Type 2 diabetes is a chronic disease that is mainly characterised by abnormally high levels of blood sugar. Diabetes care guidelines recommend lowering blood sugar levels with the drug metformin in newly diagnosed patients. If adequately low levels are not achieved with metformin alone, the addition of a second glucose-lowering drug is recommended. A class of drugs often added to metformin is the class of the so-called dipeptidyl peptidase-4 (DPP-4) inhibitors. Research has shown that the combination of metformin with DPP-4 inhibitors represents an efficient therapy to lower blood sugar levels in persons with type 2 diabetes. Some studies found that therapy with DPP-4 inhibitors could even lower the risk of developing and dying from heart and blood vessel diseases, which represent a frequent and serious complication of type 2 diabetes. Other studies, though, found no beneficial effects of DDP-4 inhibitors on the heart and blood vessels. Therefore, current scientific evidence about the potentially beneficial side-effects of DPP-4 inhibitor treatment for the heart and blood vessels in persons with type 2 diabetes is inconclusive.
Since the late 1980s, the CPRD database has collected the medical records for over 14 million people from more than 680 general practices in the UK. Using this large amount of data on patients from everyday clinical practice, we aim to investigate the risk of developing heart and blood vessel disorders in patients with type 2 diabetes treated with metformin and DPP-4 inhibitor combination therapy versus patients treated with metformin only.
Previous randomized controlled metabolic outcome trials could show that dipeptidyl peptidase-4 (DPP-4) inhibitors were associated with a lower risk of major adverse cardiovascular events and death in type 2 diabetes. Recent randomized cardiovascular safety trials, on the other hand, found no beneficial cardiovascular effects of DDP-4 inhibitors, rendering the current scientific evidence inconclusive. Large real-world observational studies can prove a valuable addition to clinical trials to gain insights into long-term cardiovascular outcomes. We therefore aim to study the comparative safety of combined treatment of metformin and DPP-4 inhibitors versus metformin monotherapy with respect to major cardiovascular events and cardiovascular mortality in type 2 diabetes patients using the CPRD database.
The study will use a prevalent new-user design. From a base cohort of new users of metformin monotherapy between January 2008 and January 2017, the study cohort will be formed by all patients who added a DPP-4 inhibitor. These patients will subsequently be matched to those who remained on metformin monotherapy. Both exposure groups will be followed for the incidence of major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death) until January 2020. Cox proportional hazards models will be fitted for each outcome measure to estimate hazard ratios and 95% confidence intervals for metformin and DPP-4 inhibitor combination therapy versus metformin monotherapy.
By means of the study´s design, elaborate matching, calculation of a propensity score and subsequent overlap weighting we aim to minimize baseline imbalances between exposure groups, as well as the chance for several forms of time-related biases. Multiple sensitivity analyses are planned to assess the robustness of the main analysis.
With maximum efforts to minimize all possible forms of bias, the current study, using real-world patient data, will complement randomized clinical trial evidence on cardiovascular effects of DPP-4 inhibitors and have the potential to influence clinical decision making.
(i) MACE (major adverse cardiac event): a composite outcome of acute myocardial infarction (AMI), stroke (ischemic or haemorrhagic) and cardiovascular mortality; (ii) cardiovascular mortality; and (iii) all-cause mortality.
Wolfgang Rathmann - Chief Investigator - University of Dusseldorf
Brenda Bongaerts - Corresponding Applicant - University of Dusseldorf
Oliver Kuss - Collaborator - University of Dusseldorf
HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation