External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants?

Saunders, Christopher; Byrne, Christopher D.; Guthrie, Bruce; Lindsay, Robert; McKnight, John; Philip, Sam; Sattar, Naveed; Walker, Jeremy; Wild, Sarah H.

doi:10.1111/dme.12047

Cited by 109 publications

(94 citation statements)

References 28 publications

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“…Conclusions Our findings from this inclusive populationlevel investigation confirm and expand on trial evidence from more selected populations [34,35], concerning the management of HbA 1c and BP but not total cholesterol. Further corroboration is necessary, particularly in prospective longitudinal trials but, if validated, the findings have several implications for type 2 diabetes management.…”

Section: Discussionsupporting

confidence: 81%

Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

et al. 2014

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Aims/hypothesis We aimed to describe the shape of observed relationships between risk factor levels and clinically important outcomes in type 2 diabetes after adjusting for multiple confounders.Methods We used retrospective longitudinal data on 246,544 adults with type 2 diabetes from 600 practices in the Clinical Practice Research Datalink, 2006Datalink, -2012 Proportional hazards regression models quantified the risks of mortality and microvascular or macrovascular events associated with four modifiable biological variables (HbA 1c , systolic BP, diastolic BP and total cholesterol), while controlling for important patient and practice covariates. Results U-shaped relationships were observed between allcause mortality and levels of the four biometric risk factors. Lowest risks were associated with HbA 1c 7.25-7.75% (56-61 mmol/mol), total cholesterol 3.5-4.5 mmol/l, systolic BP 135-145 mmHg and diastolic BP 82.5-87.5 mmHg. Coronary and stroke mortality related to the four risk factors in a positive, curvilinear way, with the exception of systolic BP, which related to deaths in a U-shape. Macrovascular events showed a positive and curvilinear relationship with HbA 1c but a U-shaped relationship with total cholesterol and systolic BP. Microvascular events related to the four risk factors in a curvilinear way: positive for HbA 1c and systolic BP but negative for cholesterol and diastolic BP. Conclusions/interpretation We identified several relationships that support a call for major changes to clinical practice. Most importantly, our results support trial data indicating that normalisation of glucose and BP can lead to poorer outcomes. This makes a strong case for target ranges for these risk factors rather than target levels.Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 81%

Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

et al. 2014

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“…That is, they would have to modify the relative or absolute treatment effects of statins on CVD as they are translated to real-world settings from the trials 15. The proportions of patients deemed eligible in our study were similar to those recently reported in the UK for RCTs on novel oral anticoagulants (48–64%)34 and for the UK Prospective Diabetes Study (32–51%)35 but clearly higher than those for various other RCTs on intensive glucose lowering (4–36%) 35. The background risk, reflected in the cumulative risk for CVD events after statin initiation among patients deemed ineligible, was either similar or remarkably higher as compared with those eligible.…”

Section: Discussionsupporting

confidence: 75%

Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland

et al. 2014

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ObjectiveTo assess the representativeness of the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) for incident statin users.DesignA population-based analysis with linked register data.SettingFinland.Population56 963 patients with diabetes initiating statin use from 2005 to 2008.Main outcome measuresWe determined the proportions of real-world patients who fulfilled the eligibility criteria for HPS and CARDS trials and assessed the cardiovascular disease (CVD) event rates, assumed to reflect the background CVD risk, for those eligible and ineligible. We used descriptive statistics to identify the patient characteristics, lipid-lowering interventions and adherence to statin therapy.ResultsOf the real-world patients, 57% (N=32 582) fulfilled the eligibility criteria for HPS (DM) and 49% (N=20 499) of those without CVD for CARDS. The patients ineligible for HPS (DM) had a higher cumulative risk for CVD events than those eligible, whereas regarding CARDS the cumulative risks were of similar magnitude. The overall CVD event rates seemed to be comparable to those in the reviewed trials. Both trials were under-representative of women and users of antihypertensive agents and metformin. 27% and 29% of real-world patients had an initial statin dose corresponding to <20 mg of simvastatin. The proportions of patients who were deemed adherent were 57% in the real world and 85% in both trials.ConclusionsOnly half of the real-world patients would have qualified for the HPS (DM) and CARDS, limiting their representativeness for clinical practice. Women and users of antihypertensive agents and metformin were under-represented in both trials. These deviations reflect the changes in diabetes treatment over the years and are not expected to modify the average treatment effects of statins on CVD. Prescribing of lower statin doses in clinical practice than used in the trials and lower adherence may, however, attenuate the benefits in the real world.

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“…Unfortunately, older patients are often underrepresented in large clinical trials; therefore, data on antihyperglycemic medications are often extrapolated from younger populations (72).…”

Section: Medications In the Management Of Hyperglycemiamentioning

confidence: 99%

The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations

2017

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Nearly a quarter of older adults in the U.S. have type 2 diabetes, and this population is continuing to increase with the aging of the population. Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. The usual defects contributing to type 2 diabetes are further complicated by the natural physiological changes associated with aging as well as the comorbidities and functional impairments that are often present in older people. This paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population.Diabetes is one of the leading chronic medical conditions among older adults, with high risk for vascular comorbidities such as coronary artery disease, physical and cognitive function impairment, and mortality. Despite decades of effort to prevent diabetes, diabetes remains an epidemic condition with particularly high morbidity affecting older adults. In fact, nearly 11 million people in the U.S. aged 65 years or older (more than 26% of adults aged 65 years or older) meet current American Diabetes Association criteria for diabetes (diagnosed and undiagnosed), accounting for more than 37% of the adult population with diabetes (1). At the same time, adults 65 years or older are developing diabetes at a rate nearly three-times higher than younger adults: 11.5 per 1,000 people compared with 3.6 per 1,000 people among adults aged 20-44 years old (1). However, increasing research in diabetes and aging has improved our understanding of the pathophysiology of diabetes and its association with aging and led to the development of a number of antihyperglycemic medications. The mechanism of diabetes complications has been previously reviewed (2). The current paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population. PATHOPHYSIOLOGY OF TYPE 2 DIABETESType 2 diabetes is by far the most prevalent form of diabetes in older adults and is an age-related disorder. The criteria for diagnosing diabetes are the same for all age groups because the risks of diabetes-related complications are associated with hyperglycemia over time across all age groups (3). Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. These factors contribute to hyperglycemia through effects on both b-cell insulin secretory capacity and on tissue sensitivity to insulin. The occurrence of type 2 diabetes in an older person is complicated by the comorbidities and functional impairments associated with aging.Hyperglycemia develops in type 2 diabetes when there is an imbalance of glucose production (i.e., hepatic glucose production during fasting) and glucose intake (i.e.,

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External validity of randomized controlled trials of glycaemic control and vascular disease: how representative are participants?

Cited by 109 publications

References 28 publications

Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study

Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland

The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations

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