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1.  Efficacy and Safety of Canagliflozin in Individuals Aged 75 and Older with Type 2 Diabetes Mellitus: A Pooled Analysis 
To compare the efficacy and safety of canagliflozin, a sodium glucose co‐transporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM), in individuals younger than 75 and those aged 75 and older.
Randomized Phase 3 studies.
International study centers.
Adults with T2DM.
Changes from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), blood pressure (BP), and body weight were measured. Efficacy was evaluated using pooled data from six randomized, double‐blind, placebo‐controlled studies (N = 4,158; n = 3,975 aged <75, n = 183 aged ≥75). Safety was assessed based on adverse event (AE) reports from eight randomized, double‐blind, placebo‐ and active‐controlled studies (N = 9,439; n = 8,949 aged <75, n = 490 aged ≥75).
Canagliflozin 100 and 300 mg were associated with placebo‐subtracted mean reductions in HbA1c in participants younger than 75 (−0.69% and −0.85%, respectively) and aged 75 and older (−0.65% and −0.55%, respectively). Dose‐related reductions in FPG, body weight, and BP were seen with canagliflozin 100 and 300 mg in participants in both age groups. Overall AE incidence was 67.1% with canagliflozin 100 mg, 68.6% with canagliflozin 300 mg, and 65.9% with non‐canagliflozin (pooled group of comparators in all studies) in participants younger than 75, and 72.4%, 79.1%, and 72.3%, respectively, in those aged 75 and older, with a similar safety profile in both groups. The incidence of volume depletion–related AEs was 2.2%, 3.1%, and 1.4% in participants younger than 75 with canagliflozin 100 and 300 mg and non‐canagliflozin, respectively, and 4.9%, 8.7%, and 2.6%, respectively, in those aged 75 and older.
Canagliflozin improved glycemic control, body weight, and BP in participants aged 75 and older. The overall incidence of AEs was high across treatment groups in participants aged 75 and older and higher than in those younger than 75. The safety profile of canagliflozin was generally similar in both age groups, with a higher incidence of AEs related to volume depletion observed with canagliflozin in participants aged 75 and older than in those younger than 75. These findings support canagliflozin, starting with the 100‐mg dose, as an effective therapeutic option for older adults with T2DM.
PMCID: PMC4819884  PMID: 27000327
Phase 3 study; SGLT2 inhibitor; canagliflozin; type 2 diabetes mellitus; older adults
2.  Hypoglycemia in Older People - A Less Well Recognized Risk Factor for Frailty 
Aging and Disease  2015;6(2):156-167.
Recurrent hypoglycemia is common in older people with diabetes and is likely to be less recognized and under reported by patients and health care professionals. Hypoglycemia in this age group is associated with significant morbidities leading to both physical and cognitive dysfunction. Repeated hospital admissions due to frequent hypoglycemia are also associated with further deterioration in patients’ general health. This negative impact of hypoglycemia is likely to eventually lead to frailty, disability and poor outcomes. It appears that the relationship between hypoglycemia and frailty is bidirectional and mediated through a series of influences including under nutrition. Therefore, attention should be paid to the management of under nutrition in the general elderly population by improving energy intake and maintaining muscle mass. Increasing physical activity and having a more conservative approach to glycemic targets in frail older people with diabetes may be worthwhile.
PMCID: PMC4365959  PMID: 25821643
hypoglycemia; frailty; old age
3.  The effect of frailty should be considered in the management plan of older people with Type 2 diabetes 
Future Science OA  2016;2(1):FSO102.
The prevalence of diabetes is increasing especially in older age due to increased life expectancy. In old age, diabetes is associated with high comorbidity burden and increased prevalence of geriatric syndromes including frailty in addition to micro- and macro-vascular complications. The emergence of frailty may change the natural history of Type 2 diabetes from a progressive to a regressive course with increased risk of hypoglycemia. This may result in normalization of blood glucose levels and lead to a state of burnt-out diabetes in frail older people with significant weight loss. Although guidelines suggest relaxed glycemic control in frail elderly with diabetes, complete withdrawal of hypoglycemic medications may be necessary in these frail populations to reduce the risk of hypoglycemia.
