Background: Type 2 Diabetes is a chronic metabolic condition which occurs as a result of insufficient insulin production and insulin resistance. This results in less glucose uptake by muscle and fat cells, allowing blood glucose levels to rise in the body. Higher blood glucose levels place patients at an increased risk of diabetes-related complications. The treatment is characterised by the initiation, switching and intensification of antidiabetic medications. The goal for patients with diabetes is to maintain glycaemic control, with blood glucose levels (HbA1c) between 6.5-7.0%(48-53mmol/mol). International guidelines recommend prescribing of metformin at initiation but there is no consensus on optimal agents in a combination regimen. The aim of this thesis was to assess the drug utilisation patterns of first-line therapies and the impact of this pathway on second-line regimens. This entailed: (i.) observing the prescribing of the first-line therapy, (ii.) characterising the medication-taking process of the first-line therapy and effectiveness of the regimens, and (iii.) determining the most effective second-line regimen in delaying the onset of microvascular complications. Methods: Patients with type 2 diabetes, prescribed a first-line antidiabetic regimen, were identified from the Clinical Practice Research Datalink (a large UK anonymised primary care database) between 01/01/05 and 31/12/09, were followed-up until 31/12/12. A multinomial logistic regression model was used to assess the relationship between patient characteristics and the choice of first-line agent. Adherence to first-line therapy was estimated using the Medication Possession Ratio calculation, expressing the percentage of days covered by a drug supply. To assess the factors influencing achievement of glycaemic goals from the first-line therapy, a logistic regression analysis was performed. To investigate second-line regimens, a Marginal Structural Cox model was implemented to explore the causal relationships between the time to development of microvascular complications and the second-line regimens. Results: Of the 72,429 individuals diagnosed with type 2 diabetes, 44,838 started therapy with an antidiabetic medication regimen. Metformin and sulphonylureas were the most frequently prescribed agents at initiation (82.9% and 9.8%,respectively). Deviations from metformin were associated with patients presenting with higher HbA1c levels, lower BMI values and had concurrent prescriptions (immunosuppressants and oral corticosteroids). Achieving glycaemic control, to the target of 6.5% (48mmol/mol), was only met in 22.7% of patients. Characteristics of the patient, choice of first-line agent and medical support influenced the effectiveness of the treatments. Patients at the greatest risk of failing to achieve the target glycaemic goal from therapy had HbA1c levels>8.0% (64mmol/mol) and a BMI≥25kg/m2. Adherence was significantly associated with greater lowering of HbA1c levels but these reductions did not guarantee reaching the ideal glycaemic target. Intensification of the monotherapy to a dual therapy regimen was observed in 30.2% of patients in a mean time of 2 years. The most frequently prescribed second-line regimens consisted of metformin/sulphonylurea (SU) (74.5%), metformin/thiazolidinediones(TZD) (11.3%) and metformin/DPP-4 inhibitors (14.2%). Metformin/SU was the most effective dual therapy regimen for delaying the onset of microvascular diagnoses. The rate of development of these events was significantly higher for the DPP-4 combination in comparison to the SU combination with a hazard ratio of 1.85 (95% CI: 1.53,2.24). A TZD combination resulted in a non-significant increase of 19% in the rate of development compared to the SU combination (HR 1.19; 95% CI: 0.98,1.47). Metformin/SU resulted in the greatest lowering in HbA1c levels (-3.3%; 12mmol/mol) in comparison to the DPP-4 and TZD regimens. Conclusions: It is unlikely that patients starting first-line therapy with high HbA1c levels will be able to reduce blood glucose levels sufficiently on a monotherapy regimen. It is important for practitioners to consider a faster uptake of a dual therapy regimen (metformin/SU) to prevent sustained suboptimal glycaemic control and reduce the risk of future complications. Other important considerations in the optimal treatment pathway would be to provide more frequent support from health professionals; this may help to highlight inadequate drug regimens, offer management of risk factors and provide education. These aspects may help patients to achieve better control of their condition, with the aim of reducing the risk of diabetes-related complications; which, severely impact patient quality of life and NHS costs and resources.

Background: T2DM patients can be treated with both Insulin or/and non-insulin antidiabetic drugs. Biguanide-derivate is the first-line antidiabetic that is cost-effective and safe. DPP-4Is are antidiabetic drugs that can be used to treat old patients and those with kidney failure. While SGLT2-inhibitors and GLP-1analogues can be used by T2DM patients with cardiovascular problems and those with overweight. The initiation of antidiabetic drug is influenced by several factors such as patient characteristic, physician’s knowledge and guidelines. Aim: The aim of this study was to study the type of antidiabetic medication initiated to naïve T2DM patients, how age and sex affect the choice of medication and difference in prescribing between Primary healthcare centers in Region Uppsala. Methods: The study was a cross-sectional based on health record data from Region Uppsala. The study included 2473 T2DM patients that were initiated antidiabetic medication between January 2019 and December 2020. Results: Non-insulins accounted for 88 % and insulins for 21.1% of the prescriptions. The proportion of men that received both insulin and non-insulins were higher than women. The proportion of patients that received insulins was higher for the age group 80 years and older. The proportion of men that received SGLT2- inhibitors was higher than for women, while women received more GLP-1- analogues. There was a variation between PHCs, but non-insulins were mostly prescribed at all PHCs. Conclusions: Initiation of antidiabetic drugs to naïve T2DM patients in region Uppsala fallowed the guidelines. There are some differences in prescription pattern between the two sexes and the age groups.

