, the time between cell divisions (G0 stage of cell cycle), appears to lengthen with age (28); the replicative capacity of b-cells might be reduced due to accumulation of DNA mutations with aging. Therefore, b-cell function in human adults might be enhanced in the setting Figure 1—Model for age-related hyperglycemia (12). Aging has direct effects on b-cell proliferation and function and contributes indirectly to impaired insulin sensitivity through life- of hyperglycemia or insulin resistance to style-related and comorbidity-related risk factors. The insulin resistance in turn may contribute maintain euglycemia. Pancreatic b-cells to further impairment of b-cell function. appear to primarily compensate for 446 Hyperglycemia Pathophysiology in Older Adults Diabetes Care Volume 40, April 2017

limited replication capacity through hy- risk for diabetes. Although aging per insulin signaling and increase insulin re- perplasia and hypertrophy. However, a se has a minimal effect on insulin action sistance and risk of type 2 diabetes number of studies have demonstrated a directly (30), many older individuals de- (41,43). decline in b-cell function and insulin se- velop insulin resistance as a result of The role of mitochondrial function in cretion with age in rodents (26). In hu- diminished physical activity, obesity, aging and type 2 diabetes remains un- mans, as shown in Fig. 2, the insulin and loss of lean body mass, particularly clear. Older adults were found to have a secretion rate in response to glucose those with a disproportional loss of decrease in mitochondrial function was significantly and progressively de- skeletal muscle over adipose tissue. compared with younger adults (i.e., de- creasedinolderindividuals,withthe Age had no independent effect on increased ATP synthesis); however, older greatest impairment in older individuals sulin sensitivity when controlled for adults with normal glucose tolerance with impaired glucose tolerance com- obesity; age-related reductions in insu- had similar ATP production level compared with older individuals with nor- lin sensitivity are likely the result of an pared with older adults with impaired mal glucose tolerance or with younger age-related increase in adiposity rather glucose tolerance (44). On the other individuals matched for degree of insu- than a consequence of advanced chro- hand, exercise reverses age-related de- lin resistance (9). In fact, a 50% reduc- nological age (31). clines in mitochondrial oxidative capac- tion in b-cell secretory capacity has Insulin resistance with aging appears ity and ATP production, which may be been observed in older men compared to reflect predominantly lifestyle factors part of the underlying mechanism through with younger men in response to argi- such as poor diet and diminished phys- which exercise improves insulin sensi- nine stimulation (29). ical activity. These changes lead to de- tivity (44,45). Impaired pancreatic b-cell adapta- creased lean body mass and increased As summarized in Fig. 1, there is a tion to insulin resistance appears to adiposity, particularly visceral adiposity, maladaptive response to insulin resistance be an important contributing factor to with aging. More than 35% of U.S. adults in the setting of impaired b-cell function age-related glucose intolerance and aged 60 years or older are obese, leading to further impairment of insulin having a BMI of 30 kg/m2 or greater secretionandprogressiontoimpairedglu- (3). An absolute or relative increase of cose tolerance and type 2 diabetes. Hyper- body adiposity, particularly central glycemia, in turn, contributes directly to body adiposity, often associated with ad- insulin resistance and impairs pancreatic vancing age, appears to account in large b-cell function, effects described as glu- part for the age-related increase in insu- cose toxicity (46). Such glucose toxicity lin resistance (32,33). Even among adults sets up a vicious cycle of maladaptive without diabetes, intraabdominal fat mechanisms leading to further deteriora- mass correlates with insulin resistance tion of b-cell function and more severe and age after controlling for obesity insulin resistance. (34). However, insulin resistance is more closely associated with abdominal COMORBIDITIES AND THEIR adiposity than with age (35,36). In addi- EFFECT ON INSULIN SENSITIVITY tion to excessive caloric intake, in- AND SECRETION creased body adiposity is partly related Coexisting illness is another factor that to a sedentary