Lay abstract: Diabetes is a common disease especially in older people. Aging is associated with reduced appetite and reduced food intake due to lack of exercise and diminished energy consumption. In certain individuals this may be significant leading to weight loss, malnutrition and the development of frailty. As a result the doses of diabetes medications may be too strong for this frail population especially if they have organ dysfunction reducing medication clearance and increasing the risk of low blood glucose level events. Therefore, reduction or complete withdrawal of diabetes medications may be considered in this frail group.
PMCID: PMC5137864  PMID: 28031949
frailty; hypoglycemia; older people; Type 2 diabetes
4.  Associations of mutually exclusive categories of physical activity and sedentary time with markers of cardiometabolic health in English adults: a cross-sectional analysis of the Health Survey for England 
BMC Public Health  2016;16:25.
Both physical activity and sedentary behaviour have been individually associated with health, however, the extent to which the combination of these behaviours influence health is less well-known. The aim of this study was to examine the associations of four mutually exclusive categories of objectively measured physical activity and sedentary time on markers of cardiometabolic health in a nationally representative sample of English adults.
Using the 2008 Health Survey for England dataset, 2131 participants aged ≥18 years, who provided valid accelerometry data, were included for analysis and grouped into one of four behavioural categories: (1) ‘Busy Bees’: physically active & low sedentary, (2) ‘Sedentary Exercisers’: physically active & high sedentary, (3) ‘Light Movers’: physically inactive & low sedentary, and (4) ‘Couch Potatoes’: physically inactive & high sedentary. ‘Physically active’ was defined as accumulating at least 150 min of moderate-to-vigorous physical activity (MVPA) per week. ‘Low sedentary’ was defined as residing in the lowest quartile of the ratio between the average sedentary time and the average light-intensity physical activity time. Weighted multiple linear regression models, adjusting for measured confounders, investigated the differences in markers of health across the derived behavioural categories. The associations between continuous measures of physical activity and sedentary levels with markers of health were also explored, as well as a number of sensitivity analyses.
In comparison to ‘Couch Potatoes’, ‘Busy Bees’ [body mass index: −1.67 kg/m2 (p < 0.001); waist circumference: −1.17 cm (p = 0.007); glycated haemoglobin: −0.12 % (p = 0.003); HDL-cholesterol: 0.09 mmol/L (p = 0.001)], ‘Sedentary Exercisers’ [body mass index: −1.64 kg/m2 (p < 0.001); glycated haemoglobin: −0.11 % (p = 0.009); HDL-cholesterol: 0.07 mmol/L (p < 0.001)] and ‘Light Movers’ [HDL-cholesterol: 0.11 mmol/L (p = 0.004)] had more favourable health markers. The continuous analyses showed consistency with the categorical analyses and the sensitivity analyses indicated robustness and stability.
In this national sample of English adults, being physically active was associated with a better health profile, even in those with concomitant high sedentary time. Low sedentary time independent of physical activity had a positive association with HDL-cholesterol.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-016-2694-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4709945  PMID: 26753523
Accelerometry; Objective; Physical activity; Sedentary; Cardiometabolic health
5.  Low HbA1c and Increased Mortality Risk-is Frailty a Confounding Factor? 
Aging and Disease  2015;6(4):262-270.
Diabetes mellitus is increasingly becoming an older person disease due to the increased survival and aging of the population. Previous studies which showed benefits of tight glycemic control and a linear relationship between HbA1c and mortality have largely included younger patients newly diagnosed with diabetes and with less comorbidities. Recent studies, which included older population with diabetes, have shown a U-shaped relationship of increased mortality associated with low HbA1c. The mechanism of such relationship is unclear. There was no direct causal link between low HbA1c and mortality. It appears that malnutrition, inflammation and functional decline are characteristics shared by the populations that showed increased mortality and low HbA1c. In these studies functional status, disability or frailty was not routinely measured. Therefore, although adjustment for comorbidities was made there may be a residual confounding by unmeasured factors such as frailty. Thus, frailty or decline in functional reserve may be the main confounding factor explaining the relationship between increased mortality risk and low HbA1c.
PMCID: PMC4509475  PMID: 26236548
Frailty; Mortality; Diabetes; Low HbA1c
6.  Management of Type 2 Diabetes in Older People 
Diabetes Therapy  2013;4(1):13-26.
