Carolina medical trials

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Participants were randomized using an interactive telephone- and web-based system in a block size of 4 to receive 5 mg of once-daily oral linagliptin or 1 to 4 mg of once-daily glimepiride Figure 1. Treatment assignment was determined by a computer-generated random sequence with stratification by center. After the first 16 weeks, participants returned for follow-up study visits every 16 weeks until the end of the study.

A final follow-up visit was scheduled 30 days after treatment cessation. Investigators were encouraged to monitor and use additional medication for glycemic control per local guidelines, particularly if HbA 1c was greater than 7.

Investigators were also encouraged to manage all other cardiovascular risk factors in accordance with applicable guidelines and current standards of care. Participants who prematurely discontinued the study medication were followed up for ascertainment of cardiovascular events, mortality, adverse events, and other end points.

Attempts were made to collect vital status and outcome event information on every randomized individual at study completion, in compliance with local law and regulations. The primary end point was time to first occurrence of cardiovascular death, nonfatal myocardial infarction MI , or nonfatal stroke 3-point major cardiovascular event [3P-MACE] composite.

The original protocol included hospitalization for unstable angina in the primary end point 4-point major cardiovascular event [4P-MACE] composite ; however, this was changed by a protocol amendment in April , based on emerging evidence that a primary end point definition of 3P-MACE was preferred by regulators and consistent with other outcome trials of glucose-lowering therapies.

Time to first occurrence of 4P-MACE was hierarchically evaluated as the first of the prespecified key secondary end points, followed by analyses of the proportion of patients receiving treatment and maintaining HbA 1c of less than or equal to 7. Other secondary cardiovascular end points included individual components of 3P-MACE and 4P-MACE and time to any confirmed adjudicated cardiovascular events cardiovascular death, including fatal stroke and fatal MI; nonfatal MI; nonfatal stroke; hospitalization for unstable angina; transient ischemic attack; hospitalization for HF; hospitalization for coronary revascularization procedures.

Secondary diabetes-related end points included change in laboratory parameters from baseline to final visit eg, HbA 1c , fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides. In addition, we prespecified several tertiary cardiovascular end points ie, occurrence of and time to first occurrence of each of the confirmed adjudicated end points , tertiary diabetes-related end points eg, change of laboratory parameters from baseline to each planned week, hypoglycemia occurrence, change in weight and rescue medication use , and other end points including noncardiovascular death and adverse events.

All predefined outcomes and end point definitions are presented in Supplement 1 , Supplement 3 eAppendix 5 , and Supplement 4. Safety was assessed based on adverse events that occurred during treatment or within 7 days after the last dose of a study drug and coded using the Medical Dictionary for Drug Regulatory Activities version Adverse events prespecified as being of special interest included hypersensitivity reactions, skin lesions, pancreatitis, pancreatic cancer, and hypoglycemia.

The primary aim of the study was to evaluate whether linagliptin was noninferior to glimepiride for the time to 3P-MACE, defined by the upper limit of the multiplicity-adjusted 2-sided A 5-step hierarchical testing strategy was prespecified, in which each subsequent test would be performed in case of significant prior results. Not adjusted for interim analyses, a total of individuals with an adjudication-confirmed 3P-MACE would provide The interim analyses were planned to be performed after and participants experienced a primary outcome event.

Outcomes were analyzed in all randomized patients treated with at least 1 dose of the study drug treated set using the intention-to-treat principle. Patients were analyzed according to their randomized treatment group. Additional sensitivity analyses are described in eAppendix 6 in Supplement 3.

Time-to-event outcomes were analyzed using a Cox proportional hazards model, with treatment assignment as a factor in the model. Further, Schoenfeld residuals were plotted against time and log time. For all Cox proportional hazards analyses, the proportional hazard assumption was met.

Subgroup analyses included additional factors for subgroup and treatment by subgroup interaction. In addition, Kaplan-Meier estimates are presented. Censoring was applied the day a participant was last known to be free of the specific outcome event.

Because of declining numbers of participants at risk, Kaplan-Meier plots were truncated at 6. As prespecified, data were included up to the planned week that could theoretically be achieved by all patients. The prespecified approach for handling missing data are described in the statistical analysis plan Supplement 2. The approach varied according to the statistical analysis employed eg, censoring in Cox models and Kaplan-Meier plots for time-to-event analysis and mixed models for continuous variables.