lifestyle, which is com- can affect insulin sensitivity and insulin mon among older adults; for example, secretion in an older person. Hyperten- only 12% of adults aged 75 or older en- sion, for example, is common in older gage in 30 min of physical activity 5 or people and has been associated with more days per week, and 65% report no diminished insulin sensitivity (47). Fur- Figure 2—Impaired b-cell function in human aging: response to nicotinic acid– leisure time physical activity (37). In- thermore, any acute illness can precip- induced insulin resistance. Reprinted with creasing physical activity in older adults itate hyperglycemia because of effects permission from Chang et al. (9). Plasma reduces insulin resistance (38), reduces of stress hormones to cause insulin resis- glucose concentrations and insulin secre- the risk of developing diabetes (39), and tance combined with the a-adrenergic ef- tion rate (ISR) are shown over time during improves glycemic control in people with fects of catecholamines released during intravenous glucose infusions, comparing young people (mean age, 26 years) with diabetes (40). stressful illness to inhibit insulin secretion. normal glucose tolerance (NGT; n =15) Low-grade inflammation and stress- Medications used in treating chronic and old people (mean age, 70 years) with response changes associated with obe- medical conditions may induce or in- NGT (n = 16) or with impaired glucose tol- sity and aging are likely to contribute to crease insulin resistance or worsening erance (IGT; n = 14). Glucose levels during the increased risk of type 2 diabetes hyperglycemia among patients with di- thevariableglucoseinfusionrateand degree of insulin resistance were similar among older adults (41). Aging and obe- abetes. Glucocorticoids, for example, in the three study groups. ISR was sig- sity are both thought to be independently promote hepatic gluconeogenesis, thus nificantly and progressively decreased in associated with the development of low- increasing hyperglycemia, and contrib- the two older groups, with the greatest grade inflammation (42), and proinflam- ute to insulin resistance by increasing impairment in old IGT. P = 0.0002, old IGT vs. young and old IGT vs. old NGT; matory cytokines, such as C-reactive visceral fat and promoting proteolysis, and old NGT vs. young NGT. Data are protein, interleukin 6, and tumor necrosis lipolysis, free fatty acid production, means 6 SE. factor-a, have been found to inhibit and fat accumulation in the liver (48). care.diabetesjournals.org Lee and Halter 447

Impaired glucose regulation over even when a new diagnosis is made in andthemaintissuesinthebodythatare time leads to overt diabetes, which in an older adult. The clinical assessment is sensitive to insulin are muscles and adi- turn leads to microvascular or macrovas- used to recommend individualized gly- pose cells. Resistance training changes cular complications. Diabetes-associated cemic, blood pressure, and lipid goals body composition (e.g., increases skeletal complications, along with other comor- for older adults with diabetes. An inter- muscle mass), improves insulin sensitivity, bidities prevalent among older adults, disciplinary expert panel that included and reduces HbA1c (61,62). such as arthritis, cognitive impairment, geriatricians, endocrinologists, and In fact, physical activity programs that and depression, may contribute to de- other diabetes health care providers include both aerobic and resistance creased physical activity and disability was convened by the American Diabetes training improve glycemic levels more (49). All of these changes can further im- Association at a Consensus Develop- than aerobic or resistance training alone pair glucose regulation and adversely af- ment Conference on Diabetes and Older (63,64). Thus, the American Diabetes fect glycemic management. Adults in 2012. This group developed a Association recommends that all adults framework to set diabetes treatment with diabetes should perform at least IMPLICATIONS FOR MANAGEMENT goals based on individual patients’ co- 150 min/week of moderate-intensity OF TYPE 2 DIABETES AMONG morbidities and physical and cognitive aerobic physical activity, spread over at OLDER ADULTS function status (54,55). least 3 days/week with no more than General Approach 2 consecutive days without exercise. The complexity of diabetes and its man- Lifestyle Interventions As part of the exercise routine, resis- agement requires a collaborative effort