Post Hoc Analysis Evaluating the Impact of Antihyperglycemic Background Therapies on Attainment of A1C Targets Without Hypoglycemia in the ACHIEVE Control Pragmatic, Real-Life Study

Primary care physicians have an increasingly important role in the treatment of type 2 diabetes (23), with >85% of recommendations to initiate BI therapy originating from them (24). It is important to understand how concomitant sulfonylurea use affects efficacy outcomes with BI, including A1C target achievement and risk of hypoglycemia. To simulate real-world clinical practice, treatment with other antihyperglycemic drugs in the ACHIEVE Control study was per clinician discretion and according to local labeling for concomitant use with BI. Thus, ACHIEVE Control provided the unique opportunity to evaluate potential effects of concomitant antihyperglycemic background therapies on BI treatment outcomes. We conducted post hoc analyses in subgroups of participants in ACHIEVE Control that were defined by the concomitant use or nonuse of common antihyperglycemic therapies, including sulfonylureas. Although GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors are not associated with increased risk of hypoglycemia, these agents were also included in the analysis.

The ACHIEVE Control study design (15) and primary outcomes (16) have been reported previously. Enrollment occurred from June 2015 to July 2017. Insulin-naive individuals with type 2 diabetes and an A1C ≥8.0 and ≤11.0% were randomized (1:1) to Gla-300 or SOC-BI (Gla-100 or insulin detemir). Randomization was stratified by A1C target (<7/<8%), sulfonylurea use (yes/no), GLP-1 receptor agonist use (yes/no), and baseline A1C (<9/≥9%). Study participants had received their type 2 diabetes diagnosis ≥1 year before the screening visit and had not achieved glycemic control (A1C <8.0%) despite treatment with two or more oral antihyperglycemic drugs or GLP-1 receptor agonists approved for concomitant use with insulin.

For the current analyses, participants in each subgroup were considered to be concomitant users of a background therapy if they were using it at the time of baseline assessment and continued use when starting BI therapy. Those who started background therapy at or after randomization were excluded from analysis. Analyses were conducted according to the intention-to-treat principle. The composite end points and components evaluated were A1C target attainment without documented symptomatic hypoglycemia (defined as glucose ≤3.9 mmol/L [≤70 mg/dL] or <3.0 mmol/L [<54 mg/dL]) or severe hypoglycemia at 6 and 12 months, A1C target attainment (irrespective of hypoglycemia) at 6 and 12 months, and absence of documented symptomatic hypoglycemia (glucose ≤3.9 mmol/L [≤70 mg/dL] or <3.0 mmol/L [<54 mg/dL]) or severe hypoglycemia at 6 and 12 months. ORs and associated 95% CIs were determined based on a logistic regression model.

The mean daily insulin doses were similar in the Gla-300 and SOC-BI treatment arms, both at the start of the study (0.156 ± 0.074 and 0.152 ± 0.079 units/kg, respectively) and at the 6- (0.335 ± 0.216 and 0.336 ± 0.220 units/kg, respectively) and 12-month time points (0.378 ± 0.235 and 0.376 ± 0.239 units/kg, respectively).

Of 3,284 randomized participants who qualified for this subgroup analysis, 2,287 (69.6%) received a concomitant sulfonylurea; 20 individuals who started sulfonylurea therapy at or after randomization were excluded. Of those who did not use sulfonylurea therapy during the study, 23.4% had used it previously but stopped use before or at the time of BI initiation. Baseline characteristics were generally well balanced between the treatment arms of subgroups (Table 1).

In both the Gla-300 and SOC-BI treatment arms, the proportions of participants who achieved their A1C target without documented symptomatic hypoglycemia (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycemia at 6 and 12 months were numerically greater among nonusers than users of concomitant sulfonylureas. Similarly, the proportions of participants with no documented symptomatic or severe hypoglycemia (≤3.9 mmol/L [≤70 mg/dL]) at 6 and 12 months were numerically greater among nonusers than users of concomitant sulfonylureas (Figure 1). ORs at 12 months (Figure 2A) strongly favored Gla-300 versus SOC-BI for all end points, including A1C target achievement without documented symptomatic hypoglycemia at either ≤3.9 mmol/L (≤70 mg/dL; OR 1.25, 95% CI 1.02–1.53) or <3.0 mmol/L (<54 mg/dL; OR 1.27, 95% CI 1.06–1.53) or severe hypoglycemia, A1C target achievement regardless of hypoglycemia (OR 1.21, 95% CI 1.01–1.44), and achievement of no documented symptomatic hypoglycemia at either ≤3.9 mmol/L (≤70 mg/dL; OR 1.23, 95% CI 1.04–1.46) or <3.0 mmol/L (<54 mg/dL; OR 1.25, 95% CI 1.02–1.52) or severe hypoglycemia.