Except for the prespecified 5-step hierarchical testing strategy, there was no adjustment for multiple comparisons and, therefore, the results of subgroup analyses and other end points should be interpreted as exploratory. Analyses were conducted using SAS version 9. Participants were screened from November through December , with final follow-up on August 21, A total of participants were randomized, of whom received at least 1 dose of the study medication and were included in the primary outcome analysis Figure 1.

Median Q1, Q3 study medication exposure was 5. Overall, Vital status was available for Because the result of the test for superiority was null, findings for the key secondary outcomes are presented descriptively. Post hoc analytic results can be found in eAppendix 9 and eTable 3 in Supplement 3. The second key secondary end point of the proportion of patients receiving treatment and maintaining HbA 1c less than or equal to7.

The third key secondary end point of the proportion of patients receiving treatment and maintaining HbA 1c less than or equal to 7. Death from any cause was not significantly different between participants in the linagliptin of [ The distribution of causes of noncardiovascular death in the linagliptin group of participants [4.

Adjudication-confirmed hospitalizations for HF, alone or included in composite outcomes with cardiovascular mortality or investigator-reported HF events, were not significantly different between groups Table 2 ; eAppendix 9 in Supplement 3. The mean SD dose of glimepiride over the trial duration was 2. Introduction of additional glucose-lowering therapies occurred in similar proportions across study groups, with a pattern of shorter time to introduction in the linagliptin group compared with the glimepiride group eAppendix 12 in Supplement 3.

Fasting plasma glucose, blood pressure, and lipid levels over time were not significantly different between groups eAppendix 13 and 14 in Supplement 3. Frequencies of adverse events, serious adverse events, and adverse events leading to discontinuation of study medication were comparable between groups Table 3.

Overall, the number of participants with at least 1 hospitalization was There was no between-group imbalance in adjudication-confirmed pancreatitis or pancreatic cancer.

Incidence of hypoglycemic events was lower in the linagliptin group than in the glimepiride group across all predefined hypoglycemia severity categories Table 3. Rates of investigator-reported hypoglycemia were 2. Rates of severe hypoglycemic events were 0. Hypoglycemia risk was increased across the entire dose range for the glimepiride group eAppendix 15 in Supplement 3.

A consistently lower hypoglycemia risk was observed in the linagliptin group than in the glimepiride group across all subgroups analyzed eAppendix 16 in Supplement 3. In this long-term, multicenter, double-blind, randomized, active comparator trial of individuals with relatively early type 2 diabetes at elevated cardiovascular risk, linagliptin was noninferior to glimepiride for the combined 3P-MACE end point.

The current study demonstrates noninferior cardiovascular safety effects for linagliptin vs glimepiride when used predominantly as a second-line glucose-lowering treatment option after metformin.

The current study reaffirms clinical recommendations to choose an oral agent after metformin based on proven cardiovascular benefit, 1 , 2 which none of the agents studied provide. However, when additional glucose-lowering therapy is required, a DPP-4 inhibitor, such as linagliptin, is an option with a low risk of hypoglycemia and weight gain. This study has several limitations. First, because the trial recruited participants with relatively early type 2 diabetes and insulin treatment was an exclusion criterion, the results may not necessarily be applicable to patients with more advanced disease.

While there was no statistically significant heterogeneity in the effects on the 3P-MACE outcome in subgroups based on diabetes duration or cardiovascular risk at baseline, the study may have been underpowered to test for interactions. Second, inherent for many long-term trials is the early termination of study medication, which could have influenced the results. However, medication exposure was comparable between study groups, and annualized discontinuation rates are in line with most of the contemporary cardiovascular outcome trials of glucose-lowering therapies, all of which were of shorter duration.

Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median of 6. Published Online: September 19, Author Contributions: Drs Rosenstock and Marx had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Johansen is employed by Boehringer Ingelheim, Norway. Dr Espeland reported receiving consulting fees from Boehringer Ingelheim during the conduct of the study and grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Aging outside the submitted work. Mr Baanstra is employed by Boehringer Ingelheim, the Netherlands.