Lifestyle interventions, including regular tance training should be performed at by a team of health care providers, which physical activity and mild-moderate least twice weekly (65). may include physicians, nurse practi- weight loss, are the first-line intervention Given the high prevalence of coronary tioners, nurses, dietitians, pharmacists, for diabetes prevention and for treatment artery disease in older patients with di- social workers, and mental health profes- of hyperglycemia in older people. Lifestyle abetes, which may be asymptomatic or sionals. Patients and family members interventions are particularly effective in atypical in symptoms, it is important for must also assume an active role (50). reducing the risk of developing diabetes such patients to have medically super- When developing a treatment plan, in ad- among older adults (39,56) and are also vised stress testing before entering any dition to targeting the various factors in- beneficial in improving diabetes manage- challenging exercise training program. volved in the pathophysiologic pathways ment among older adults (57). Lifestyle Additional issues to consider in an older of type 2 diabetes, providers should ad- interventions can reduce insulin resis- person participating in an exercise pro- dress other relevant comorbid conditions tance and thereby help reverse the vicious gram include the potential for foot and that are common among older adults and cycles in Fig. 1. However, there is no evi- joint injury with upright exercise, such can easily affect the ability of the patient dence that lifestyle interventions can re- as jogging, unstable comorbidities, to manage diabetes. Aging is associated verse the effects of aging on b-cells; thus, autonomic neuropathy, peripheral neu- with increasing risk of developing geriat- such interventions may delay, but are not ropathy, or foot lesions that may pre- ric syndromes, such as visual impairment, likely to completely prevent, the ultimate dispose to injures, and the ability to cognitive impairment, and functional im- development of hyperglycemia. promptly identify and treat hypoglyce- pairment, and diabetes is also associated mia, which can be induced by exercise with an increased risk of retinopathy (51) Physical Activity if the patient is on insulin or a sulfonyl- and deficits in cognitive and physical func- Regular physical activities for older adults urea. Therefore, each patient’s exercise tioning (52). Geriatric syndromes will in with diabetes, particularly activities of prescription needs to be individualized turn affect the ability of older adults to moderate to vigorous intensity, can im- based on his or her capability to safely manage their diabetes. Such limitations prove insulin sensitivity (38). Regular phys- participate in an exercise program. may affect a patient’s ability to obtain ical activities are a useful adjunct to drug food or medications, to exercise, or to therapy to manage glucose levels and may Obesity and Diet see his or her health care providers. well contribute to enhanced effectiveness Even a modest to moderate body weight Because older adults with diabetes of glucose-lowering agents. Furthermore, loss (5–10% of initial body weight) in- are quite heterogeneous with respect increasing physical activity as part of a life- creases insulin sensitivity and improves to their health status and available style intervention is effective in reducing glucose tolerance in obese individuals as care support, the goal for hyperglycemia physical functioning impairment among well as in those with impaired glucose management should be individualized patients with diabetes, improving glucose, tolerance or type 2 diabetes (66). As part based on their comorbidities and physi- lipid, and blood pressure control, and en- of diabetes management, the American cal and cognitive function status. A com- hancing weight loss (40,56,58–60). Diabetes Association recommends that prehensive geriatric assessment (53) Traditionally, aerobic training activi- overweight adults with type 2 diabetes will help the providers to assess an older ties have been recommended for older lose 2–8 kg weight through lifestyle patient’s ability to safely follow a com- adults, given their benefits in cardiore- changes (65). Recent studies have not sub- plex diabetes treatment plan. Given that spiratory fitness. Evidence also supports stantiated previous concerns about the type 2 diabetes develops after years of regular whole-body resistance training for risksofweightlossamongolderadults, metabolic abnormalities, a thorough older adults with type 2 diabetes. As pre- where older adults who intentionally lost medical evaluation in search for existing viously discussed, the pathophysiology of weight by combining caloric restriction diabetes complications is warranted type 2 diabetes involves insulin resistance, and exercise had minimal reduction in 448 Hyperglycemia Pathophysiology in Older Adults Diabetes Care Volume 40, April 2017

