Discussion
This is a large nationwide observational study analyzing the durability of metformin, SU, and meglitinide in real life. We found that almost half of the patients got add on of a second agent, switched to a new agent, or discontinued the initial agent when followed for up to 5.5 years. SU and meglitinide, as compared with metformin, were associated with a significantly increased risk of overall monotherapy failure, taking differences in baseline demographics and patient characteristics into account. The increased risk of overall monotherapy failure associated with SU and meglitinide was driven by a twofold to fourfold increased risk of add on of a second agent and switch to a new agent, whereas the risk of discontinuation of the initial OHA did not differ significantly between the groups. Patients continuing their initial monotherapy throughout the study showed improved HbA1c levels of approximately 10% irrespective of the type of OHA used, whereas patients who switched to a new agent or got add on of a second agent showed stable or slightly increased HbA1c levels. The improved HbA1c levels among patients who continued their initial monotherapy throughout the study confirm that these patients represented responders to treatment. Somewhat more surprisingly, patients who discontinued their initial OHA showed similar improvement in glycemic control. This group most certainly represents a very heterogenic group of patients, with a range of different underlying causes explaining their treatment discontinuation. Patients who got add on of a second agent or switched to a new agent showed unchanged or slightly increased HbA1c-levels leading up to these events. This indicates that deterioration of glycemic control was the primary underlying cause of events of add on of a second agent or switch to a new agent, and that these end points can be used as a measure of glycemic durability.
To the best of our knowledge, this is the first study reporting real-world data on the durability of meglitinide, an agent that contributes a therapeutic option in patients with contraindications for metformin or in those requiring a second agent to attain glycemic control.1 Our results, with highly significantly increased risks for add-on treatment of a second agent and switch to a new agent associated with SU, are in line with results from ADOPT. In ADOPT, initial monotherapy with metformin provided superior glycemic durability compared with glyburide,7 caused by a faster decline in β-cell function and insulin sensitivity in patients initiated on glyburide.25 In ADOPT, the Kaplan-Meier cumulative incidence of monotherapy failure (fasting plasma glucose >10 mmol/L) at 5 years was lower than in this study. This study and ADOPT differ in many respects, which could explain the difference in the cumulative incidence of monotherapy failure. First, this study is observational and represents the durability of different OHAs in real life. In contrast, ADOPT was a clinical trial, which reported the effects of protocol-driven treatments in a selected group of motivated patients who were followed closely with frequent visits. Second, the treatment guidelines available during the study period of this study recommended lower glycemic thresholds for treatment intensification than a fasting plasma glucose level >10 mmol/L,26 which was used in ADOPT. Finally, the patients included in this study were older and had a longer diabetes duration, suggesting that these patients had a more advanced disease than those included in ADOPT.
What about the results from other observational studies? A Canadian cohort study analyzed the risk of progression to combination oral therapy or a switch in oral therapy associated with metformin compared with SU.13 They found a modest decrease in risk of monotherapy failure associated with metformin compared with SU (HR 0.89; 95% CI 0.82 to 0.98). There were, however, important differences between this study and the Canadian study. Most importantly, we had information about essential covariates such as diabetes duration, HbA1c, and BMI, which were lacking in the Canadian study. Both HbA1c and BMI have been shown to be associated with progression from prediabetes to overt diabetes;27 ,28 diabetes duration is related to the remaining β-cell function. As a result, these variables are crucial covariates for estimating the glycemic durability of hypoglycemic agents. Another observational study of 12 697 veterans, including mainly male patients with T2DM, investigated the importance of study design choices in durability analyses. Interestingly, they found no significant difference in the durability (time to reach HbA1c >8%) between SU and metformin when extremely strict criteria for continuous treatment were used. However, when using criteria comparable to the ones used in this and other studies,9 ,11 SU was associated with a highly significantly increased risk of reaching HbA1c >8% (HR 1.45; 95% CI 1.29 to 1.63). The analyses were adjusted for important covariates, including diabetes duration, HbA1c, and BMI, but the follow-up time was short (approximately 1 year). ADOPT showed superior effects on β-cell function and glycemic control with glyburide compared with metformin or rosiglitazone during the first 6 months. After 6 months, patients on glyburide had a faster decline in β-cell function and loss of glycemic control, which resulted in significantly lower long-term glycemic durability with glyburide compared with metformin or rosiglitazone. Therefore, the risk of reaching HbA1c >8% during the first treatment year may not represent a good measure of long-term durability.
We were able to study smaller matched cohorts with well-balanced baseline covariates, as well as larger samples, of patients with T2DM for up to 5.5 years. Data were collected from the NDR database, which contains data from primary healthcare clinics and hospital outpatient clinics in all geographical areas of Sweden. The extensive information on patient characteristics and demographics enabled us to perform Cox proportional hazards regression analyses adjusted for many important covariates. Adjustments were made by several different statistical techniques and managed to balance baseline variables adequately between the groups with use of matching based on propensity scores. Despite extensive adjustments for relevant covariates, the possibility of residual confounding due to unknown and unmeasured covariates is a limitation in this study. However, the performed sensitivity analyses showed that a very strong confounder (HR 2.0) had to be present in more than 80% more SU or meglitinide users than metformin users to invalidate our findings concerning risk of add-on treatment of a second agent or switch to a new agent. To ensure complete data on all covariates, a large portion of patients had to be excluded due to missing data. However, owing to the large number of eligible patients, the study still had reasonable power to detect differences between the groups. Furthermore, sensitivity analyses on a larger group of patients (n=59 495) with missing data on some covariates showed similar results. The analyses in this study were based on filled prescriptions, which carry several limitations. Even though 12 months of continuous treatment was required to be included in the study, some treatment switches may have been due to late adverse effects and not loss of glycemic control. However, the results were similar when analyzing the risk of add-on treatment of a second agent, an event that should be less susceptible to misclassification due to adverse effects. There is an ongoing debate concerning criteria for continuous medication use in studies determining drug exposure using electronic data on filled prescriptions.8 We allowed gaps of maximum twice the day’s supply of an ordinary prescription, which was considered reasonable in a validation study of persistence and durability to diabetes medication.8 Similar criteria have been used in most previous studies in the field.9–11 Finally, the original objective of this study was to evaluate the durability of many different OHAs. Since few patients were initiated on newer OHAs, the analyses were restricted to metformin, meglitinide, and SU.
In conclusion, in this nationwide observational study of drug naïve patients with T2DM, the majority discontinued treatment, switched to a new agent, or got add-on treatment of a second agent when followed for up to 5.5 years. SU and meglitinide, as compared with metformin, were associated with a considerably increased risk of switch to a new agent and add on of a second agent, which remained during the entire follow-up period. These results strengthen the current evidence of a superior durability with metformin compared with SU in real life. The results from this study suggest that this also applies when comparing metformin with meglitinide.