Among those with no concomitant sulfonylurea use, the most favorable trends with Gla-300 versus SOC-BI were seen for achievement of no documented symptomatic hypoglycemia <3.0 mmol/L (<54 mg/dL) or severe hypoglycemia at 6 months (OR 1.20, 95% CI 0.83–1.73) and 12 months (OR 1.27, 95% CI 0.94–1.71) (Figure 2A). Because of the smaller sample size of this subgroup compared with users of a concomitant sulfonylurea, OR-associated 95% CIs were wider. ORs for treatment comparison in both subgroups were generally consistent with those in the overall study population, and no subgroup interactions were identified for any of the end points.

Of the 3,224 randomized participants who qualified for the GLP-1 receptor agonist subgroup analysis, 428 (13.3%) received a concomitant GLP-1 receptor agonist, making this the smallest subgroup. Of the 3,273 randomized participants who qualified for the DPP-4 inhibitor subgroup analysis, 1,276 (39.0%) received a concomitant DPP-4 inhibitor. Of the 3,215 randomized participants who qualified for the SGLT2 inhibitor subgroup analysis, 756 (23.5%) received a concomitant SGLT2 inhibitor. Participants who started therapy at or after randomization were excluded (n = 80 for GLP-1 receptor agonist, n = 31 for DPP-4 inhibitor, and n = 89 for SGLT2 inhibitor therapy). Baseline characteristics were well balanced between treatment groups in all three analyses (Tables 1 and 2).

Observed attainment rates for the composite end points were numerically higher for Gla-300 versus SOC-BI at both 6 and 12 months for both concomitant GLP-1 receptor agonist users versus nonusers (Figure 3) and concomitant DPP-4 inhibitor users versus nonusers (Figure 4). ORs were consistent with those in the overall study population, generally showing favorable trends for Gla-300 versus SOC-BI (Figures 2B and 5A).

Observed attainment rates of the end points for concomitant SGLT2 inhibitor users versus nonusers were similar for those who received Gla-300 or SOC-BI with the exception of absence of documented symptomatic hypoglycemia or severe hypoglycemia (Figure 6). OR estimates for concomitant SGLT2 inhibitor users did not suggest a greater benefit of Gla-300 versus SOC-BI for any of the efficacy end points tested (Figure 5B). There were no statistically significant subgroup interactions for any of the analyses except for absence of documented symptomatic hypoglycemia <3.0 mmol/L (<54 mg/dL) or severe hypoglycemia at 12 months for the SGLT2 inhibitor analysis (P = 0.0446). CIs were wide due to the relatively small sample sizes of participants who used concomitant GLP-1 receptor agonist, DDP-4 inhibitor, or SGLT2 inhibitor therapy.

In these post hoc analyses of the prospective, randomized, pragmatic, real-life ACHIEVE Control study, we evaluated clinical outcomes for Gla-300 versus SOC-BI in adults using various background therapies, namely a sulfonylurea, GLP-1 receptor agonist, DPP-4 inhibitor, or SGLT2 inhibitor.

Sulfonylureas were used concomitantly by ∼70% of the study population, suggesting that, in real-world clinical practice, the concomitant use of sulfonylureas with insulin remains widespread despite sulfonylureas being associated with an increased risk of hypoglycemia (7). This analysis shows that, among participants treated with insulin and concomitant sulfonylureas, ORs consistently favored Gla-300 versus SOC-BI for all end points, suggesting that the use of Gla-300 may improve A1C target achievement without hypoglycemia and may be associated with lower risk of hypoglycemia versus first-generation BIs for this participant subgroup. This strategy may allow patients better control of their diabetes, which data suggest is associated with prevention of microvascular and macrovascular complications, while also limiting the risk of the serious impact of hypoglycemia on day-to-day life.

This potential benefit of Gla-300 compared with first-generation BI analogs is likely attributable to its prolonged and flatter PK and PD profiles (12). Although ORs for users of concomitant GLP-1 receptor agonist, DPP-4 inhibitor, or SGLT2 inhibitor therapy were associated with wide 95% CIs due to small sample sizes, our findings suggest that the hypoglycemia benefits of Gla-300 versus SOC-BI observed at 12 months in the overall study population were maintained in users of concomitant GLP-1 receptor agonist or concomitant DPP-4 inhibitor therapy and included a greater likelihood of remaining without serious or severe hypoglycemia at 12 months. Just under one-fourth of the ACHIEVE Control population used an SGLT2 inhibitor as background therapy, but the ORs in this subgroup did not support a greater benefit of Gla-300 versus SOC-BI for any end point, being similar for Gla-300 and SOC-BI.

The main limitation of these subgroup analyses is that all end points other than the composite primary end point for the overall study population were exploratory and did not qualify for statistical analysis of superiority due to the lack of prospective adjustments for multiple testing. Thus, interpretation of the results is limited by both multiple testing and variable statistical power, and the findings should be considered hypothesis-generating only.