lean muscle mass and actually had in- Treatment of older adults with diabe- progressing smoothly and that hypogly- creasedbonedensityandimprovement tes needs to account for the progression cemia does not occur. in physical function compared with individ- of type 2 diabetes over time (73). Be- uals who lost weight by caloric restriction cause of the age-related decline of Biguanides aloneorbyexercisealone(67–69). Hence, b-cell function, maintaining target lev- Metformin, a biguanide, is the first-line weight loss programs for older adults with els of glycemic control may necessitate oral medication for hyperglycemia for diabetes should incorporate caloric restric- escalation of drug doses or the addition older adults (76). Because metformin’s tion with physical activity. of other antihyperglycemic agents (74). mechanism of action predominately in- Caloric restriction is appropriate for Thus, medications that target the volves reducing hepatic glucose produc- healthier overweight and obese older b-cells, such as sulfonylureas or GLP-1– tion, it rarely causes hypoglycemia when diabetes patients as part of manage- related drugs, are likely to become used alone. Some older patients may ex- ment of hyperglycemia but is not appro- less effective over time. Medications perience intolerable gastrointestinal dis- priate for some older patients who are such as metformin, thiazolidinediones comfort, decreased appetite, and modest at risk for undernutrition already. More (TZDs), and sodium glucose transporter weight loss associated with metformin. pressing dietary issues for these pa- 2 (SGLT2) inhibitors may help to reverse tients are how to maintain adequate ca- some of the vicious cycles contributing Metformin is contraindicated in pa- fi loric intake and coordinate food intake to hyperglycemia but do not directly ad- tients with renal insuf ciency, and the with administration of glucose-lowering dress the effects of aging on b-cells. U.S. Food and Drug Administration recom- agents appropriately to avoid hypogly- A review of the pharmacologic treat- mends against the use of metformin in patients with an estimated glomerular filtration cemia. Older adults with mobility limita- ment for hyperglycemia is beyond the 2 tion or who lack transportation are likely scope of this article but has been exten- rate (eGFR) of less than 30 mL/min/1.73 m . to have limited access to healthy and sively discussed elsewhere (75,76). Tables Furthermore, metformin is recommended fresh food (70). Social isolation (i.e., liv- 1 and 2 list most of the currently available to be discontinued at the time of or being alone, eating alone), poverty, and antihyperglycemic agents (noninsulin and fore an iodinated contrast imaging procedure in patients with an eGFR between functional reliance on others to pur- insulin), including a brief description of the 2 chase food are all risk factors for de- physiological action of the medication and 30 and 60 mL/minute/1.73 m , and can creased food intake. The presence of the advantages and disadvantages of the be restarted if the eGFR is stable 48 h impaired cognitive function may make agentwhenusedbyolderpatients.Treat- after the imaging procedure. following a dietary prescription particu- ment choices should be tailored to the larly difficult. Furthermore, dietary hab- specific situation of the individual patient, Sulfonylureas its established for a lifetime and often as determined in part by the initial com- Sulfonylureas are probably overused in with a cultural background may be par- prehensive assessment of the patient’sco- older adults with type 2 diabetes. These ticularly difficult to modify. Problems morbidities, cognition, functional status, drugs are inexpensive, and their overall with taste and oral health, which are care support, and financial situation (55). safety record is good. Their primary common in older people, may further Although it is common for an older adult to mechanism of action is to enhance insulin limit adaptation to a prescribed