R E V I E W
`Antihyperglycaemic therapy in elderly patients with
`type 2 diabetes: potential role of incretin mimetics and
`DPP-4 inhibitors
`
`C. Mathieu, K. Bollaerts
`
`Katholieke Universiteit Leuven,
`Belgium, Leuven, Belgium
`
`Correspondence to:
`Chantal Mathieu,
`Katholieke Universiteit Leuven,
`Belgium,
`UZ Gasthuisberg,
`Herestraat 49,
`3000 Leuven,
`Belgium
`Tel.: +32 16 345970
`Fax: +32 16 345934
`Email: chantal.mathieu@
`med.kuleuven.be
`
`Disclosure
`Development of this review
`article was supported by an
`unrestricted educational grant
`from Novartis Pharma AG.
`C.M. is a consultant for
`Novartis Pharma AG.
`K.B. declares no conflicts of
`interests.
`
`S U M M A R Y
`Management of elderly patients with type II diabetes is complicated by age-related
`changes in physiology, comorbidities, polypharmacy and heterogeneity of functional
`status. A minimum goal in antidiabetic treatment in this population is to achieve a
`level of glycaemic control that avoids acute complications of diabetes, adverse
`effects and reduction in quality of life. Hypoglycaemia is a particular problem in
`elderly patients, and many antidiabetic agents pose increased risk for hypoglycae-
`mia. In addition, many standard agents pose risks for older patients because of
`reduced renal function and common comorbidities. Newer agents based on enhan-
`cing incretin activity, including the glucagon-like peptide-1 mimetics exenatide and
`liraglutide and the oral dipeptidyl peptidase-4 inhibitors sitagliptin and vildagliptin,
`may offer particular advantages in elderly patients with diabetes.
`
`Review criteria
`Information for this review was based on MEDLINE
`literature searches (1970–2006) and abstracts
`from major diabetes meetings.
`
`Message for the clinician
`Optimal strategies for achieving glycaemic control
`in elderly patients with diabetes must consider
`the clinical status of the patient. Antidiabetic
`agents can pose an increased risk of
`hypoglycaemia in the elderly. Incretin-based
`therapies are associated with improved glucose-
`dependent insulin secretion and therefore offer
`an advantage over other standard medications.
`
`Introduction
`
`The 1999–2002 National Health and Nutrition
`Examination Survey
`(NHANES)
`in the United
`States reported that more than 20% of adults aged
`65 years or older have diabetes (1). These elderly
`individuals often are undertreated with respect to
`glucose-lowering medications,
`and their
`care
`is
`complicated by the heterogeneity of
`their clinical
`and functional status. Age-related changes in physi-
`ology, diabetes-associated morbidities
`and other
`comorbidities, and polypharmacy make standard
`oral antihyperglycaemic therapy and insulin use
`problematic in many cases. Avoidance of hypogly-
`caemia is paramount in elderly persons with diabe-
`tes,
`and many
`commonly
`used
`antidiabetic
`medications are associated with substantial risk for
`hypoglycaemia. The new classes of antidiabetic ther-
`apies based on enhancing the activity of
`incretin
`hormones
`–
`glucagon-like
`peptide-1
`(GLP-1)
`mimetics or receptor agonists such as exenatide and
`liraglutide and oral
`inhibitors of dipeptidyl pepti-
`dase-4 (DPP-4) such as sitagliptin and vildagliptin
`– have a number of characteristics that may make
`them particularly suitable for use in elderly patients.
`This review discusses the pathophysiology of diabe-
`tes and challenges that uniquely confront the elderly
`
`and considers the role of current and future therap-
`ies for this population.
`
`Pathophysiology of diabetes in the elderly
`Ageing is associated with alterations in insulin secre-
`tion, insulin action and hepatic glucose production
`(2–5), and elderly patients are likely to have comor-
`bidities and to be receiving medications that can also
`alter glucose metabolism. Moreover, the evolution of
`type II diabetes with age and the data on pathophysi-
`ology of elderly-onset diabetes lead to differences in
`presentation of
`the disease in elderly individuals
`compared with middle-aged
`individuals
`(5–7).
