PROFESSOR ALAN J SINCLAIR (Orcid ID : 0000-0001-6712-7805)

DR ANGUS FORBES (Orcid ID : 0000-0003-3331-755X)

Accepted Article
Article type : Invited Review

Title: Diabetic Medicine

Created by: Maria Hale
Accepted: 04.11.2018
Email proofs to: Sinclair.5@btinternet.com
Copyright: Diabetes UK
Article no.: DME–2018-00550
Article type: Review
Short title/Authors running head: Diabetes in old age – evidence base  A. J. Sinclair et al.

Evidence-based diabetes care for older people with Type 2

diabetes: a critical review

A. J. Sinclair1, A. H. Abdelhafiz2, A. Forbes3 and M. Munshi4

1
Foundation for Diabetes Research in Older People, Diabetes Frail Ltd, Luton, 2Rotherham

General Hospital, Rotherham and 3Kings College, London, UK, and 4Harvard Medical

School and Joslin Clinic, Boston, MA, USA

Correspondence to: Alan Sinclair. E-mail: Sinclair.5@btinternet.com.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/dme.13859
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 Abstract

In our ageing society diabetes imposes a significant burden in terms of the numbers of people
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with the condition, diabetes-related complications including disability, and health and social

care expenditure. Older people with diabetes can represent some of the more complex and

difficult challenges facing the clinician working in different settings, and the recognition that

we have only a relatively small (but increasing) evidence base to guide us in diabetes

management is a limitation of our current approaches. Nevertheless, in this review we

attempt to explore what evidence there is to guide us in a comprehensive scheme of treatment

for older adults, often in a high-risk clinical state, in terms of glucose lowering, blood

pressure and lipid management, frailty care and lifestyle interventions. We strive towards

individualized care and make a call for action for more high-quality research using different

trial designs.

What’s new?

 This review represents a modern, up-to-date account of published evidence that seeks

to examine the significance of previous research relating to the management of

diabetes in older people.

 The review also provides a diagrammatic view of the development of the complex

illness scenarios seen in ageing people with diabetes, and provides the first detailed

algorithm for developing individualized care programmes in this often vulnerable

group.

 The evidence review takes us through glucose-lowering trials involving older people,

a discussion of important cardiovascular outcome and safety trials relevant to the

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 elderly, in addition to a discussion of insulin therapy, lifestyle interventions and

managing frailty.
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 This review concludes with a call to action to promote new research in older adults

with diabetes with the hope of optimizing clinical outcomes in the future.

<H1>Introduction and background

It is estimated that in 2017 there were 451 million (age 18–99 years) people with diabetes

worldwide, and these figures are expected to increase to 693 million by 2045 [1]. A major

shift in the epidemiology of diabetes has been to those aged 60–79 years [2]. Apart from this

advancing tide of older people with diabetes, the ageing process itself is increasing the

number of people living with the sequelae of ill health, chronic diseases, frailty and injuries,

all of which enhance disability and functional decline, and pose real clinical challenges and

burdens in those with Type 2 diabetes [3]. Older people with diabetes should be a priority

target for focused interventions that bring about improved cardiovascular outcomes,

enhanced safety and improved survival if the latter has worthwhile disability-free years and

associated quality of life [4]. The important area of Type 1 diabetes in older adults is outside

the scope of this review but must be addressed in due course.

We recognize that older people with diabetes can span four decades (ages 60–90 years and

older), are not a homogeneous group and range from robust adults still in employment to frail

residents of nursing homes. Thus, their cognitive and physical status vary widely, and they

often have complex health and social care needs [4]. We therefore consider that our review of

the literature in general pertains to those aged 70 years and over because the risks of

comorbid illness, frailty and dependency begin to rise after this age, but we accept that other

organizations may define being ‘old’ as less or more than 70 years [5]. It is also important to

recognize that to produce valid and evidence-based recommendations for care, it is usually

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 necessary to extrapolate research findings from clinical trials in younger adults, which is a

limitation that has implications for developing clinical guidelines [6]. The modern
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management of older people with diabetes requires an acceptance by clinicians that

recommendations of care should be tailored to the individual and take into consideration

important factors such as changes in functional status, the comorbid illness profile, whether

or not a person is dependent and their estimated life expectancy. These can have a marked

influence on management goals, what care model is adapted, and how ongoing and follow-up

care is delivered. We call this an ‘individualizing care’ scheme (Box 1).

Diabetes care for older people is often not straightforward for the reasons cited above, but as

advancing age brings about increasing complexity of both the person with diabetes and the

management of the illness itself, clinicians face greater challenges to their skills and

competence. The different pathway to Type 2 diabetes in older individuals compared with

younger individuals reflects changes in body composition, marked changes in insulin

resistance in muscle and adipose tissues, a decrease in -cell capacity and loss of normal

insulin pulsatility, and the progressive negative effects on glucose tolerance of comorbid

illness, onset of frailty and polypharmacy, all of which are superimposed on the ageing

process [4,9]. It is inevitable that some alterations or modulation of management goals will be

necessary with advancing age as health risk increases and, for convenience, we have used age

by decade as a way of demonstrating this. Some of the components of this pathway to

diabetes and person–illness complexity are shown in Fig. 1.

<H2>Purpose of the review

This review provides an up-to-date summary of the evidence that defines the relationship

between glycaemic control and outcome in older people with Type 2 diabetes, what

interventions have been undertaken that relate to glucose-lowering and other care outcomes,

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 what clinical guidance is available to enhance quality of care, and what research is needed to

assist the clinician in providing evidence-based individualized diabetes care.

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<H1>Review methodology

Initial screening was undertaken by each author to remove studies that were not appropriate

or had no relevance to their assigned tasks within the writing group. As documented

previously [10], we used a model of methodology to conduct a comprehensive and detailed

narrative review that minimizes selection bias according to the elements given below.

