General Practice ACF Projects 2021

A list of ACF 2021 projects within the speciality of General Practice.

Project lead: Prof Kamlesh Khunti kk22@leicester.ac.uk

Project 1- Incidence and prevalence of cardiometabolic-renal multimorbidities using the Clinical Practice Research Datalink

In the last decades, research into diabetes has been conducted in the attempt to improve medication, blood glucose monitoring and identification of risk factors. To assess the impact of these and other changes in diabetes treatment, it is important to examine trends in mortality rates over time. This research aims to use the Clinical Practice Research Datalink (CPRD) data to provide a real-world view of the change in mortality rates over time in people with and without diabetes in the UK and other countries. Although previous observational cohort studies have shown declining mortality rates over time among in people with diabetes, mainly from the USA and Sweden, data from other countries are limited. The objective of this epidemiological project is to examine trends in the incidence and prevalence of cardio-renal-metabolic disease in the UK population with and without type 2 diabetes, with data extracted from the CPRD, and to compare them with those of other countries. The exposure measure is a diagnosis of type 2 diabetes and the outcome measures are: all-cause mortality and cardio-renal-metabolic disease incidence, prevalence and mortality. As in CPRD several baseline characteristics and lifestyle factors associated with the risk of death are available, adjusting for  these confounders will give an aetiological perspective to this research; likewise, the results of this project will provide a contemporary real-world assessment of overall and cardio-renal-metabolic disease burden, thus allowing comparisons with across countries (descriptive epidemiology/demography).

Project 2 - Use of Clinical Practice Research Datalink to assess the clinical effectiveness of SGLT-2 and GLP-1RAs in a real-world setting

Randomised controlled trials (RCTs) must be carried out to ensure high internal validity and reduce the risk bias when quantifying treatment effects. To be clinically useful, trial results must also be externally valid and reflect treatment effect in a definable group of patients and in a specific clinical setting. Lack of external validity is the most frequent criticism by clinicians of RCTs. Unfortunately, the results of RCTs might not be relevant to all patients and all settings and hence the effectiveness of drug treatments in real world settings is becoming increasingly important for informing clinical practice (pharmacoepidemiological comparative effectiveness study). To aim of this project is to compare the effectiveness of sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RAs), two new classes of glucose-lowering medications, in RCTs vs “real world evidence”. The project will consist in three complementary objectives. First, to use population matching techniques to extract patient data from the Clinical Practice Research datalink (CPRD) and assess whether the effects on metabolic outcomes from the main trials are replicable in a real-world UK setting. Second, to assess effectiveness of SGLT-2 inhibitors and GLP-1RA agonists in major cardiovascular outcome trials and compare them with the clinical population who receive the treatment in the UK and assess the impact of patient characteristics such as age, ethnicity, gender and co-morbidities on clinical effectiveness. Third, in all patients within CPRD who have been prescribed SGLT-2 inhibitors and GLP1RA agonists, clinical effectiveness will be assessed also in terms of absolute efficacy as this is more relevant given the dissimilar baseline risk of outcomes in RCTs vs “real-world” patients with diabetes.

Project 3- Association between drug adherence and outcomes in patients with multimorbidity: A Clinical Practice Research Datalink epidemiological study

Multiple lines of evidence have shown that adherence to prescribed therapies is suboptimal and can be considered one of the largest unmanaged issues in modern medicine, with a significant cost burden on healthcare systems. Poor adherence, moreover, is an independent risk factor for poor health outcomes, such as cardiovascular diseases and death. With the increase in life expectancy, a growing number of people suffer from more than one serious long-term medical condition such as diabetes, kidney disease or depression - a condition known as multimorbidity (MM). Patients having more than one medical condition are at greater risk of frailty and disability and have a lower quality of life and shorter life expectancy. Because the number of medications prescribed to patients with multimorbidity is, by definition, higher, individuals with multimorbidity may be at most risk of adherence. Therefore, nonadherence could be the potential link between the presence of multimorbidity and the risk of long-term outcomes and the shorter life expectancy in patients with multiple medical conditions. Using the Clinical Practice Research datalink, this project will help clarify: 1) the burden of MM; 2) the pattern of nonadherence and its risk factors; 3) the interaction between MM and nonadherence on the risk of long-term outcomes. If the results will indicate that nonadherence is a key determinant of poor outcomes in patients with MM, the clinical and public health impact would be very relevant. In fact, initiatives focusing at both individual and population level to underpin the importance of taking medications should be implemented.

 

Project leads:

Prof Melanie Davies (lead for Projects 1 and 2 below) melanie.davies@uhl-tr.nhs.uk

Prof Kamlesh Khunti (lead for Projects 3 and 4 below) kk22@Leicester.ac.uk

Project 1. Multimorbidity in early-onset adult type 2 diabetes: incidence, prevalence and association with long-term outcomes

Once considered a condition of mid-to-late adulthood, the prevalence of type 2 diabetes (T2D) in younger individuals is increasing. In the UK, the incidence of “early-onset adult T2D” (defined as T2D diagnosis aged 18-39 years) has more than doubled since the 1990s, and individuals with early-onset adult T2D now represent up to 15-20% of the T2D population worldwide. Individuals with early-onset adult T2D are a particularly high-risk group, even compared to later-onset T2D and type 1 diabetes, with increased risk of microvascular, cardiovascular, renal, and non-vascular complications, resulting in a greater number of life-years lost compared to older patients. Increased risk and poorer outcomes are underpinned by several factors, including accelerated disease progression; behavioural factors (e.g. sub-optimal self-care practices); and socio-economic factors (e.g. early careers, young families).