`Whereas disease of earlier onset typically involves
`resistance
`to insulin-mediated glucose disposal,
`impaired glucose-dependent insulin production, and
`increased fasting hepatic glucose production, elderly
`patients may not exhibit an increase in fasting hep-
`atic glucose. Obese elderly patients still have a greater
`deficit in insulin-mediated glucose disposal, but in
`most elderly patients, especially the leaner patients, a
`deficit in glucose-dependent insulin secretion because
`failing b-cell
`of
`function is prominent. Typically,
`elderly patients will require b-cell-stimulating drugs
`and very often insulin to reach acceptable glucose
`levels. The age-related reduction in counter-regula-
`tory responses to decreased glucose levels is part of
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`30
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`Antihyperglycaemic therapy in elderly patients with type 2 diabetes
`
`the increased risk of hypoglycaemia in the elderly
`(8,9).
`
`Burden of disease in the elderly
`The recently reported NHANES data indicate preval-
`ence rates of 15.3% for diagnosed diabetes and 6.9%
`for undiagnosed diabetes among individuals 65 years
`or older (1). As shown in Table 1, elderly individuals
`with diabetes have much higher rates of vascular dis-
`ease than do their counterparts without diabetes.
`Those with middle age-onset diabetes have a similar
`prevalence of macrovascular disease but higher rates
`of microvascular disease and worse glycaemic control
`when compared with individuals with elderly-onset
`disease. Use of glucose-lowering medications was less
`common in those with elderly-onset diabetes.
`elderly
`Other
`studies have demonstrated that
`patients with diabetes are at increased risk for micro-
`vascular and macrovascular complications and heart
`failure
`compared with
`age-matched
`controls
`(3,10,11). Cardiovascular disease is also more com-
`mon in elderly patients with diabetes
`than in
`younger patients
`(12–14), as are diabetes-related
`end-stage
`renal disease,
`retinopathy
`and visual
`impairment,
`and
`lower-extremity
`amputation
`(12,13,15). Elderly patients with diabetes also have
`higher frequencies of depression, decreased neuro-
`psychologic function and vascular dementia (16,17).
`These individuals may exhibit such syndromes as
`diabetic amyotrophy and diabetic neuropathic cach-
`exia, as well as accidental hypothermia (3). Elderly
`patients with diabetes are at increased risk of hypo-
`glycaemia because of
`impaired counter-regulatory
`responses, comorbidities and polypharmacy, with the
`risk of severe or fatal hypoglycaemia associated with
`oral antihyperglycaemic agents or insulin increasing
`exponentially with age (3,18,19). Older patients with
`diabetes have poorer quality of
`life and increased
`hospital days and use of outpatient services com-
`pared with their counterparts without diabetes (20).
`
`Reducing burden of disease in the elderly
`Management of
`elderly patients with diabetes
`requires efforts at both improving glycaemic control
`and reducing other risk factors. Goals depend on the
`physical and functional status of patients and their
`life expectancy. A number of studies have indicated
`that
`risk factor
`reduction through treatment of
`hypertension (21–23)
`and dyslipidaemia
`(24,25)
`decreases poor outcomes in older patients with dia-
`betes. For example, the Heart Outcomes Prevention
`Evaluation trial in patients older than 55 years (23)
`showed large reductions
`in risk for myocardial
`infarction (22%), stroke (33%), cardiovascular death
`(37%) and overt nephropathy (24%) with ramipril
`
`treatment. Both European and American recommen-
`dations include aspirin use in elderly patients with
`diabetes in whom it is not contraindicated. European
`guidelines (26) indicate that blood pressure should
`be reduced to <140/80 mmHg in relatively healthy
`patients (e.g. no other major comorbidities) and to
`<150/<90 mmHg in the frail elderly. Abnormal lipid
`levels that may require intervention consist of total
`cholesterol ‡5 mmol/l, LDL cholesterol ‡3 mmol/l
`and triglycerides ‡2.3 mmol/l. American guidelines
`for elderly patients (27) indicate a blood pressure
`target of <140/80 mmHg (with potential additional
`benefit by reduction to <130/80 mmHg) and lipid
`targets of LDL cholesterol <100 mg/dl, HDL choles-
`terol >40 mg/dl and triglycerides <150 mg/dl.