<H2>Data sources and search enquiry

Our detailed literature enquiry also required an assessment of relevant articles/reviews and

outputs from key national and international diabetes, endocrine and clinical gerontological

societies, and professional bodies. These were: Diabetes UK, American Endocrine Society,

International Diabetes Federation (IDF), American Diabetes Association (ADA), Canadian

Diabetes Association, European Association for the Study of Diabetes, American Medical

Directors Association, British Geriatrics Society, New Zealand Society of Diabetes,

Australian Diabetes Society and the American Geriatrics Society.

Databases searched were: Google Scholar, MEDLINE, CINHAL Complete and Embase. We

used the following medical subject heading (MeSH) terms: older people, diabetes mellitus,

aged, glucose control, guidelines, evidence base, interventions and clinical trials. We limited

our selection to English language articles. The titles of all articles were reviewed for

relevance. Inclusion criteria were then applied to all articles by examining abstracts, full book

texts or a combination of these. A manual review of any further relevant citations was

undertaken if they had been overlooked during the database searches. The authors recognize

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 that a limitation of this search strategy is that we may be missing contributions from non-

English language scientific resources and journals.

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<H2>Study selection

We included studies only if the following inclusion criteria were satisfied: (1) randomized

clinical trials (RCTs) or smaller clinical studies that contain information about or derived

from the generic terms ‘older people’, ‘aged’, ‘senior citizens’ or ‘elderly’; (2) they included

interventional, observational or descriptive data from studies involving older people with

diabetes, or data or reviews of relevant audit, diabetes care policies, or educational

programmes for our defined subject population; and (3) described a range of glucose-

lowering therapies or other non-pharmacological treatments that sought to enhance diabetes

care in older people.

Guidelines (and Position Statements) were included if they had clinical relevance to the

subject population (e.g. diabetes in older people) or topic area (e.g. cardiovascular outcome),

and were written by professional societies or by national or international consensus expert

groups. The key issue was that guidance was designed to improve the quality of diabetes care

delivered.

<H2>Data extraction

All articles/studies derived from the search enquiry were independently examined by two

authors (AJS, AHA) and data were extracted using a standardized format according to their

relevance to the review subject. AF and MM also independently examined all reference

materials relating to glycaemic control in older people, while each intervention study was

independently reviewed by the authors according to their writing group tasks. AJS and AHA

independently reviewed guidelines and related material. Detailed discussion, review of any

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 conflicts in data interpretation and mutual agreement resolved any disagreements between the

reviewers. We have included data relating to the design of studies, the nature of the research
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question, characteristics of people involved as participants, key findings and outcomes

achieved. For the intervention trials, we have included information on study design, nature of

participants, the intervention used and main findings. The information obtained for the

clinical guidelines reviews summarized the names of the professional organization, the main

reason for the guideline development, what was the key methodology involved and how

recommendations were framed.

<H1>The issue of glycaemic control – what studies tell us?

In Table 1, we summarize the key studies that have examined the role of glycaemic control,

the intensity of treatment regimens and their impact on microvascular and macrovascular

complications. Although some benefits of intensive glycaemic control were seen in the

prevention of microvascular complications, there were no benefits for major cardiovascular

events or mortality. Although these studies primarily evaluated middle-aged people (mean

age 55–65 years), subgroup analysis in the older age cohort did not show distinct differences

in the role of glycaemic control. In recent years, several studies have looked specifically at

older adults with diabetes. Almost all of them are observational or retrospective cohort

studies.

The common themes emerging from these studies are:

 there are no benefits of tight control below a HbA1c range of 53–59 mmol/mol (7.0–

7.5%) in older adults;

 there is a ‘J’- or a ‘U’-shaped relationship between HbA1c and the risk of diabetic

complications including mortality, with an optimal HbA1c around 59–64 mmol/mol

(7.5–8%);

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  the presence of a high comorbidity burden reduces the benefits of improved

glycaemia;
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 low (< 42 mmol/mol; <6%) and high (> 75 mmol/mol; >9%) HbA1c levels show more

harm than benefit in older adults;

 stable glycaemic control, measured by HbA1c values in the mid-range (42–64

mmol/mol; 6–8%), over time may be more beneficial than lower HbA1c values.

A comprehensive review of care home diabetes, including an examination of interventions

undertaken has been published recently [10].

<H1>Summary of blood pressure and lipid-lowering studies in older adults with

diabetes

The active management of both hypertension and dyslipidaemia in older adults with diabetes

is crucial to reduce cardiovascular risk.

People with diabetes have a high baseline cardiovascular risk and for every 1 mmHg fall in

blood pressure, additional benefit is seen compared with in those without diabetes, and may

be more beneficial overall than lowering of blood glucose [25–27]. Table S1 gives a detailed

summary of recent studies on the cardiovascular benefits of blood pressure control in people

with diabetes. In people aged ≥ 65 years (but < 85 years) with Type 2 diabetes, the evidence

supports the recommendation that the target blood pressure should be < 140/90 mmHg to

decrease cardiovascular disease outcomes, including stroke and progressive chronic kidney

disease. Lower blood pressure targets (e.g. < 130/80 mmHg may be warranted in higher risk

individuals; previous stroke or progressive chronic kidney disease with eGFR

< 60 ml/min/1.732) but this would require shared decision-making with the clinician and the

person with diabetes, with full discussion of the benefits and risks of each target [28]. If

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 lower blood pressure targets are selected, careful monitoring is needed to avoid orthostatic

hypotension.
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All the major anti-hypertensive drug classes can be used in older people with diabetes and a

recent meta-analysis has shown no difference in total or cardiovascular mortality between

single drug classes, but drug combinations were superior to monotherapy in reducing blood

pressure and achieving better outcomes [29]. The benefits of blood pressure control in older

people with diabetes are summarized in Box 2(a).

There are no large clinical trials of statin therapy specifically designed for older people with

diabetes and the evidence is based on data extrapolated from younger trial populations. In

Table S2, we give descriptions of the main studies on the cardiovascular benefits of lipid-

lowering in older people with diabetes. Evidence of benefit for statin therapy is generally

established for those adults up to age 80 years as evidenced by the PROSPER [30] and HPS

[31] with similar risk reductions (15–22%) in young and old. Further evidence of

cardiovascular benefit in older adults from statin therapy comes from the Cholesterol

Treatment Trialists Collaborators (CTTC) systematic prospective meta-analysis [32] and the

post hoc analysis of the Collaborative Atorvastatin Diabetes Study (CARDS) trial [33]. Two

large RCTs have failed to show any important cardiovascular benefits from adding

fenofibrates or niacin to statin therapy in young ‘elderly’ populations [34,35]. In Box 2(b),

we summarize the key messages for lipid lowering and cardiovascular benefit in older adults

with diabetes.