Alongside disproportionately high representation of BAME populations and more severe levels of individual risk factors (e.g. higher BMI, more adverse lipid profile), the extreme risk phenotype associated with early-onset adult T2D includes higher rates of diverse multimorbidity. Importantly, this includes not only concordant multimorbidity traditionally associated with T2D but also discordant conditions such as anxiety, depression, and social isolation.

In this project, we will perform much-needed analyses to further understand the complex dynamic of diverse multimorbidity in individuals with early-onset adult T2D, using: (i) UK Clinical Practice Research Datalink (primary care data from ~14M records); (ii) Data from the National Diabetes Audit, the largest dataset in T2D worldwide (~3.4M cases). Using CPRD we aim to: (i) Characterise heterogeneity between individuals at T2D diagnosis, including individual risk factors and “clusters” of multimorbidity; (ii) Estimate differences between and early- and later-onset T2D in the incidence/prevalence of risk factors; vascular and non-vascular complications; and mortality; (iii) Examine whether outcomes in early-onset T2D differ between common “clusters” of multimorbidity. The analyses using NDA data will complement CPRD investigations by using data collected through both primary and secondary care and exploring additional clinical characteristics/outcomes not available through CPRD (e.g. treatment target achievement).

Project 2. Combining glucose-lowering therapies and lifestyle intervention to improve glycaemic control and wellbeing in adults with early-onset type 2 diabetes and depression

Once considered a condition of mid-to-late adulthood, the prevalence of type 2 diabetes (T2D) in younger individuals is increasing. In the UK, the incidence of “early-onset adult T2D” (defined as T2D diagnosis aged 18-39 years) has more than doubled since the 1990s, and individuals with early-onset adult T2D now represent up to 15-20% of the T2D population worldwide. Individuals with early-onset adult T2D are a particularly high-risk group, even compared to later-onset T2D and type 1 diabetes, with increased risk of microvascular, cardiovascular, renal, and non-vascular complications, resulting in a greater number of life-years lost compared to older patients. Increased risk and poorer outcomes are underpinned by several factors, including increased risk of depression, poorer quality of life and socio-economic factors (e.g. early careers, young families).

Several glucose-lowering therapies (GLTs) are available in the management of type 2 diabetes, each of which share the common theme of improving glycaemic control. However, these therapies differ in several other ways. For example, some have weight-lowering properties, whilst others are weight-neutral or even promote weight gain. They also have different associated side effects, some of which include gastro-intestinal effects, genital infections etc. Each of these factors may affect positively or negatively mental wellbeing.

Lifestyle management, including increased physical activity, is also a cornerstone of T2D management and is known to meaningfully reduce symptoms of depression and increase quality of life. However, several psychosocial factors (including those listed above) may present barriers to participation. The aim of this project consists of the development and feasibility testing of an intervention that combines pharmacological GLT with a tailored lifestyle intervention, to improve glycaemic control and psychosocial wellbeing in individuals with early-onset adult T2D and depression. Exact details of the intervention (e.g. exact GLT, format of the lifestyle intervention) will be developed within the project using a range of different methodologies, including literature reviews, patient involvement and focus groups, along with intervention mapping. Once developed, the intervention will be tested in a pilot trial where the primary outcome will be depressive symptoms.

Project 3. Burden of Multimorbidity In Black, Asian or Minority Ethnic populations and years of life lost

Many countries, including the United Kingdom, have now become ethnically diverse. Despite the growing epidemiological research, there remains limited evidence on the relationship between the different ethnic groups and the burden of multimorbidity (MM) on life expectancy. In this project, both the UK Biobank and the Clinical Practice Research Datalink (CPRD) databases will be used to clarify the relationship between ethnicity, MM and life expectancy. The first aim is to quantify the association between MM and years of life lost in different in ethnic groups. Secondly, to assess whether the impact of non-modifiable and modifiable risk factors on the relationship between MM and years of life lost differs in relation to ethnicity. Third, to investigate the transition of the phenotypical patterns of MM across different ages in diverse ethnic groups, i.e. to clarify whether the natural history of MM clusters is heterogeneous. Fourth, to explore the mediation role of risk factors on the risk on MM among ethnic groups, i.e., to clarify the extent to which the risk of MM may be explained by uncontrolled risk factors. By estimating associations in terms of years of life lost, this project will help elucidate the role of MM on the risk of death across different ages: while traditionally MM develops in older subjects and epidemiological investigations have been conducted in this patient group, less is known about the relative and absolute risk in younger subjects. In this respect, the estimation of years of life lost will clarity the impact of MM across different ages.

Project 4. Multimorbidity, genetic factors, and life expectancy

Non-genetic factors, including a healthy lifestyle (balanced diet, exercising regularly, avoiding smoking and excess alcohol consumption, and living in a good environment), have been consistently associated to an improved longevity in different patient groups; their effects have been shown to nullify the presence of multimorbidity (MM) on the risk of death. However, to date there is limited evidence over the role of genetic factors on the risk of MM and mortality in people with MM. Moreover, although available evidence suggests a limited use of polygenic risk scores in determining the risk of future CVD in the general population, it is unclear whether information on the genetic background would be more useful in younger patients with MM, where in general non-genetic risk factors are less common and the phenotypical clusters of MM may significantly differ from those observed in older subjects with MM. Using the UK Biobank database, this project aims to decipher the relationship between genetic and non-genetic risk factors on the risk of MM and mortality in subjects with MM across different ages. To this end, the project will be articulated in three phases: (1) Develop polygenic risk scores using cross-sectional data; (2) Evaluate whether a polygenic risk score adds further information, on top of well-established non-genetic risk factors, on the identification of trajectories of MM (i.e., prognostic research); (3) Investigate the interaction between the genetic score and lifestyle factors on the risk of all-cause mortality and life expectancy in people with and without multimorbidity.


 

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