`There are few data specifically on the benefits of
`long-term tight glycaemic control in reducing vascu-
`lar complications in elderly patients. However, a size-
`able proportion of patients in the United Kingdom
`Prospective Diabetes Study (UKPDS) (28) were older
`than 65 years by the end of the study, and it is gen-
`erally accepted that the benefits of tight glycaemic
`control observed in this study may be extrapolated
`to the elderly population. Several studies have indica-
`ted, however, that poor glycaemic control is associ-
`ated with poor outcome in elderly patients. The
`Verona Diabetes Study in patients aged 75 years or
`older (29) showed that the coefficient of variation of
`the fasting glucose level is an independent predictor
`of mortality. A study in patients with an average age
`of 66 years who had newly diagnosed diabetes (30)
`showed that average fasting blood glucose level above
`7.8 mmol/l is associated with a 50% greater mortality
`than an average level below 7.8 mmol/l. Another
`study in patients with an average age of 68.9 years
`with or without diabetes (31) showed significant
`relationship of stroke risk with fasting and postpran-
`dial glucose, A1C, and duration of illness in patients
`with diabetes. Cardiovascular mortality and non-fatal
`cardiovascular problems were significantly increased
`in those with A1C >7% compared with lower A1C.
`It
`is recognised that
`improved glycaemic control
`results in improved affective and cognitive function
`in elderly patients (16,32), which may also improve
`ability to manage their illness.
`Antidiabetic treatment in the elderly should, at the
`very least, focus on efforts to achieve glycaemic con-
`trol
`that avoids acute complications of diabetes,
`including symptomatic hyperglycaemia and hypogly-
`caemia, and that do not put patients at risk for seri-
`ous adverse effects or diminish quality of life. Older
`patients often lack the typical symptoms of hypergly-
`caemia; they do not develop glucosuria until there
`are marked elevations in blood glucose and fre-
`quently do not experience polydipsia because of
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`Antihyperglycaemic therapy in elderly patients with type 2 diabetes
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`31
`
`Table 1 Characteristics of middle-aged and elderly adults with and without diabetes, NHANES 1999–2002
`
`Middle aged, 40–64 years
`
`Elderly, ‡ 65 years
`
`No diabetes
`
`Diabetes
`
`No diabetes
`
`Middle age-onset
`diabetes
`
`Elderly-onset
`diabetes
`
`n
`Mean fasting glucose (mg/dl)
`Mean A1C (%)
`A1C >7% (%)
`A1C >8% (%)
`Mean age at diagnosis (years) 
`Years since diagnosis (%) 
`>10
`5–10
`<5
`Glucose-lowering medication (%) 
`No medication
`Insulin
`Oral medication
`Both insulin and oral
`Conditions (%)
`Cardiovascular disease
`Stroke
`Coronary heart disease
`Peripheral arterial disease
`Peripheral neuropathy
`Retinopathy 
`
`3391
`99.8
`5.4
`1.4
`<1
`
`100
`
`5.6
`1.7
`4.3
`2.4
`7.9
`–
`
`374
`148.9
`7.7
`55.3
`36.7
`46.7
`
`25.4
`26.9
`47.7
`
`18.9
`9.4
`61.4
`10.2
`
`13.9
`5.0
`10.4
`6.0
`16.9
`24.8
`
`2344
`105.4
`5.6
`2.1
`<1
`
`100
`
`19.6
`7.8
`14.0
`12.0
`21.5
`–
`
`272
`172.4
`7.4
`59.9
`27.9
`53.2
`
`76.7
`17.6
`5.7
`
`9.0
`31.7
`45.6
`13.7
`
`36.1
`14.0
`30.1
`22.4
`35.5
`39.4
`
`193
`132.3*
`6.9*
`41.6*
`20.2
`71.8*
`
`10.9*
`24.1
`65.0*
`
`22.5
`6.9*
`67.5
`3.2*
`
`34.7
`11.4
`28.2
`18.4
`37.1
`12.6*
`
`*p < 0.05 for comparison of middle age-onset vs. elderly-onset diabetes.  Question asked only for individuals with diagnosed diabetes. Adapted from Ref. (1).