<H1>Cardiovascular benefits and the safety of older and newer glucose-lowering agents

The cardiovascular safety of glucose-lowering agents is essential in all people with diabetes,

particularly older groups who are already at high clinical risk (see Fig. 2). Up to the end of

2017, more than 190 000 people have been studied in nine longer-term cardiovascular

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 outcome trials, and appear to have yielded important information about the benefits and

associated risks of the therapies studied. These outcome trials have involved three dipeptidyl
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peptidase-4 (DPP-4) inhibitor trials, four glucagon-like peptide 1 (GLP-1) receptor agonist

trials and two sodium–glucose cotransporter 2 (SGLT2) inhibitor trials [36].

A comprehensive discussion of this area has been published by an expert review group [36]

and the results of subgroup analyses relating to event rate by age of various cardiovascular

outcome trials has also been recently examined [37]. We summarize the results of the

outcome studies for both older and newer blood glucose-lowering agents in Tables S3and S4

in which we also report recently released data from the CARMELINA trial. The data did not

identify any safety concerns with linagliptin of the DPP-4 inhibitor class, which provides

additional reassurance for clinicians (see Ref. 9 in Table S4).

These studies were undertaken in people with Type 2 diabetes, mainly with pre-existing

cardiovascular disease, with more than three-quarters on statins, a high proportion receiving

anti-hypertensive and anti-platelet medications, and a mean age of 60–65 years. Overall

cardiovascular safety was demonstrated across all classes mainly using the three-point

MACE (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) as the main

primary composite outcome.

In relation to prescribing glucose-lowering medication to older adults as part of an

individualized approach to enhance cardiovascular protection, DPP-4 inhibitors have not

shown cardiovascular benefits, whereas empagliflozin and canagliflozin (SGLT2 inhibitors)

demonstrated significant reductions in cardiovascular events and renal events, with

empagliflozin also reducing hospitalization for heart failure and worsening nephropathy.

Time to benefit was short (< 3 months) in the EMPA-REG outcome study [38]. In relation to

GLP-1 receptor agonist trials, exenatide (but not liraglutide or semaglutide) showed

cardiovascular benefit in older participants (≥ 65 years) but had a 43% discontinuation rate.

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 A summary of the cardiovascular safety of oral glucose-lowering agents in older people with

diabetes is given in Box 3.

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<H1>Insulin therapy in older adults

In general, several small studies have helped guide therapy recommendations in older adults

with diabetes [43]. Insulin therapy has a higher risk of hypoglycaemia in older adults

compared with most of the oral hypoglycaemic agents [44,45]. However, it is possible to

decrease the risk of hypoglycaemia and associated harm by carefully choosing the insulin

preparation to match the timing of hyperglycaemia and by matching the coping ability of the

person with diabetes to the complexity of the insulin [46]. The relative contribution of basal

hyperglycaemia is lower, and that of postprandial hyperglycaemia higher in older people with

diabetes compared with their younger counterparts [47], suggesting that different therapeutic

approaches may be required to treat hyperglycaemia effectively in these different age groups.

In a small randomized trial of older adults (≥ 65 years), addition of morning daily glargine

with oral agents was found to improve hyperglycaemia and decrease the risk of

hypoglycaemia compared with mixed insulin twice a day[48].

The availability of various basal insulin with a half-life of 24 h or longer, including insulin

glargine, degludec, glargine U300 and detemir, has provided much needed options to lower

baseline glucose levels with a once-a-day injection in addition to non-insulin agents.

Comparisons of different types of insulin preparations have shown mostly comparable

efficacy in older adults. Some insulins such as degludec and glargine U300 have shown a

better risk profile with lower risk of hypoglycaemia and less weight gain compared with

glargine [49,50].

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 Methods of insulin administration have also been a topic of research in older adults. There

appear to be no benefits of using a different modality such as an insulin pen, insulin pump or
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vial/syringe on glycaemic control in older populations. However, vision impairment and low

dexterity due to arthritis may impede use of a vial/syringe in frail older adults. It has been

long recognized that pre-filled insulin pens are safe and effective for older adults [51,52]. In

institution-based diabetes care, various factors related to the institution, staff, person with

diabetes and medication lead to the use of pen injectors as a preferred mode of insulin

delivery to improve care and cost [53].

<H1>The place of recent international clinical guidelines

There is a paucity of clinical intervention trials in older people with diabetes and optimal

metabolic targets in this age group are still not very clear. Initially, guidelines recommended

a target HbA1c of ≤ 53 mmol/mol (< 7.0%) for all people without consideration of age or

comorbidities [54]. This was based on results from the UKPDS study, which included

relatively younger people with fewer comorbidities and a new diagnosis of diabetes [55].

However, the more recent ACCORD, ADVANCE and VADT studies, which included a

cohort of older people with more comorbidities and longer duration of diabetes, failed to

demonstrate that tight glycaemic control will reduce cardiovascular mortality and in fact,

significantly increase the risk of hypoglycaemia [13,15,16].

In 2011, the European Diabetes Working Party for Older People (EDWPOP) published a

comprehensive set of guidelines that were evidence-based as far as possible, set glycaemic

targets that were later adopted by many later guidelines and gave the first algorithm for

glucose-lowering for frail people with Type 2 diabetes [7]. This was followed by the ADA

and the European Association for the Study of Diabetes proposing a person-centred approach

with individualization of targets based on the age of the person with diabetes and any

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 comorbidities [56]. Other international guidelines followed [6,8,57–60] (Table 2). The

International Diabetes Federation global guidance on managing older people with Type 2
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diabetes provided, for the first time, care recommendations for those with different categories

of functional status and dependency including frailty [6]. The recent publication of an

international Position Statement focusing on the management of frailty in diabetes provides

clinicians with recommendations that may assist in the clinical management of a wide range

of ill health-associated functional impairment characteristic of frailty [59]. Table S5 gives a

general descriptive account of the guidelines shown in Table 2.