diet have multiple comorbidities, impairment secretion by b-cells of the pancreas. Hy- (71). Oral health problems can be exac- in cognition or functional status, and lim- poglycemia is a serious risk, however, and erbated by diabetes, which may in- ited financial support, a strong supportive conservative use is thus recommended crease the rate of periodontal disease. care system may be sufficient to help the for older people. Glyburide is associated Xerostomia is also more common in patient to safely implement a complex with a high risk for hypoglycemia in older older people owing to decreased sali- medical treatment plan. patients due to its long half-life so is not vary gland flow and is sometimes exac- The treatment plan should minimize recommended in this population (77). erbated by coexisting medication use. risk for hypoglycemia, especially in frail, Other sulfonylureas may be safer to use vulnerable older patients and when using in older patients, but all have a hypogly- MEDICATIONS IN THE agents with high risk for hypoglycemia cemia risk. Another concern about use of MANAGEMENT OF such as insulin and sulfonylureas. Thus, sulfonylurea drugs in older adults is a HYPERGLYCEMIA emphasis on lifestyle interventions and higher secondary failure rate than other Most medications to treat hyperglycemia classes of drugs that do not cause hypo- drugs, probably related to progressive in older adults with type 2 diabetes target glycemia can often result in safe achieve- b-cell dysfunction (78). one or more of the pathophysiological ment of lower A1C targets, especially impairments of age-related type 2 diabe- early in the course of type 2 diabetes. TZDs tes: reducing hepatic glucose production, As these safer interventions become less TZDs improve insulin sensitivity in skeletal increasing insulin secretion, increasing in- effective as a result of progressive b-cell muscle, reduce hepatic glucose produc- sulin sensitivity, decreasing glucagon se- failure with aging, insulin may be needed, tion, and have the advantages of low cretion, increasing incretin levels, and and the A1C target may need to be higher risk for hypoglycemia. However, con- decreasing satiety. Unfortunately, older to avoid hypoglycemia. Sulfonylurea cerns over potential adverse effects as- patients are often underrepresented in drugs should be used only with extreme sociated with TZDs have been raised, large clinical trials; therefore, data on anti- caution in any vulnerable older patient. including increased risks of bladder can- hyperglycemic medications are often ex- Frequent follow-up should be provided cer, weight gain, fluid retention, and trapolated from younger populations (72). to ensure that the treatment program is bone fractures (75). TZDS are usually care.diabetesjournals.org Lee and Halter 449

Table 1—Noninsulin antihyperglycemic agents (75,76) Class Primary physiological action Advantages Disadvantages

c Biguanide c ↓Hepatic glucose production, c No weight gain c Gastrointestinal side effects (diarrhea c Metformin possible ↑insulin-mediated Minimal hypoglycemia and abdominal discomfort) uptake of glucose in muscles Likely ↓in both microvascular Lactic acidosis (rare) and macrovascular events Contraindicated in renal insufficiency, Extensive clinical experience liver, or cardiac failure c Sulfonylureas c ↑Insulin secretion from c ↓Μicrovascular events c Hypoglycemia (esp. with longer c Glipizide pancreatic b-cells Extensive clinical experience half-life: glyburide) c Glyburide Weight gain c Glimepiride Skin rash (including photosensitivity) c Gliclazidea c Meglitinides c ↑Insulin secretion from c ↓Postprandal glucose c Hypoglycemia c Repaglinide pancreatic b-cells excursions Weight gain c Nateglinide Dosing flexibility Frequent dosing schedule (before meals) c TZDs c ↑Insulin sensitivity c Minimal hypoglycemia c Weight gain c Pioglitazone ↑HDL-C Edema/heart failure c Rosiglitazoneb ↓Triglycerides (pioglitazone) Bone fractures ↑LDL-C (rosiglitazone) ?↑MI c DPP-4 inhibitors c ↑Insulin secretion c Minimal hypoglycemia c Urticaria/angioedema c Sitagliptin (glucose-dependent) Well tolerated ?Increased risk of pancreatitis c Saxagliptin ↓Glucagon secretion Once-daily dosing ?