`
`impaired thirst mechanisms (3,5). Older patients
`with poor glycaemic control are more likely to have
`such acute complications as hyperglycaemic hyperos-
`molar coma. Hypoglycaemia is probably the major
`safety concern in pharmacologic treatment of diabe-
`tes in elderly patients. Many of the classes of anti-
`hyperglycaemic medications have hypoglycaemia as a
`prominent adverse effect, and elderly patients have
`reduced awareness of the autonomic symptoms of
`impending hypoglycaemia (5,33). Risk factors for
`hypoglycaemia in elderly patients with diabetes are
`shown in Table 2 (33). In the attempt to balance the
`potential benefits of tight glycaemic control against
`the risk of adverse effects in elderly patients, both
`European and American authorities suggest basing
`glycaemic targets on functional and physical status
`and life-expectancy (26,27,34). Thus,
`for example,
`European guidelines suggest a target A1C of <6.5%
`to 7.5% in relatively healthy elderly patients and a
`target of >7.5% to £8.5% in the frail elderly (26).
`The American Diabetes Association (ADA) notes that
`elderly patients with life-expectancy long enough to
`derive benefits from glycaemic control (10 years)
`and who are active, cognitively intact, and able to
`
`Table 2 Risk factors for hypoglycaemia in elderly
`patients with type II diabetes
`
`Advanced age
`Polypharmacy
`Use of sulfonylurea or insulin
`Poor nutrition or fasting
`Intercurrent illness
`Chronic liver, renal or cardiovascular disease
`Prolonged physical exercise
`Alcohol ingestion
`Endocrine deficiency (thyroid, adrenal, pituitary)
`Loss of normal counter-regulation
`Hypoglycaemic unawareness
`
`From Ref. (33).
`
`undertake self-management should have the same
`target of <7.0% as younger patients (34); the guide-
`lines promoted by the American Geriatrics Society
`(27) and supported by the ADA include a recom-
`mendation of <7.0% in relatively healthy/functional
`patients and a less stringent goal (e.g. £8.0%) in the
`
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`32
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`Antihyperglycaemic therapy in elderly patients with type 2 diabetes
`
`frail elderly, those with life expectancy below 5 years,
`and those in whom the risks associated with attempt-
`ing to achieve tight control outweigh the potential
`benefits.
`
`Antihyperglycaemic medications
`Any antihyperglycaemic medication that can be used
`in younger patients can also be used in older
`patients. However, many of these medications have
`adverse effects that are of particular concern in the
`elderly, and elderly patients have age-related decrea-
`ses in renal function, higher frequency of polyphar-
`macy and higher rates of comorbidity,
`including
`diabetes-related conditions, that increase their risk
`for adverse effects. As noted, hypoglycaemia is a pri-
`mary concern in the elderly population, because it
`can have such a profound impact on patient health,
`function and quality of life. Avoiding hypoglycaemia
`can significantly improve quality of life and patient
`compliance with antidiabetic treatment.
`Sulfonylureas
`(SUs) pose considerable risk for
`hypoglycaemia in elderly patients (18,27,33,35–37).
`In addition to age, risk factors for SU-related hypo-
`glycaemia include disability, poor nutrition and poly-
`pharmacy.
`SUs
`with
`longer
`time-action
`characteristics are associated with greater risk; it is
`recommended that chlorpropamide not be used in
`elderly patients (27), and gliclazide (including its
`extended-release form), glipizide and glimepiride are
`associated with less risk than glyburide (glibencla-
`mide) (33). It should be noted that many drugs may
`potentiate the activity of SUs and/or contribute to
`risk of hypoglycaemia via displacement of SUs from
`plasma proteins,
`reducing hepatic metabolism of
`SUs, decreasing SU urinary excretion, or exhibiting
`intrinsic hypoglycaemic activity that is additive to
`the effects of SUs (33). The rapid-acting secreta-
`gogues repaglinide and nateglinide do pose risk for
`hypoglycaemia, but this risk appears to be less than
`that associated with SUs (35–39). These agents may
`pose particular benefits for elderly patients because
`they target postprandial hyperglycaemia, which may
`possibly be a better predictor of risk for diabetic
`complications than fasting glucose in elderly patients
`(5,39). Insulin is associated with increased risk of
`hypoglycaemia in elderly patients (Table 3) (33), and
`its use in this population is complicated by the need
`for good visual/motor skills and cognitive function
`for appropriate administration (19,33). The most
`common causes of hypoglycaemia associated with
`insulin use appear to be excessive dosing and use of
`improper insulin combinations. Missing of meals
`and failure to adjust insulin for physical exercise also
`contribute to risk of hypoglycaemia. Insulin is also
`associated with substantial weight gain.