The prevalence of diabetes is increasing due to aging of the population and increasing obesity. In the developed world, there is an epidemiologic shift from diabetes being a disease of middle age to being a disease of older people due to increased life expectancy. In old age, diabetes is associated with high comorbidity burden and increased prevalence of geriatric syndromes in addition to the traditional vascular complications. Therefore, comprehensive geriatric assessment should be performed on initial diagnosis of diabetes. Due to the heterogeneous nature of older people with diabetes and variations in their functional status, comorbidities, and life expectancy, therapeutic interventions, and glycemic targets should be individualized taking into consideration patients’ preferences and putting quality of life at the heart of their care plans.
PMCID: PMC3687094  PMID: 23605454
Diabetes mellitus; Geriatric assessment; Glycemic targets; Older people; Management; Type 2 diabetes
7.  An evaluation of the effectiveness of a multi-modal intervention in frail and pre-frail older people with type 2 diabetes - the MID-Frail study: study protocol for a randomised controlled trial 
Trials  2014;15:34.
Diabetes, a highly prevalent, chronic disease, is associated with increasing frailty and functional decline in older people, with concomitant personal, social, and public health implications. We describe the rationale and methods of the multi-modal intervention in diabetes in frailty (MID-Frail) study.
The MID-Frail study is an open, randomised, multicentre study, with random allocation by clusters (each trial site) to a usual care group or an intervention group. A total of 1,718 subjects will be randomised with each site enrolling on average 14 or 15 subjects. The primary objective of the study is to evaluate, in comparison with usual clinical practice, the effectiveness of a multi-modal intervention (specific clinical targets, education, diet, and resistance training exercise) in frail and pre-frail subjects aged ≥70 years with type 2 diabetes in terms of the difference in function 2 years post-randomisation. Difference in function will be measured by changes in a summary ordinal score on the short physical performance battery (SPPB) of at least one point. Secondary outcomes include daily activities, economic evaluation, and quality of life.
The MID-Frail study will provide evidence on the clinical, functional, social, and economic impact of a multi-modal approach in frail and pre-frail older people with type 2 diabetes.
Trial registration NCT01654341.
PMCID: PMC3917538  PMID: 24456998
Multi-modal intervention; Frail; Pre-frail; Type 2 diabetes
9.  Factors associated with initiation of antihyperglycaemic medication in UK patients with newly diagnosed type 2 diabetes 
To assess the factors associated with antihyperglycaemic medication initiation in UK patients with newly diagnosed type 2 diabetes.
In a retrospective cohort study, patients with newly diagnosed type 2 diabetes were identified during the index period of 2003-2005. Eligible patients were ≥ 30 years old at the date of the first observed diabetes diagnosis (referred to as index date) and had at least 2 years of follow-up medical history (N = 9,158). Initiation of antihyperglycaemic medication (i.e., treatment) was assessed in the 2-year period following the index date. Adjusted Cox regression models were used to examine the association between time to medication initiation and patient age and other factors.
Mean (SD) HbA1c at diagnosis was 8.1% (2.3). Overall, 51% of patients initiated antihyperglycaemic medication within 2 years (65%, 55%, 46% and 40% for patients in the 30- < 45, 45- < 65, 65- < 75, 75+ age groups, respectively). Among the treated patients, median (25th, 75th percentile) time to treatment initiation was 63 (8, 257) days. Of the patients with HbA1c ≥ 7.5% at diagnosis, 87% initiated treatment within 2 years. These patients with a higher HbA1c also had shorter time to treatment initiation (adjusted hazard ratio (HR) = 2.44 [95% confidence interval (CI): 1.61, 3.70]; p < 0.0001). Increasing age (in years) was negatively associated with time to treatment initiation (HR = 0.98 [95% CI: 0.97, 0.99]; p < 0.001). Factors significantly associated with shorter time to treatment initiation included female gender and use of cardiovascular medications at baseline or initiated during follow up.
In this UK cohort of patients with newly diagnosed type 2 diabetes, only 51% had antihyperglycaemic medication initiated over a 2-year period following diagnosis. Older patients were significantly less likely to have been prescribed antihyperglycaemic medications. Elevated HbA1c was the strongest factor associated with initiating antihyperglycaemic medication in these patients.