<H1>Lifestyle interventions in older people with diabetes

Maintaining a healthy diet and activity level are important elements of diabetes care in older

age, as in earlier life phases. The limited number of studies that have been conducted on

dietary interventions targeting older people have shown that nutritional education

incorporating portion control, carbohydrate and lipid intake, meal spacing and nutritional

awareness can improve metabolic outcomes [61,62]. There is some limited evidence to show

that in fitter older people, weight-reducing interventions with calorific restriction may also

result in metabolic improvements [63,64], although compensatory exercise to ensure fat

rather than muscle deposition needs to be considered [65]. It has also been noted that in older

frailer people, intentional weight loss leads to bone and mineral depletion [66].

The nutritional needs of older people vary across groups and may be striking in those with

co-morbid frailty, those with loss of the ability to prepare a meal or loss of appetite, and those

with poor oral health [67]. These deficits may accelerate problems such as sarcopenia and

reduce metabolic well-being [68]. Hence, the diet in the older person should be nutritionally

dense, have an optimal protein intake, and be balanced in respect of micro- and

macronutrients, which helps to preserve lean body mass [69].

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 Body mass and physical stature may decline in older age making BMI a less reliable indicator

of weight-related hazard [70]. A decline in body weight should be considered a significant

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risk factor, as it is associated with elevated mortality in the general and diabetes older

populations [71,72]. The ADA guideline advocates the use of the Mini-Nutritional

Assessment scale which has been used to assess older people with diabetes [61]. Weight and

waist circumference has been suggested as a more useful indicator in older people in

assessing visceral fat and associated metabolic hazards [73].

Evidence from the large diabetes prevention studies such as the US Diabetes Prevention

Programme [74], emphasized how an integrated lifestyle programme can have an enduring

benefit. At 15 years post intervention, the lifestyle group had a 27% lower incidence of

diabetes compared with the control group. The lifestyle cohort from the US Diabetes

Prevention Programme have a mean age of 67 years, emphasizing the importance of exercise

and weight reduction in the middle years to realize benefits in older age.

In terms of exercise intervention in older people with diabetes, a systematic review of these

studies showed some benefits on skeletal muscle mass and diabetes outcomes [75]. Larger

studies in the wider older age population have shown that structured physical activity

intervention can significantly decrease age-related mental and physical disability [76]. In

2013, The Look AHEAD (Action for Health in Diabetes) trial [77] was the largest

randomized trial evaluating a lifestyle intervention in obese or overweight older adults (aged

45–76 years) with Type 2 diabetes compared with a diabetes support and education control

group. Unfortunately, no significant difference in cardiovascular events rates was observed.

In 2016, the ADA published a Position Statement on physical activity and exercise in

diabetes [78], which concluded that both resistance training and aerobic exercise are required

for optimizing glycaemic and other health outcomes.

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 Studies have also shown that inactivity in older age can contribute to metabolic dysfunction

and accelerate the ageing process [79,80]. Hence, continuing to provide older people with
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targeted lifestyle intervention is important to improve both their physical health and

functioning.

<H1>Interventions for frailty in diabetes

Frailty is a dynamic condition that can worsen or improve over time [81]. Preventing

sarcopenia may in turn prevent frailty [82], but once frailty is established, the treatment

requires regular functional assessments followed by timely multimodal interventions

including adequate nutrition, physical exercise, managing glycaemia and the use of

hypoglycaemic agents that have a high benefit to risk ratio. In the Women’s Health and

Aging Study II [83], a HbA1c ≥ 64 mmol/mol (≥ 8%) vs. < 37 mmol/mol (< 5.5%) was

associated with an approximately threefold increased risk of incident frailty and three- to

fivefold increased risk of lower extremity mobility limitations (all P < 0.05) measured at

baseline in participants aged 70–79 years.

In the NHANES study [84], up to 85% of the disability excess identified in those with

diabetes was explained by the presence of comorbidities (mainly cardiovascular disease and

obesity), and poor glucose regulation (HbA1c ≥ 8%). However, the aim in managing older

people with diabetes is to identify frailty early enough to stop disability developing in the

first place.

Exercise interventions have beneficial effects on glycaemic control, muscle insulin

sensitivity, intra-abdominal adipose tissue, muscle fat infiltration and on attenuating

cardiovascular risk factors associated with diabetes [85]. In relation to older adults with

diabetes, combined resistance and endurance training appears to serve as an effective exercise

intervention to promote overall physical fitness [75,86] and may even have a positive

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 influence in those with dementia [87]. It is suggested that the exercise prescription for

resistance training must be a frequency of one to six sessions per week, training volume of
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one to three sets of 6–15 repetitions, with an intensity of 30–70% one repetition maximum to

promote significant enhancements in muscle strength, muscle power and functional outcomes

[88].

Two studies reported in the Lancet [89,90] were important attempts to study the short-term

benefits of glucose-lowering using DPP-4 inhibitors in ‘frail’ populations of older people

with Type 2 diabetes. The first study was a randomized, double-blind, parallel-group phase 3

study [89] that examined the outcomes in terms of HbA1c using linagliptin 5 mg or matching

placebo in a group of highly comorbid older adults (n = 241; mean age 74.9 years).

Tolerability was good and safety was similar in both groups, but at week 24, compared with

placebo, the linagliptin group has a significant fall in HbA1c of 0.64% (95% confidence

interval: −0.81 to −0.48); unfortunately, despite this being a high-risk population, no

objective measures of frailty were undertaken. The second study [90] was a similar double-

blind, placebo-controlled, 24-week investigation of vildagliptin in adults aged ≥ 70 years

(n = 278; mean age 75 years) with Type 2 diabetes, who were drug naïve or inadequately

controlled (HbA1c 53–86 mmol/mol; 7–10%), and ~ 1 in 10 were described as frail using a

modified Fried’s criteria assessment tool [91]. Each had been set individualized targets based

on age, baseline HbA1c, comorbidities and frailty status. This study showed that, compared

with 27% in the placebo group, more than half (52.6%) of all those receiving vildagliptin met

their set individualized targets (P < 0.0001) and had a between-group difference in HbA1c fall

of 0.6% (P < 0.0001), with a similar tolerability and safety.

