Patients with type II diabetes (T2DM) have elevated blood glucose which is associated with an increased risk of a range of conditions including heart disease, stroke, kidney disease and eye complications. Approximately 5.4% of people in the United Kingdom have T2DM. Initially, patients may try to control their glucose levels by lifestyle and dietary modifications but most patients will require medication. Various therapies exist, and some may be more appropriate than others depending on the characteristics of the individual patient. Often, glucose levels will increase after a period of time on one drug, and it may be decided that another drug should be added to the patient’s regimen. In this study we want to use the Clinical Practice Research Datalink to see what happens to HbA1c, a measure of blood glucose, when patients initially taking one of two drugs (dapagliflozin or sitagliptin), with or without metformin background therapy, have the other drug added. We will compare HbA1c and other relevant indicators at baseline (before the second drug is added) to two subsequent timepoints (90–270 days and 271–450 days). We will also see if these patients have side-effects in the 12 months after taking the two drugs together and compare them to other patients on the same initial drug who have a different drug added. By conducting such a study, we aim to show that the use of the drugs in combination is effective and safe which may improve patient outcomes and provide savings for healthcare services.
Type II diabetes (T2DM), affects 5.4% of the UK population and is associated with increased risk of vascular complications. Assuming an absence of contra-indications, guidelines recommend patients initiate treatment with metformin. If their glycaemic control worsens, treatment is intensified with another anti-diabetic agent as dual-therapy. Patients may then progress to triple-therapy. We propose a retrospective, single-arm study in the Clinical Practice Research Datalink GOLD and Aurum databases to evaluate the association of initiation with combination dapagliflozin/sitagliptin therapy (with or without metformin background therapy) upon T2DM biochemical markers and safety outcomes. T2DM patients prescribed dapagliflozin or sitagliptin who were first treated with the other drug will form the study cohort. Index date will be the date that dapagliflozin and sitagliptin are prescribed concomitantly. Patients prescribed other antidiabetic agents will be excluded with the exception of metformin, provided the metformin therapy is not initiated or modified 3 months prior to index date and is prescribed a daily dose ≥1500mg. A reference group whose antidiabetic therapy (dapagliflozin or sitagliptin) is augmented with a different antidiabetic agent will be matched for safety evaluation. Baseline HbA1c (measurement within 6 months and nearest to index date)”will be compared to two subsequent timepoints post index date (90–270 days and 271–450 days) using the dependent t test or paired sample Wilcoxon signed-ranks test. The proportion of patients reaching targets (HbA1c reduction of 1%, HbA1c <6.5%, HbA1c <7%) will be reported and mean changes in fasting glucose, weight, systolic blood pressure and lipids at both checkpoints will be compared. The incidence of safety events will be reported in the year post-index and compared to the reference group by incidence rate ratios evaluated by the mid-p test. This study will provide valuable data to inform the impact of these drugs in combination on outcomes with ultimate efficiencies for health services.
Mean change from baseline in HbA1c at checkpoint 1, mean change from baseline in HbA1c at checkpoint 2, proportion of subjects with in HbA1c <6.5% checkpoint 1, proportion of subjects with in HbA1c <6.5% checkpoint 2, proportion of subjects with in HbA1c <7% checkpoint 1, proportion of subjects with in HbA1c <7% checkpoint 2, proportion of subjects with HbA1c reduction from baseline ≥ 1% at checkpoint 1, proportion of subjects with HbA1c reduction from baseline ≥1% at checkpoint 2, rolling average of each HbA1c measurement during entire observation period, mean change from baseline in fasting plasma glucose at checkpoint 1, mean change from baseline in fasting plasma glucose at checkpoint 2, mean change from baseline in weight (kg) at checkpoint 1, mean change from baseline in weight (kg) at checkpoint 2, mean change from baseline in systolic blood pressure at checkpoint 1, mean change from baseline in systolic blood pressure at checkpoint 2, mean change from baseline in total cholesterol at checkpoint 1, mean change from baseline in total cholesterol at checkpoint 2, mean change from baseline in low density lipoprotein at checkpoint 1, mean change from baseline in low density lipoprotein at checkpoint 2, mean change from baseline in high density lipoprotein at checkpoint 1, mean change from baseline in high density lipoprotein at checkpoint 2, mean change from baseline in triglycerides at checkpoint 1, mean change from baseline in triglycerides at checkpoint 2, adverse events (presented individually, by type/site and overall): acute pancreatitis, acute renal failure, angioedema, arthralgia, arthropathy, back pain, balanitis and related genital infections, blood creatinine increased, blood urea increased, bullous pemphigoid, constipation, creatinine renal clearance decreased, cutaneous vasculitis, diabetic ketoacidosis, dizziness, dry mouth, dyslipidaemia, dysuria, exfoliative skin conditions including Stevens-Johnson syndrome, fatal and non-fatal haemorrhagic and necrotizing pancreatitis, fungal infection, haematocrit increased, headache, hypersensitivity reactions including anaphylactic responses, hypoglycaemia, impaired renal function, interstitial lung disease, myalgia, necrotising fasciitis of the perineum (Fournier's gangrene), nocturia, polyuria, pruritus, pruritus genitalia, rash, thirst, thrombocytopenia, tubulointerstitial nephritis, urinary tract infection, urticaria, volume depletion, vomiting, vulvovaginal pruritus, vulvovaginitis, weight decreased.
- Chief Investigator -
- Corresponding Applicant -
Elgan Mathias - Collaborator - Pharmatelligence Limited t/a Human Data Sciences
Irena Orel - Collaborator - Krka - Slovenia
Nina Lukač - Collaborator - Krka - Slovenia
Sara Jenkins-Jones - Collaborator - Pharmatelligence Limited t/a Human Data Sciences
Sara Redenšek Trampuž - Collaborator - Krka - Slovenia
Sarah Holden - Collaborator - Pharmatelligence Limited t/a Human Data Sciences