`
`Table 3 Risk factors for insulin-induced hypoglycaemia
`in elderly patients with diabetes
`
`Insulin administration errors
`Excessive dose
`Improper timing relative to food intake
`Wrong insulin type
`Decreased glucose influx
`Missed meals
`Fasting
`Gastroparesis with delayed carbohydrate absorption
`Increased insulin sensitivity
`Weight loss
`Intensive insulin therapy
`Increased exercise
`Delayed insulin clearance, erratic absorption
`Renal failure
`Insulin injection in hypertrophic sites
`Decreased endogenous glucose production
`Severe liver disease
`Defective glucagon or epinephrine counter-regulation
`Alcohol ingestion
`
`From Ref. (33).
`
`(TZDs) and the
`thiazolidinediones
`Metformin,
`a-glucosidase inhibitors pose little risk for hypogly-
`caemia when used as monotherapy. Metformin is
`currently recommended as first-line therapy along
`with lifestyle interventions in all patients with type II
`diabetes (38). In addition to minimal risk of hypo-
`glycaemia, metformin is also associated with weight
`neutrality or a small reduction in body weight, which
`is advantageous in obese elderly patients. However,
`care should be taken when using metformin in the
`frail elderly patient and metformin should preferen-
`tially be avoided in older patients with elevated
`serum creatinine levels (‡1.5 mg/dl in men, 1.4 mg/
`dl in women) or reduced creatinine clearance (indic-
`ative of reduced renal function), because the risk of
`lactic
`acidosis
`is
`increased
`in these
`patients
`(27,35,36). Metformin is especially contraindicated in
`patients with heart failure and in patients with other
`conditions that are associated with increased risk of
`lactic acidosis. However, the stringent contraindica-
`tion formulated for metformin, based solely on age,
`should be dropped (37). Whenever possible, patients
`should be given an opportunity to use metformin.
`Older patients
`receiving metformin should have
`regular monitoring of renal function and whenever
`there is a dosage change. In addition, metformin is
`associated with a high frequency of gastrointestinal
`(GI) adverse effects that may be poorly tolerated by
`older patients. Although there is also minimal risk
`of hypoglycaemia with TZDs,
`these agents are
`
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`Antihyperglycaemic therapy in elderly patients with type 2 diabetes
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`33
`
`associated with substantial weight gain and oedema,
`with the oedema frequently causing or exacerbating
`heart failure (35–38,41,42). TZDs are contraindicated
`in patients with evidence of heart failure, and the use
`of these agents in combination with insulin was even
`until
`recently contraindicated in Europe
`exactly
`because of the risk of heart failure. TZDs are also
`contraindicated in patients with active hepatic dis-
`ease. Increased plasma volume may require monitor-
`ing of haemoglobin or haematocrit. Although the
`agents can be used in patients with mild or moderate
`renal impairment, vigilance should be maintained for
`the possibility of oedema. The a-glucosidase inhibi-
`tors (e.g. acarbose) lower postprandial glucose levels
`while posing little risk for hypoglycaemia (5,35,36).
`However, these agents have to be taken three times
`daily before meals containing digestible carbohy-
`drates, and they are associated with a high frequency
`of GI adverse effects that many patients cannot toler-
`ate. In addition, patients experiencing hypoglycaemia
`while receiving these agents in combination with
`other antihyperglycaemic agents must ingest glucose
`rather than complex carbohydrates.