More recently, the EU-funded multinational MID-FRAIL Trial [92] has been completed.

Unpublished observations of this cluster randomized trial of resistance exercise and

nutritional education (vs. usual care) in pre-frail and frail older people (n = 964; > 70 years)

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 show a significant improvement in physical performance at 1 year (measured by changes in

Short Physical Performance Battery scores) associated with reduced healthcare costs [93].
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<H1>Management strategies

Although diabetes management strategies for robust and high-functioning older adults should

be similar to those for their younger counterparts [4,6], a safer, risk-stratification approach is

required for those who are highly comorbid and/or frail. The focus and main goals are

described above (Box 1) but also require a quality use of medicines approach to be achieved

[4,6]. All treatment strategies require a risk–benefit analysis and the use of glucose-dependent

strategies is preferred because they are less likely to cause unwanted hypoglycaemia,

particularly in those with renal impairment [37]. A UK national stakeholder group has

recently released a statement of the key principles of modern-day management of frail older

adults with diabetes which focuses on the identification of frailty, reducing the vascular

complications of diabetes and improving quality of life [94].

Once functional, cardiovascular and diabetes-related complications assessments have been

completed (post-assessment stage), and the treatment phase modulators have been applied,

the individualized care approach can be realized, including setting glycaemic goals and blood

pressure targets according to a multifactorial strategy (see Fig. 2). Although we indicate that

life expectancy is an important influence in modulating goals, we accept that we have not

discussed end of life as a specific management approach and how decisional capacity can

affect planning care. Management of people with diabetes at end of life has been reviewed

previously in detail by the lead author and others [6].

For example, the clinician will balance the potential side-effects of SGLT2 inhibitors or GLP-

1 receptor agonists in older people with evidence relating to their proven cardiovascular

benefits. The choice of using DPP-4 inhibitors will be a balance between minimal

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 hypoglycaemia, lack of weight gain and broad use in renal impairment against neutral

cardiovascular benefits. Insulin treatment can also be based on the use of NPH (wide
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experience, low cost, but higher hypoglycaemia risk) or the newer insulins such as glargine

(U100/U300) or deglutec (U100/U200) – less glycaemic variability, lower hypoglycaemia

risk, flexible timing but more expensive.

Preventing severe cardiovascular or renal disease and delaying the onset of frailty and

disability require frequent review of nutritional status, exercise involvement,

pharmacovigilance and the application of a deintensification programme where appropriate

(Fig. 2) [95]. A recent Veteran Affairs Health System study of people with diabetes aged

≥ 70 years found that as many as one in five older people may be overtreated as evidenced by

low HbA1c levels (< 48 mmol/mol; < 6.5%) [96]. Deintensification (de-prescribing) has thus

become an important strategy for reducing the risks of overtreatment and hypoglycaemia,

particularly in frail older people with Type 2 diabetes and multiple comorbidities, and may be

achieved without undue harm and no loss of glycaemic control [95,97–99].

<H1>Future research: a call for action

In Box 4, we indicate key areas for future research that will address current shortfalls and

gaps in evidence, and provide a framework for investment by pharmaceutical companies,

medical research organizations, and diabetes and geriatric societies nationally and worldwide.

New research directions must take into account the characteristics of older people with

diabetes (increased risk of cardiovascular disease, renal impairment, polypharmacy and

frailty), the likely complexity of illness management (see Fig. 1) and the inherent

vulnerability to strict glucose lowering in terms of hypoglycaemia and premature mortality.

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 Research into the associations between functional class/category of individuals (e.g. moderate

or severe frailty) and HbA1c and blood pressure targets, and their influence on clinical
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outcome are encouraged. We also recognize the need to study the effects of treatments on

both traditional cardiovascular and functional outcomes, as shown in Box 4. What is

becoming evident is that RCTs are becoming inefficient, complex, time-consuming and

expensive, and the exclusion of various subgroups such as the ‘elderly’ imposes many

restrictions on how healthcare policies can be reliably applied. Hence, a move to

observational studies and more innovative clinical designs is encouraged.

Future research may need to focus on comparisons of effective interventions among people in

typical care settings, with decisions tailored to individual needs, sometimes referred to

comparative effectiveness research [100], an initiative that requires new partnerships with

industry, major pharma, private institutions and the public.

<H1>Summary of key conclusions

Compilation of this review has been challenging but immensely rewarding. It is obvious that

there is increasing interest among clinical researchers, the pharmaceutical industry and

government in how older people with Type 2 diabetes should be effectively managed to

reduce excessive healthcare costs, and the impact on the individual with diabetes and their

family and carers. There is now sufficient evidence and guidance available to present a

framework of diabetes care that places an important emphasis on individualized care and how

targets of care should be influenced by other factors such as functional status, the presence of

frailty or cognitive impairment, and life expectancy. Further research into more innovative

trail designs and the benefits of multicomponent interventions should also be encouraged.

This article is protected by copyright. All rights reserved.

 Funding sources

None.
Accepted Article
Competing interests

None declared.

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FIGURE 1. Diabetes in older adults – illness complexity leading to modulation of goals. *Provides an

opportunity for screening for diabetes in high-risk groups and at opportunistic healthcare encounters.

**Chronological age is only one of several factors modulating goals, but this framework represents a guide to

decision-making and focusing care

FIGURE 2. A comprehensive management scheme leading to individualized care for diabetes in older adults.

CVOT, cardiovascular outcome trial; RCT, randomized controlled trial

BOX 1. Modern goals of diabetes care for older adults – generic to the person with diabetes, carers and health

professionals [6–9]

BOX 2. Summary of (a) benefits of blood pressure control and (b) cardiovascular benefits of lipid lowering in

older people with diabetes

BOX 3. Summary of cardiovascular safety of hypoglycaemic medications

BOX 4. Future research

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 <H1>Supporting Information

Additional Supporting Information may be found in the online version of this article:
Accepted Article
Table S1. Recent studies on cardiovascular benefits of blood pressure control in people with

diabetes and implications for older people.