PMCID: PMC3353844  PMID: 22397700
Clinical inertia; Age; Type 2 diabetes mellitus; Antihyperglycaemic medication
10.  Reasons given by general practitioners for non-treatment decisions in younger and older patients with newly diagnosed type 2 diabetes mellitus in the United Kingdom: a survey study 
Older patients with newly diagnosed type 2 diabetes mellitus are less likely to receive antihyperglycaemic therapy compared to their younger counterparts. The purpose of this study was to assess the reasons of general practitioners (GPs) for not treating younger and older patients with newly diagnosed type 2 diabetes mellitus with antihyperglycaemic agents.
In a survey conducted between November 2009 and January 2010, 358 GPs from the United Kingdom selected reasons for not initiating antihyperglycaemic therapy in younger (< 65 years) and older (≥65 years) patients with newly diagnosed type 2 diabetes mellitus and untreated with any antihyperglycaemic agent for at least six months following diagnosis. Thirty-six potential reasons were classified into four major categories: Mild hyperglycaemia, Factors related to antihyperglycaemic agents, Comorbidities and polypharmacy, and Patient-related reasons. Reasons for non-treatment were compared between younger (n = 1, 023) and older (n = 1, 005) patients.
Non-treatment reasons related to Mild hyperglycaemia were selected more often by GPs for both younger (88%) and older (86%) patients than those in other categories. For older patients, Factors related to antihyperglycaemic agents (46% vs. 38%) and Comorbidities and polypharmacy (33% vs. 19%), both including safety-related issues, were selected significantly (p < 0.001) more often by GPs. No between-group difference was observed for the Patient-related reasons category. The GP-reported HbA1c threshold for initiating antihyperglycaemic therapy was significantly (p < 0.001) lower for younger patients (mean ± standard deviation: 7.3% ± 0.7) compared to older patients (7.5% ± 0.9).
GPs selected reasons related to Mild hyperglycaemia for non-treatment of their untreated patients with newly diagnosed type 2 diabetes mellitus, despite nearly one-third of these patients having their most recent HbA1c value ≥7%. The findings further suggest that safety-related issues may influence the non-treatment of older patients with type 2 diabetes mellitus.
PMCID: PMC3219572  PMID: 22035104
11.  Hypoglycaemia in residential care homes 
Hypoglycaemia is the most common metabolic complication occurring in older people with type 2 diabetes. Limited data are available about prevalence of diabetes or its complications in care homes. However, the prevalence of residents with diabetes in care homes seems to be significant. There is high level of disability, dependency, and polypharmacy among residents in these settings. Hypoglycaemia is both an important adverse reaction of treatment and an outcome measure. This study reviews the relevant literature and reports a case of hypoglycaemia to demonstrate the causes of hypoglycaemia, characteristics of these patients, and the complexity of their problems.
PMCID: PMC2605531  PMID: 19105916
elderly; homes for the aged; hypoglycemia
12.  Use of short-acting insulin aspart in managing older people with diabetes 
Type 2 diabetes mellitus affects 5.9% of the world adult population, with older people and some ethnic groups disproportionately affected. Treatment of older people with diabetes differs in many ways from that in younger adults since the majority have type 2 disease and are at particular risk of macrovascular rather than disabling microvascular disease. Insulin therapy, the most effective of diabetes medications, can reduce any level of elevated HBA1c if used in adequate doses. However, some clinicians are often reluctant to initiate insulin therapy in older people with diabetes mainly out of their concerns about adverse reactions to insulin, particularly hypoglycemia. There is evidence suggesting that insulin aspart appears to act similarly to regular human insulin in older people with type 2 diabetes mellitus. Insulin aspart can be used in the treatment of older people with diabetes, but this should be individualized. There is evidence that it improves postprandial glucose control, improves long-term metabolic control, reduces risk of major nocturnal hypoglycemia and increases patient satisfaction compared with soluble insulin.
PMCID: PMC2685239  PMID: 19503780
older people; diabetes; insulin aspart; hypoglycemia

Results 1-12 (12)