`
`Injectable GLP-1 mimetics and
`oral DPP-4 inhibitors
`Effects of the incretin GLP-1 include regulation of
`glucose-dependent
`insulin secretion and glucose-
`dependent glucagon release,
`inhibition of gastric
`emptying and appetite suppression, with preclinical
`studies also showing an effect in expansion of islet
`b-cell mass (43–46). The oral DPP-4 inhibitors selec-
`tively inhibit the DPP-4 enzyme responsible for rap-
`idly degrading the incretin hormones GLP-1 and
`gastric inhibitory polypeptide, with most of the phar-
`macologic effects of these agents being attributed to
`the ability to increase levels of biologically active
`intact GLP-1 (46–48), whereas the larger-molecule
`injectable GLP-1 mimetics act as GLP-1 receptor ag-
`onists. These agents regulate glucose homeostasis by
`improving glucose sensitivity of a and b cells, pro-
`moting
`glucose-dependent
`insulin secretion and
`
`suppressing inappropriate glucagon secretion and
`thus hepatic glucose production. Initial studies of
`exogenously administered GLP-1 infusions showed
`that the glucose-dependent nature of the GLP-1 insu-
`linotropic effect resulted in little risk of hypoglycae-
`mia compared with SU treatment in elderly patients
`(49) and that
`the glucose-dependent
`effect on
`glucagon preserved the counter-regulatory response
`to hypoglycaemic levels of glucose (50). Perhaps
`because of the more modest stabilisation of post-
`prandial GLP-1 levels, the oral DPP-4 inhibitors do
`not promote slowing of gastric emptying and weight
`loss associated with the GLP-1 mimetics; as a result,
`the oral agents, which have weight-neutral effects, are
`also associated with a lower frequency of GI adverse
`effects.
`The GLP-1 mimetic exenatide is approved for use
`in the United States as a twice-daily subcutaneous
`injection for add-on treatment to SU and/or metfor-
`min. It reduced A1C by about 1% and resulted in
`significant weight loss (0.9–2.5 kg) in 6-month stud-
`ies as add-on treatment (51–53), with maintained
`reduction in A1C and continued weight
`loss
`observed in overweight patients over 82 weeks (54).
`Effects on hyperglycaemia include sizeable reductions
`in both fasting and postprandial glucose levels (55).
`Rates of hypoglycaemia were similar in the two
`groups, with overnight hypoglycaemia being less
`common with exenatide and daytime hypoglycaemia
`being less common with insulin glargine. Severe
`hypoglycaemia has been rare with exenatide alone;
`however,
`there are dose-related increases
`in fre-
`quency of hypoglycaemia in combination with SU,
`metformin or SU plus metformin (Table 4), with
`dose adjustments being recommended for SU in
`combined therapy (55). Exenatide is associated with
`a relatively high frequency of GI adverse events
`(Table 5). A once-weekly formulation of exenatide
`has been studied as add-on to SU and/or metformin
`in a small group of patients, with promising results;
`sizeable reductions in A1C were observed at both tes-
`ted doses, with no severe hypoglycaemia reported
`
`Table 4 Incidence of hypoglycaemia with exenatide plus metformin and/or sulfonylurea (SU) in three 30-week trials
`
`Exenatide + metformin
`
`Exenatide + SU
`
`Exenatide + metformin/SU
`
`Placebo
`
`Exenatide
`5 lg b.i.d.
`
`Exenatide
`10 lg b.i.d.
`
`n
`Hypoglycaemia (%)
`
`113
`5.3
`
`110
`4.5
`
`113
`5.3
`
`From Ref. (55).
`
`Placebo
`
`123
`3.3
`
`Exenatide
`5 lg b.i.d.
`
`Exenatide
`10 lg b.i.d.
`
`125
`14.4
`
`129
`35.7
`
`Placebo
`
`247
`12.6
`
`Exenatide
`5 lg b.i.d.
`
`Exenatide
`10 lg b.i.d.
`
`245
`19.2
`
`241
`27.8
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`Antihyperglycaemic therapy in elderly patients with type 2 diabetes
`
`Table 5 Adverse events in ‡5% of patients receiving
`exenatide in controlled trials
`
`Placebo b.i.d.
`(n ¼ 483)
`
`Exenatide b.i.d.
`(n ¼ 963)
`
`18
`4
`6
`4
`6
`6
`3
`
`44
`13
`13
`9
`9
`9
`6
`
`Event (%)
`
`Nausea
`Vomiting
`Diarrhoea
`Feeling jittery
`Dizziness
`Headache
`Dyspepsia
`
`From Ref. (55).
`
`frequent adverse event being mild
`and the most
`nausea (57). Because exenatide is a GLP-1 homo-
`logue derived from a reptile (Gila monster), antibod-
`ies are formed in a substantial number of patients
`(55). The impact of these antibodies is unclear at
`present but may limit the use of this agent. Liraglu-
`tide is a GLP-1 analogue that can be dosed once
`daily (58,59). Similar effects on A1C–lowering, dose-
`dependent weight reduction, and GI side effects as
`reported for exenatide have been described for lira-
`glutide (59).