Particularly in subgroups with small sample sizes such as users of concomitant GLP-1 receptor agonist or SGLT2 inhibitor therapy, ORs were associated with wide 95% CIs. The low percentage of patients on a GLP-1 receptor agonist could be explained by the time at which this study was initiated. At this time, use of GLP-1 receptor agonists in particular was not as widespread as it is today. Because of the statistical limitation of these post hoc analyses, OR estimates should not be used to infer efficacy differences between treatment groups.

It is also important to note that, with the exception of one exploratory end point in the SGLT2 inhibitor analysis, subgroup interactions were not statistically significant, consistent with large overlaps of the 95% CIs of ORs in binary subgroup analyses. Therefore, OR estimates suggesting potential differences in the comparative effectiveness of Gla-300 versus SOC-BI between binary subgroups (particularly in the SGLT2 inhibitor subgroup analyses) require confirmation in appropriately designed and powered prospective studies.

Another limitation is that information on the number of patients on maximal doses was not collected. Although treatment comparisons were adjusted for stratification factors and use-by-treatment interaction, outcomes in specific subgroups may have been influenced by use of additional background therapies. Thus, the results should be interpreted with caution when assessing the merit of using specific background therapies concomitantly with BIs.

Other limitations of these analyses were that, owing to the real-world design of the primary study, insulin titration was not mandated, and adjustment of background medication therapy after trial entry was at the discretion of the health care professional. Thus, it was not possible to assess treatment compliance. However, insulin doses were similar for both treatment arms throughout the study. The study had only three mandated visits, and as a result, participants were not assessed by their health care provider at regular mandated visits, but rather every 3–6 months.

To summarize, the results of these exploratory subgroup analyses were generally consistent with previously published findings from the primary analysis of the ACHIEVE Control study for the overall study population (16,17), suggesting similar benefits of Gla-300 versus SOC-BI (to varying degrees) for all subgroups except users of a concomitant SGLT2 inhibitor, for whom OR point estimates suggested similar effectiveness of Gla-300 and SOC-BI. Thus, the results suggest that the improved PK/PD profile of Gla-300 renders it a safe and effective BI for use in combination with insulin secretagogues, as well as with incretin-based and SGLT2 inhibitor therapies.

Our findings confirm that concomitant use of sulfonylureas with BIs remains common practice despite the increased risk of hypoglycemia and guidance that sulfonylurea therapy should be dose-reduced or discontinued when BI therapy is initiated (3). Importantly, we found that users of concomitant sulfonylureas achieved better outcomes with Gla-300 than with SOC-BI in the ACHIEVE Control study. These results suggest that, when individuals with type 2 diabetes use BI therapy in combination with sulfonylureas, Gla-300—a second-generation BI analog with a prolonged and more stable PK/PD profile (12)—is more likely than first-generation BI analogs to mitigate serious or severe hypoglycemia. This strategy may facilitate optimal dosing of BI and thereby support the goal of achieving better glycemic outcomes.

This study was funded by Sanofi. Medical writing support was provided by Roland Tacke, PhD, and Helen Jones, PhD, CMPP, of Evidence Scientific Solutions, Inc., and funded by Sanofi.

T.S.B. received research support from Abbott Diabetes, Abbott Rapid Diagnostics, Biolinq, Capillary Biomedical, Dexcom, Eli Lilly, Kowa, Lexicon, Livongo, Medtronic, Medtrum, Novo Nordisk, REMD, Sanofi, Sanvita, Viacyte, vTv Therapeutics, and Zealand Pharma; is a consultant for Abbott, Lifescan, Novo Nordisk, and Sanofi; and is a speaker for BD, Medtronic, and Sanofi. P.E., J.G., and P.B. are employees and stockholders of Sanofi. R.R. is a biostatistician (as a contractor) for Sanofi. J.S. is on the advisory board of Merck, Novo Nordisk, and Sanofi and is a speaker for Abbott, the American Diabetes Association, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk, Salix, and Sanofi. E.E.W. is on the speakers’ bureau of Abbott Diabetes, Boehringer Ingelheim, and Eli Lilly; on advisory boards for Abbott Diabetes, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Mannkind, Merck, PTS Diagnostics, Sanofi, and Voluntis; and serves as a consultant for Abbott Diabetes, Boehringer Ingelheim, Eli Lilly, and Voluntis. No other potential conflicts of interest relevant to this article were reported.

T.S.B., P.E., J.G., P.B., J.S., and E.E.W. contributed to research data, contributed to manuscript development and discussion, reviewed/edited the manuscript, and approved the final version of the manuscript. R.R. defined, provided, and interpreted the statistical analyses for these data; reviewed/edited the manuscript; and approved the final version of the manuscript. T.S.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Parts of this study were presented at the American Association of Clinical Endocrinologists’ 28th Annual Meeting & Clinical Congress, 24–28 April 2019, and published in abstract form in Endocrine Practice 2019;25(Suppl. 1):138–139 (abstract 322).