↑Ηeart failure hospitalization c Vildagliptina (glucose-dependent) High cost c Linagliptin c Alogliptinc c GLP-1 receptor agonists c ↑Insulin secretion c Minimal hypoglycemia c Gastrointestinal adverse effects c Exenatide (Byetta) (glucose-dependent) Weight reduction (nausea, vomiting) c Exenatide extended release ↓Glucagon secretion ↓Postprandial glucose ↑Heart rate c Liraglutide (glucose-dependent) excursions ?Acute pancreatitis C-cell hyperplasia/ c Dulaglutide Slows gastric emptying medullary thyroid tumors in animals c Albiglutide ↑Satiety c Lixisenatidea c a-Glucosidase inhibitors c Slows intestinal carbohydrate c Minimal hypoglycemia c Generally modest A1C reduction c Acarbose digestion or absorption ↓Postprandial glucose Flatulence c Miglitol excursions Abdominal discomfort ?↓CVD events (STOP-NIDDM) Contraindicated in cirrhosis Frequent dosing schedule (with meals) c Bile acid sequestrantd c Unclear c Minimal hypoglycemia c Generally modest A1C efficacy c Colesevelam ?↓Ηepatic glucose ↓LDL-C Constipation production ↑Triglycerides ?↑Ιncretin levels Reduced absorption of fat-soluble vitamins High cost c Dopamine-2 agonist c Modulates hypothalamic c Minimal hypoglycemia c Nausea, headache, orthostatic c Bromocriptine, immediate release regulation of metabolism hypotension, potential exacerbation formc ↑Insulin sensitivity of psychosis High cost c Amylin-like c ↓Glucagon secretion c ↓Postprandial glucose c GI adverse effects (nausea, vomiting) c Pramlintidec Slows gastric emptying excursions ↑Ηypoglycemic risk of insulin ↑Satiety Weight reduction Frequent dosing schedule High cost c SGLT-2 inhibitors c ↓Glucose reabsorption by c Minimal hypoglycemia c Caution in patients with renal insufficiency c Canagliflozin the kidney Weight reduction Genitourinary infections c Empagliflozin ↑Urinary glucose excretion ↓Βlood pressure Genital yeast infections c Dapagliflozin Effective at all stages of T2D Polyuria Once-daily dosing Hyperkalemia Orthostatic hypotension Pancreatitis CVD, cardiovascular disease; GI, gastrointestinal; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; MI, myocardial infarction; STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus; T2D, type 2 diabetes. aNot licensed in the U.S. bPrescribing highly restricted in the U.S.; withdrawn in Europe. cNot licensed in Europe. dLimited use in the U.S. and Europe. 450 Hyperglycemia Pathophysiology in Older Adults Diabetes Care Volume 40, April 2017

Table 2—Insulin for treatment of type 2 diabetes (75,76) effect may contribute to increased risk Onset Duration for diabetic ketoacidosis in people with Insulin agents of action Peak effect of action type 1 diabetes. There is increased risk for genital yeast infection and urinary c Long-acting Glargine 100 About 2 h No peak 20 to .24 h tract infection, likely resulting from the Detemir About 2 h 3–9h 6–24 h† induced glycosuria. Because of these ad- c Ultra-long-acting verse effects, relatively high cost, and Degludec About 2 h No peak .40 h limited experience with these drugs in Glargine 300 About 6 h No peak 28–36 h older adults, their use is usually reserved c Intermediate-acting for situations in which other classes of Human NPH About 2 h 4–12 h 18–28 h drugs are not tolerated. Neutral protamine lispro** About 2 h 6 h 15 h c Short-acting Insulin Human regular About 30 min 2–4h 5–8h Because b-cell dysfunction plays a major c Rapid-acting 5–15 min 45–75 min 2–4h role in type 2 diabetes in older adults, Lispro insulin replacement therapy may be Aspart necessary to achieve the goal for hyper- Glulisine glycemia control, especially in patients – – c Inhalation powder 5 15 min 50 min (wide 2 3h with longer duration of type 2 diabetes Human insulin# variation) with progressive b-cell dysfunction. The The insulin agents lead to increased glucose disposal and decreased hepatic glucose production. approach to use of insulin in older adults They are nearly universal responsive and likely lead to ↓microvascular risk (UK Prospective Diabetes Study [UKPDS]). Disadvantages are hypoglycemia risks, which varies based on the with type 2 diabetes is to start with a individual agent’s dose and its course of the action **Only available in the U.S. in a premixed once-daily, long-acting insulin (basal in- combination with insulin lispro. #Inhaled human insulin (Afrezza) is contraindicated in patients sulin), with minimal peak or trough ef- with chronic lung disease such as asthma or chronic obstructive pulmonary disease. †Duration of fect. Long-acting agents, such as insulin action is dose dependent; at $0.8 units/kg, mean duration of action is longer and less variable: 22 to 23 h). glargine 100 and detemir insulin, have a lower incidence of nocturnal hypoglycemia than shorter-acting insulin agents, not considered as first-line