`Based on current experience with the GLP-1 mi-
`metics, one potential role that can be envisioned in
`elderly patients is as a step before insulin in patients
`with inadequate control using oral agents. The
`weight reduction produced by these agents would be
`advantageous in obese elderly patients. The develop-
`ment of formulations requiring less frequent injec-
`tion would be of considerable benefit in the elderly
`population. The increased risk of hypoglycaemia
`observed when exenatide is combined with SUs indi-
`cates that this combination should be avoided in the
`elderly population. The exenatide clinical program
`included 282 patients aged 65 years or older and 16
`patients 75 years or older, with no differences in
`safety or efficacy observed compared with younger
`patients (55). Age had no effect on exenatide phar-
`macokinetics. The drug is cleared renally, and while
`no dosing modification is needed in patients with
`mild or moderate renal impairment, exenatide is not
`recommended for use in patients with end-stage
`renal disease or severe renal impairment (creatinine
`clearance <30 ml/min) (55).
`The oral DPP-4 inhibitors have a number of char-
`acteristics that make them highly suitable for use in
`elderly patients, including minimal risk for hypogly-
`caemia alone or in combination, once daily oral dos-
`ing, reductions
`in both fasting and postprandial
`
`glucose levels, and a safety profile very similar to pla-
`cebo (47,48,60–62). Sitagliptin has been approved for
`use as monotherapy or add-on treatment with met-
`formin or TZDs. Sitagliptin labelling indicates that
`treatment with 100 mg/day reduces A1C by 0.5–0.6%
`from a baseline of 8.0% (63). In a recently reported
`monotherapy trial of sitagliptin (60), placebo-sub-
`tracted reductions were
`approximately 0.6% in
`patients with baseline below 8.0%, 0.8% in those
`with baseline of 8.0% to <9.0%, and 1.5% in those
`with baseline 9.0% or higher. A pooled analysis of
`1301 patients receiving vildagliptin 100 mg/day in
`monotherapy studies with similar entry criteria indi-
`cate A1C reductions from baseline of 1.1% overall,
`1.3% in those with baseline above 8.0% (n ¼ 838),
`and 1.7% in those with baseline above 9.0% (n ¼
`440) (48). Both agents have been associated with
`minimal risk for hypoglycaemia. For example, in a
`large-scale year-long comparison with metformin,
`mild hypoglycaemia occurred in 0.6% of patients
`receiving vildagliptin and 0.4% of patients receiving
`metformin (64). In controlled trials of sitagliptin,
`hypoglycaemia occurred in 1.2% of patients receiving
`sitagliptin and 0.9% of patients receiving placebo
`(63). Adverse event profiles of sitagliptin and vilda-
`gliptin monotherapy are
`similar
`to those with
`placebo (Tables 6 and 7) (48,60,63,65), with no
`prominent adverse effects observed and GI adverse
`event rates comparable to those in patients receiving
`placebo. A study of vildagliptin added to metformin
`showed a significant reduction in metformin-related
`GI adverse
`events
`in the vildagliptin/metformin
`group (66). Neither sitagliptin nor vildagliptin causes
`weight gain (48,63,67).
`
`Table 6 Select adverse events in monotherapy trial of
`sitagliptin 100 mg/day
`
`Placebo
`(n ¼ 253)
`
`Sitagliptin
`100 mg/day
`(n ¼ 238)
`
`66.0
`1.6
`
`Any adverse event
`Discontinuation because of
`adverse event
`0.8
`Hypoglycaemia
`11.5
`Any GI adverse event
`Prespecified select GI adverse events
`Abdominal pain
`1.6
`Nausea
`1.2
`Vomiting
`1.2
`Diarrhoea
`2.4
`
`66.0
`2.1
`
`1.3
`16.4
`
`2.1
`2.1
`1.3
`4.6
`
`Values are expressed as percentage. Adapted from Ref. (60).