Table S2. Main studies on cardiovascular benefits of lipid lowering treatment in older people

with diabetes.

Table S3. Main studies on cardiovascular safety of hypoglycaemic medications – older

agents.

Table S4. Main studies on cardiovascular safety of hypoglycaemic medications – newer

agents.

Table S5. Summary of main clinical guidelines in older people with diabetes – general

recommendations.

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 Table 1 Key intensive glucose control and other studies – with relevance to older people
Accepted Article
Study/review; year Design and methods Principal conclusions Implications

UKPDS [11,12] Participants: middle aged, newly Median HbA1c in Participants were newly
diagnosed Type 2 diabetes intensive vs. standard diagnosed without many
Multicentre (n = 3867). arm 53 mmol/mol (7%) diabetic complications at
randomized vs. 63 mmol/mol (7.9%). the start of the study.
controlled clinical Median age: 54 years ( ≥ 65
trial years excluded). Showed benefits of Tighter control of
tighter glycaemic control diabetes during middle
Intervention: intensive control in prevention of age improves
(FPG < 6 mmol/l) vs. standard microvascular microvascular end points.
care (best achieved FPG with complications (25% risk
diet). reduction). Tighter control of
diabetes during middle
Median follow-up: 10 years. Showed persistence in age has ‘legacy effect’
Primary outcomes: sudden benefits to prevent micro- observed at 10 years in
death, death from and macrovascular older age and improves
hyperglycaemia or complications during micro- and macrovascular
hypoglycaemia, fatal or non- post-trial follow-up endpoints even when
fatal MI, angina, heart failure, period. glycaemic control is not
stroke, renal failure, amputation, maintained in a tight
vitreous haemorrhage, range in later years.
retinopathy needing
photocoagulation, blindness in
any eye, or cataract extraction,
diabetes-related death, all-cause
mortality.

ACCORD [13,14] Participants: middle to older age Mean HbA1c in intensive Tighter glycaemic control
(mean age 62 years) with high vs. standard arm to near normal levels in
Multicentre risk of CVD or pre-existing 46 mmol/mol (6.4%) vs. middle/old age persons
randomized CVD (n = 10 250). 59 mmol/mol (7.5%). with existing
controlled clinical cardiovascular disease or
trial Participant age: 40–79 years. Excessive deaths in high risk of CVD did not
intensive control arm. show benefits and may
Intervention: intensive control
[HbA1c goal < 42 mmol/mol Trial terminated early have shown harm.
(<6%)] vs. standard care [HbA1c after 3 years. Subgroup analysis show
goal 53–63 mmol/mol (7– higher mortality in
7.9%)]. No benefits of intensive
control on cardiovascular younger age group
Median follow-up: 3.5 years outcomes. (< 65 years) but more
(early termination). hypoglycaemia in older
age group (> 65 years).
Primary outcome: non-fatal MI,
non-fatal stroke, CVD death

ADVANCE [15] Participants: middle to older age Mean HbA1c in intensive Subgroup analysis found
(mean 66 years) with pre- vs. standard arm no difference in benefits
Multicentre existing CVD (n = 11 140). 45 mmol/mol (6.3%) vs. of intensive control by
randomized 53 mmol/mol (7%). age group (< 65 or > 65
controlled clinical Participant age: ≥ 55 years. years).
trial No benefits of intensive
Intervention: intensive control control on primary

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 [HbA1c goal < 48 mmol/mol outcomes.
(< 6.5%)] vs. standard care
(HbA1c goal based on local Significant reduction in
guidelines). incidence of nephropathy.
Accepted Article
Median follow-up: 5 years.

Primary outcomes: non-fatal

MI, non-fatal stroke, CVD
death.

VADT [16–18] Participants: middle to older age Mean HbA1c in intensive Post hoc analysis found
military veterans in USA (mean vs. standard arm 52 mortality benefits in
Multicentre 60 years) with suboptimal mmol/mol (6.9%) vs. 69 participants with diabetes
randomized glycaemic control (n = 1791). mmol/mol (8.5%). duration < 15 years.
controlled clinical
trial Participant age: all adults. No benefits of intensive No benefits of intensive
control on primary control in older age
Intervention: intensive control outcomes. group.
vs. standard care (goal for
absolute reduction of HbA1c of Significant reduction in More recent 15-year
1.5%). onset and progression of review of 1655
albuminuria. participants showed no
Median follow-up: 5.6 years. cardioprotective ‘legacy’
Primary outcomes: non-fatal effect.
MI, non-fatal stroke, CVD
death, hospitalization for heart
failure, revascularization.

Japanese Elderly Participants: Japanese older Mean HbA1c in Lowering of HbA1c in

Diabetes adults (n = 1173) with Type 2 intervention vs. standard addition to geriatric-
Intervention Trial diabetes. care 63 mmol/mol (7.9%) specific interventions was
[19] vs. 65 mmol/mol (8.1%). not beneficial in this
Participant age: all participants study of Japanese older
Randomized were > 65 years (mean No difference in primary adults.
controlled, 72 years). outcomes between the
multicentre, groups.
prospective Intervention: multifactorial
intervention trial intervention vs. standard care.

Median follow-up: 6 years.

Primary outcomes: fatal or non-

fatal events, composite events.

UK General Participants: two cohorts of U-shaped relationship Too high as well as too
Practice Research people with Type 2 diabetes seen between HbA1c and low values of HbA1c have
Database (n = 27 965 using oral therapy mortality risk with lowest higher risk of adverse
and 20 005 using insulin). hazard ratio at an HbA1c outcomes.
Observational of 59 mmol/mol (7.5%).
study [20] Participant age: ≥ 50 years Higher mortality was
(mean 64 years). seen with higher or lower
Intervention: intensification of HbA1c.
glycaemic regimen. Hazard ratio (HR) for
Period: November 1986 to primary outcome in
November 2008. insulin-treated vs. oral
medication-treated people
Objective: evaluate relationship was 1.49.