antihyper- outcomes, but the results from two re- even among older adults (81). glycemic agents. cent large trials are mixed. Among pa- Premeal injections of a rapid-acting in- tients with type 2 diabetes and high sulin analog can be added to the basal in- fi GLP-1 Agents cardiovascular risk, the rate of the rst sulin, if necessary, in older patients in GLP-1 is an incretin, an intestinal hor- occurrence of death from cardiovascular whom the physician has determined can mone that is released as glucose levels causes, nonfatal myocardial infarction, safely administer insulin and monitor for increase with meals and cause glucose- or nonfatal stroke was lower with liraglu- hypoglycemia. Insulin aspart and insulin dependent insulin secretion; therefore, tide than with placebo (79), but among lispro have a very rapid onset and short GLP-1 agents are unlikely to cause hy- patients with type 2 diabetes and recent duration of action and are used just before fi poglycemia. Two classes of GLP-1 drugs acute coronary syndrome, no signi cant meals. They are less likely to result in post- are used clinically: effect on the rate of major cardiovascu- meal hypoglycemia than human regular in- lar events was found with lixisenatide sulin (82). These rapid-acting insulin agents 1. The injectable GLP-1 receptor ago- compared with placebo (80). can be given within 20 min after starting a nists stimulate insulin section in a meal, and hence, are particularly useful in glucose-dependent fashion, sup- SGLT-2 Inhibitors older patients who may not eat regularly. press glucagon output, slow gastric SGLT-2 inhibitors allow the kidneys to emptying, and decrease appetite. reabsorb most filtered glucose. SGLT-2 Combination Therapy These agents have the advantages is found only in the proximal tubule of Use of combination antihyperglycemic of modest weight loss, but for some the kidney and accounts for 90% of the agents in older patients may be neces- patients, the weight loss can be too reabsorption of glucose. SGLT-2 inhibi- sary with the progression of the disease. much and there may be resistance tors are oral agents that lower glucose Combinations of different classes of against performing injections. levels by increasing urinary excretion of drugs are theoretically attractive be- 2. The oral dipeptidyl peptidase-4 glucose. They are approved for use in cause their different modes of action (DPP-4) inhibitors enhance circulat- both type 1 and type 2 diabetes. They address various aspects of the patho- ing concentrations of active GLP-1. areusedoncedaily,resultinmodest physiology of hyperglycemia. For older lowering of A1C similar to DPP-4 inhibi- patients who have persistent hypergly- When used alone, both classes of GLP-1 tors, and rarely cause hypoglycemia. cemia (above their individualized A1C agents rarely cause hypoglycemia, but high They are contraindicated in chronic kid- target) with lifestyle intervention and cost may be prohibitive for some older ney disease. These agents increase urine metformin (if not contraindicated), add- adults. Pilot studies of myocardial ische- volume and sodium excretion, so usually ing another agent would be recom- mia and animal studies suggested that lower blood pressure modestly but may mended. The options include adding GLP-1 agonists may improve cardiovascular cause volume depletion. This volume an oral agent such as short-acting care.diabetesjournals.org Lee and Halter 451

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Role of body fat distribution in contents do not represent the views of the U.S. 17. Perl S, Kushner JA, Buchholz BA, et al. Signifi- the decline in insulin sensitivity and glucose tol- Department of Veterans Affairs or the U.S. canthumanbeta-cellturnoverislimitedtothefirst erance with age. J Clin Endocrinol Metab 1992; – Government. three decades of life as determined by in vivo thy- 75:1125 1132 36. Kohrt WM, Kirwan JP, Staten MA, Bourey Conflict of Interest. No potential conflicts of midine analog incorporation and radiocarbon dat- – RE, King DS, Holloszy JO. Insulin resistance in interest relevant to this article were reported. ing. J Clin Endocrinol Metab 2010;95:E234 E239 18. Menge BA, Tannapfel A, Belyaev O, et al. aging is related to abdominal obesity. Diabetes P.G.L. and J.B.H. re- Author Contributions. Partial pancreatectomy in adult humans does 1993;42:273–281 searched the data, wrote the manuscript, and not provoke beta-cell regeneration. 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