`
`ª 2007 The Authors
`Journal compilation ª 2007 Blackwell Publishing Ltd Int J Clin Pract, August 2007, 61 (Suppl. 154), 29–37
`
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`Antihyperglycaemic therapy in elderly patients with type 2 diabetes
`
`35
`
`Table 7 Adverse events reported in ‡5% in any group in controlled trials with vildagliptin 100 mg/day
`
`Vildagliptin 100 mg/day*
`(n ¼ 1530)
`
`Metformin up to 2 g/day
`(n ¼ 252)
`
`Rosiglitazone 8 mg/day
`(n ¼ 267)
`
`Placebo
`(n ¼ 255)
`
`Any adverse event
`Nasopharyngitis
`Headache
`Dizziness
`Upper respiratory tract infection
`Diarrhoea
`Nausea
`Abdominal pain
`
`63.6
`7.6
`7.1
`5.8
`4.6
`3.1
`2.9
`1.2
`
`75.4
`9.5
`7.1
`6.0
`6.0
`26.2
`10.3
`7.1
`
`64.0
`7.5
`5.2
`4.1
`3.0
`2.6
`0.7
`0.7
`
`60.0
`7.1
`5.9
`4.3
`2.7
`3.1
`3.9
`1.2
`
`*Pooled data from monotherapy trials with 50 mg b.i.d. and 100 mg q.d. Values are expressed as percentage. Adapted from Ref. (64).
`
`Sitagliptin does not undergo extensive metabolism
`and is excreted mostly unchanged in the urine. Si-
`tagliptin dosage requires adjustment in patients with
`moderate (creatinine clearance 30 to <50 ml/min)
`or severe (<30 ml/min) renal
`impairment or end-
`stage renal disease. Pharmacokinetic studies showed
`that
`elderly patients had higher drug exposure
`because of age-related reduction in renal function,
`but no dosage adjustment is necessary on the basis
`of age alone (63). No dosage adjustments are neces-
`sary in mild or moderate hepatic impairment, and
`the drug has not been evaluated in patients with
`severe hepatic impairment. Vildagliptin is metabo-
`lised via hydrolysis and does not undergo cyto-
`chrome P450 (CYP)3A4 metabolism (data on file,
`Novartis Pharmaceuticals Corporation). No CYP
`involvement has been identified, with the major
`metabolite being pharmacologically inactive. Most
`of
`the vildagliptin dose is excreted in the urine.
`Pharmacokinetic studies indicate an increase in drug
`exposure in patients with severe hepatic impairment
`and in elderly patients, the latter reflecting reduced
`renal clearance, with the increases not being clinic-
`ally significant and requiring no dosage adjustment
`on the basis of hepatic impairment or age (68,69).
`No specific data on vildagliptin in patients with
`renal impairment have been reported. Vildagliptin is
`not extensively bound to plasma proteins, which
`further limits the potential
`for drug–drug interac-
`tions. A recent analysis showed that efficacy and
`safety with vildagliptin treatment were similar in
`patients 65 years or older and those younger than
`65 years (70).
`
`Conclusion
`
`Management of diabetes in the elderly population is
`complicated by age-related changes in physiology,
`
`comorbidities and polypharmacy. Glycaemic goals in
`elderly patients and interventions to achieve such
`goals must take into account the clinical status of
`individual patients. Avoidance of hypoglycaemia is a
`primary concern in antihyperglycaemic treatment,
`because hypoglycaemia can have a profound impact
`on health and quality of life in elderly patients. Many
`antidiabetic treatments pose increased risk for hypo-
`glycaemia in the elderly patient. The new incretin-
`based therapies offer advantages over some of the
`standard medications by improving glucose-depend-
`ent insulin secretion. A number of roles can be envi-
`sioned for the oral DPP-4 inhibitors in particular in
`treating elderly patients with diabetes. Monotherapy
`in the frail elderly will provide meaningful reductions
`in A1C while posing minimal risk for hypoglycaemia,
`small risk for other troublesome adverse events, and
`small risk for drug–drug interactions. A further bene-
`fit is elimination of the need for dose titration. Com-
`bination of these agents with metformin in elderly
`patients who can receive the latter may provide an
`ideal strategy for achieving more robust reductions
`in A1C while avoiding hypoglycaemia. Continued
`experience with these agents will help to optimise
`strategies for glycaemic control
`in elderly patients
`with diabetes.
`
`Acknowledgements
`
`Editorial assistance in the preparation of this paper
`was provided by BioScience Communications, New
`York, NY.
`
`References
`
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`ª 2007 The Authors
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`Mylan EX 1009, Page 7
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`

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`36
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