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 between HbA1c and outcomes.

Primary outcome: all-cause

mortality.
Accepted Article
Diabetes and aging Participants: Type 2 diabetes U-shaped relationship Authors recommend
study [21] enrolled in Kaiser Permanente between HbA1c and target HbA1c < 64
Northern California mortality with lowest risk mmol/mol (< 8%) in
Retrospective (n = 71 092). of mortality between older people.
cohort study HbA1c 42 and 75
Participant age: ≥ 60 years mmol/mol (6–9%).
(mean 71 years).
Higher risk of any
Period: 2004–2008. outcome at HbA1c ≥ 64
Objective: evaluate relationship mmol/mol (≥ 8%) and
between baseline HbA1c and increased risk of
outcomes. mortality when HbA1c
< 42 mmol/mol (< 6%).
Primary outcomes: acute, non-
fatal metabolic , microvascular Outcomes were not
and cardiovascular events and different between age
mortality. groups of 60–69, 70–79
and ≥ 80 years.

Italian study [22] Participants: people with Type 2 Tighter glycaemic control Benefits of tighter
diabetes from diabetes [HbA1c < 48 mmol/mol glycaemic control might
Longitudinal outpatient and general (≤ 6.5%) or < 53 be diminished in
observational practitioner clinics in Italy mmol/mol (< 7%)] at participants with a high
study (n = 3074). baseline was associated burden of comorbidities.
with lower 5-year
Participant age: mean 63 years. incidence of
Period: November 1986 to cardiovascular events in
November 2008. those with fewer
comorbidities.
Median follow up: 5 years.
No benefits seen in group
Objective: evaluate benefits of with high number of
level of glycaemic control < 48 comorbidities.
mmol/mol (< 6.5%) or < 53
mmol/mol (<7%) in individuals
with high vs. low levels of
comorbidities.

Primary outcome: total

mortality, incident
cardiovascular events.

Retrospective Participants: older cohort with J-shaped relationship Not just the HbA1c value,
cohort study [23] Type 1 or Type 2 diabetes, from with most benefits at but variability of HbA1c
The Health Improvement HbA1c values between 42 value over time, are
Network Database. Data from and 64 mmol/mol (6– important considerations
primary care practices in the UK 8%). for older adults.
(n = 54 803)
Higher mortality was Stable glycaemic control
Participant age: ≥ 70 years. associated with higher in middle range over time
variability in HbA1c. might be more beneficial
Median follow-up: 5 years. than tighter control in
Objective: association between older adults.
mean HbA1c and variability of

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 HbA1c and mortality.

Primary outcome: time to all-

cause mortality.
Accepted Article
The Fremantle Participants: adults with Type 2 Metformin group had Tight glycaemic control,
Diabetes Study diabetes recruited between 2008 higher mortality when < 48–53 mmol/mol,
Phase II [24] and 2011 (n = 367). HbA1c < 48 mmol/mol (< 6.5–7%) is harmful in
(<6.5%). older adults irrespective
Prospective cohort Participant age: ≥ 75 years of pharmacotherapy but
study Sulfonylurea and insulin more so when they are
Study duration: median follow- group had higher
up 6.7 years. treated with sulfonylureas
mortality when HbA1c and insulin.
Objective: relationship between <53 mmol/mol (< 7%).
tight glycaemic control with
different pharmacological
agents and outcomes.

Primary outcome: all-cause

mortality.

FPG, fasting plasma glucose; CVD, cardiovascular disease.

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 Table 2 Summary of main guidelines in older people with diabetes – metabolic targets

Organization HbA1c Blood pressure Lipids

EDWPOP, 2011 [7] A. Independent: 53–59 A. Independent: A. Statins generally

Accepted Article
mmol/mol (7–7.5%). < 140/80 mmHg. recommended.

B. Dependent: 60–69 B. Non-frail > 80 years B. Fibrates can be

mmol/mol (7.6–8.5%). old: < 140– considered for high
145/90 mmHg. triglyceride in spite of
statin therapy.
C. Dependent:
< 150/90 mmHg.

AGS, 2012 [7] A. Healthy: < 59 A. Healthy: < 140/80 A. Healthy: statins
mmol/mol (< 7.5%). mmHg. recommended.

B. Moderate morbidity: B. Moderate morbidity: B. Moderate morbidity:

< 64 mmol/mol < 140/80 mmHg. statins recommended.
(< 8.0%).
C. Severe morbidity: C. Severe morbidity:
C. Severe morbidity: < 150/90 mmHg. statins considered.
< 69 mmol/mol
(< 8.5%).

IAGG-EDWPOP- A general target of 53 59 A. Independent: No recommendations.

ITFED, 2012 [57] mmol/mol (7–7.5%) is < 140/80 mmHg.
recommended.
B. Dependent or ≥ 75
years old: < 150/90
mmHg.

IDF 2013 [6] A. Independent: 53–59 A. Independent: A. Statins recommended

mmol/mol (7–7.5%). < 140/90 mmHg. for most.

B. Dependent: 53–64 B. Dependent: < 140/90 B. Not recommended for

mmol/mol (7–8%). mmHg. those with limited life
expectancy.
C. Frail/dementia: < 69 C. Frail: < 150/90
mmol/mol (< 8.5%). mmHg.

D. End of life: D. Dementia: < 140/90

symptomatic, HbA1c not mmHg.
recommended.
E. End of life: blood
pressure control is not
recommended.

Diabetes Canada, 2018 A. Independent: ≤ 53 A. Independent: A. Statins recommended

[58] mmol/mol (≤ 7.0%). < 130/80 mmHg. for most.

B. Dependent: < 64 B. Dependent: B. Not recommended for

mmol/mol (< 8.0%). individualized targets. those with limited life
expectancy.
C. Frail/dementia: < 69
mmol/mol (< 8.5%).