Abstract Endometrial cancer (EC) is the fifth most common female cancer worldwide and its incidence is increasing. The prognosis of EC is fairly good. Histologically, ECs are categorized into endometrioid and non-endometrioid subtypes. Lately, the idea of repurposing existing medications for the prevention and co-treatment of EC has evoked interest in the scientific community. The results of preclinical studies involving various forms of antidiabetic medication (ADM) such as metformin, or cholesterol-lowering statins have been promising. In the previous epidemiological studies, the results of metformin and/or statin use and the risk and prognosis of EC have indicated either neutral or beneficial effects. At least some of these studies have several limitations, including a potential for several types of bias, and missing information on the dose and timing of medication, cancer-specific mortality or the histology of EC. The aim of this study was to find reliable further evidence on whether the use of metformin or statins could have beneficial effects on the risk and prognosis of EC in women with type 2 diabetes (T2D). Endometrioid and non-endometrioid EC were analyzed separately based on data from the Finnish Cancer Registry (FCR). In our study cohort of 92 366 women obtained from a nationwide diabetes database (FinDM) (1996 to 2011), the incidence rates of endometrioid (n = 590 cases) and non-endometrioid (n = 57 cases) EC were not found to differ between metformin users and users of other forms of oral ADM when adjusted for age, duration of T2D and use at any time of other forms of medication under study. We found insufficient evidence that metformin affects the prognosis of patients diagnosed with endometrioid (n = 1215) or non-endometrioid (n = 105) EC (1998 to 2011) after adjusting for year, age and stage at diagnosis of EC, and duration of T2D. However, in patients with endometrioid EC, mortality from other (predominantly cardiovascular) causes of death was decreased in metformin users compared with users of other types of oral ADM. Despite promising preclinical data, we were not able to confirm a beneficial effect of metformin use on the risk or prognosis of EC in women with T2D. In statin users, a lower risk of both EC subtypes and reduced cancer-specific mortality from non-endometrioid EC were observed. / Tiivistelmä Kohdun runko-osan syöpä on naisten viidenneksi yleisin syöpä, ja todettujen tapauksien määrä kasvaa. Syövän paranemisennuste on melko hyvä. Histologisesti syöpä jaetaan endometrioidi-muotoon ja ei-endometrioidi -muotoon. Alun perin muihin tarkoituksiin kehitettyjen lääkkeiden käyttö kohdun runko-osan syövän ehkäisyssä ja hoitoyhdistelmissä on ollut viime aikoina tieteellisen mielenkiinnon kohteena. Prekliinisten tutkimusten tulokset diabeteslääke metformiinin ja hyperkolesterolemian hoitoon käytettyjen statiinien osalta ovat olleet lupaavia. Aiemmissa epidemiologisissa tutkimuksissa metformiinin tai statiinien käytön vaikutukset kohdun runko-osan syövän riskiin ja ennusteeseen ovat olleet vaihtelevia. Osassa tutkimuksista on ollut ongelmia liittyen tilastollisten harhojen riskiin, puutteellisiin tietoihin lääkityksen kestosta ja kumulatiivisista annoksista sekä spesifisestä syöpäkuolleisuudesta ja syövän histologiasta. Kansalliseen diabetestietokantaan (FinDM) perustuvan tutkimuksemme tavoitteena oli selvittää, onko metformiinin tai statiinien käytöllä (Kelan lääkekorvaustilastot) kohdun runko-osan syövän riskiä vähentävää tai ennustetta parantavaa vaikutusta tyypin 2 diabetesta sairastavilla naisilla. Endometrioidit-syövät ja ei-endometrioidit -syövät analysoitiin erikseen Suomen Syöpärekisterin tietoihin perustuen. Kohortissamme (n = 92 366) ei todettu eroa endometrioidin (n = 590) tai ei-endometrioidin (n = 57) kohdun runko-osan syövän ilmaantuvuudessa metformiinia tai muita oraalisia diabeteslääkkeitä käyttävien naisten välillä (1996-2011), kun ikä, diabeteksen kesto ja muiden lääkitysten käyttö vakioitiin. Emme löytäneet näyttöä metformiinin käytön yhteydestä syöpäkuolleisuuteen endometrioidissa (n = 1 215) tai ei-endometrioidissa (n = 105) alatyypeissä verrattuna muihin diabeteslääkityksiin (1998-2011), kun ikä, syövän diagnoosivuosi ja levinneisyys sekä diabeteksen kesto vakioitiin. Endometrioidiin syöpään sairastuneilla metformiinia käyttävillä naisilla muu, valtaosalla sydän- ja verisuonitautiperäinen, kuolleisuus oli vähentynyt verrattuna muiden oraalisten diabeteslääkkeiden käyttäjiin. Aiemmista lupaavista tutkimustuloksista huolimatta emme todenneet metformiinilla olevan edullisia vaikutuksia kohdun runko-osan syövän kannalta. Statiinien käyttöön liittyi vähentynyt tämän syövän riski sekä vähentynyt syöpäkuolleisuus ei-endometrioidissa alatyypissä.

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