D. End of life:
symptomatic, HbA1c not
recommended.

IPS, 2018 [59] A. Mild–moderate A. < 140/90 mmHg for A. Statins recommended

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 frailty: 53–64 mmol/mol all. for all unless
(7–8.0%). contraindicated.
B. All anti-hypertensive
B. Severe frailty: 59–69 drug classes can be used. B. Addition of fibrates or
Accepted Article
mmol/mol (7.5–8.5%). niacin to statins is not
recommended.

ADA, 2018 [60] A. Healthy: < 58 A. Healthy: < 140/90 A. Healthy: statins
mmol/mol. mmHg. recommended.

B. Morbidity: < 64 B. Morbidity: < 140/90 B. Morbidity: statins

mmol/mol. mmHg. recommended.

C. Limited life C. Limited life C. Limited life

expectancy: < 69 expectancy: < 150/90 expectancy: statins
mmol/mol. mmHg. considered.

EDWPOP, European Diabetes Working Party for Older People; AGS, American Geriatrics Society; IAGG,
International Association of Geriatrics and Gerontology; ITFED, International Task Force of Experts in
Diabetes; IDF, International Diabetes Federation; IPS, International Position Statement; ADA, American
Diabetes Association.

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Accepted Article

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Accepted Article

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  Mandatory individualized management plan that takes into consideration different functional and
comorbid categories, and duration of diabetes.
Accepted Article
 Evidence-based prescribing for glucose-lowering agents and setting appropriate targets adjusted for
patient category and patient wish.
 Proactive shared commitment to reduce the risk of cardiovascular disease and other non-cardiac
vascular disorders, renal failure, visual loss, cognitive dysfunction, mobility disorder, functional decline and
the development of frailty or disability.
 Minimize the risk of hypoglycaemia and prevent unnecessary hospitalization.
 Proactive monitoring to minimize the threat to independence, self-care capacity and quality of life

Box 1

(a)

 A target systolic blood pressure around 140 mmHg is reasonable.

 Lower target < 130 mmHg may have benefit of reducing stroke risk but is associated with increased
adverse events – requires a shared decision approach.
 High risk of adverse events exists in older people with recurrent falls, cognitive dysfunction or
frailty.
 Targets are best based on level of function with tight control in the fit but relaxed in frail individuals
(145–160/90 mmHg).
 All major anti-hypertensive classes have similar efficacy and achieving target blood pressure is
more beneficial than a single class effect.
(b)

 Older people with diabetes up to the age of 80 years will benefit from cholesterol-lowering
treatment.
 Older people with diabetes are likely to benefit more than younger people due to their higher
baseline risk.
 There is some evidence from observational trials that cholesterol lowering may be beneficial in
people aged 80–85 years.
 There is no extra benefit of additional fenofibrate or niacin to statin therapy.
See Tables S1 and S2.

Box 2

Older agents

 Metformin: collectively shows modest cardiovascular benefits and evidence of safe use in various
organ dysfunctions.

 Sulfonylureas: controversial cardiovascular benefits/risks but likely neutral.

 Glinides and α-glucosidase inhibitors: cardiovascular benefits when added to metformin.

 Thiazolidinediones (TZDs): rosiglitazone has had mixed concerns in terms of cardiovascular risk
and remains suspended in Europe; pioglitazone use associated with a reduction in major adverse
cardiovascular events and in all-cause mortality, and a lowered risk in recurrent stroke. The increased risk of
heart failure remains an important concern.

Newer agents

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  Dipeptidyl peptidase-4 (DPP-4) inhibitors: neutral cardiovascular effects. Saxagliptin associated
with a significant increase in heart failure hospitalization in the SAVOR-TIMI trial [1.27 (1.07–1.51)] with a
trend to an increased risk of heart failure in the alogliptin EXAMINE trial.
Accepted Article
 Glucagon-like peptide-1 (GLP-1) receptor agonists: liraglutide demonstrates a significant reduction
in three-point MACE in the LEADER Trial but subgroup analysis of people aged 60 years and above showed
no benefit; exenatide showed cardiovascular benefits in older participants on subgroup analysis of the
EXSCEL trial. Some recent concerns noted about liraglutide in people with chronic heart failure and reduced
left ventricular function [39].

 Sodium–glucose cotransporter-2 (SGLT2) inhibitors: empagliflozin (EMPA-REG) and canagliflozin

(CANVAS) show significant reductions in the three-point MACE in older participants, and a reduction in
hospitalization for heart failure shown in the overall analysis of the studies.

Note: previous studies in Type 2 diabetes have shown that both insulin glargine [ORIGIN Study [40,41];
people with dysglycaemia, mean age 63.5 years] and insulin degludec [DEVOTE trial [42]; people with a
high cardiovascular risk, mean age 65 years] have no effects on MACE outcomes.

Also see Cefalu et al. [36] and Tables S3 and S4.

Box 3

Longer term observational studies

 To assess cardiovascular risk with modern-day glucose-lowering treatment classes, particularly dipeptidyl
peptidase-4 (DPP4) inhibitors, sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like
peptide-1 (GLP-1) receptor agonists in different participant functional categories or complexities of illness
as part of large prospective cohort studies.
 To assess: the impact of HbA1c variability in the development of microvascular disease and frailty.
 Determine which HbA1c and blood pressure targets provide the greatest benefit in different functional
categories.

Development of clinical trial methodology

 Instigate randomized clinical trials in primary care to examine the benefits of structured assessment and
management pathways using appropriate primary and secondary outcome measures such as disability,
cognitive dysfunction, frailty and quality of life.
 Apply comparative effectiveness research techniques to create new innovative clinical trial designs.

Randomized clinical trials of glucose lowering to a specific HbA1c range

 In high cardiovascular risk older people with Type 2 diabetes.

 In older people with Type 2 diabetes and stage 3 renal disease.

Randomized trials of multicomponent interventions

 In people with sarcopenia to prevent frailty and disability.

 In people with functional loss, frailty and lower limb physical restrictions to improve physical performance
and prevent immobility and loss of independence.

Influencing commissioners of clinical diabetes and geriatric services

 Health economic analyses of interventions.

 Study designs that allow relevant and appropriate cost comparisons.
Box 4

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