Comparative effectiveness of second line oral antidiabetic medications on cardiovascular outcomes in type 2 diabetes
The Importance of Second Line Treatment in Type 2 Diabetes
About 463 million people worldwide (9.3%) have type 2 diabetes mellitus.1 In most people this disease is progressive, and it is associated with risks of multiple complications, including cardiovascular disease (CVD) and chronic kidney disease.2 Interventions that improve biomarkers of type 2 diabetes mellitus, such as glycated haemoglobin A1c (HbA1c), blood pressure, and lipid levels, can reduce the risk of these complications.3456
International clinical guidelines recommend additional drugs (second line treatment) if glycaemic control is inadequate after metformin monotherapy.789 A recent study of second line treatments for people with type 2 diabetes mellitus across 38 countries reported that the most commonly used oral drugs were dipeptidyl peptidase-4 (DPP-4) inhibitors (48.3%), sulfonylureas (40.9%), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors (8.3%).10 Of these oral treatments, SGLT-2 inhibitors are newer and more costly classes of drugs.11
In England, SGLT-2 inhibitors are recommended second line treatments in preference to other drug classes for some people with type 2 diabetes mellitus—those with pre-existing CVD, at high risk of CVD, or with kidney disease.7 For most people with type 2 diabetes mellitus, however, evidence on the comparative effectiveness of these alternative drugs classes, particularly in relation to reducing HbA1c levels, is insufficient to recommend a particular second line treatment.7
An international consensus statement9 and guidelines from the National Institute of Health and Care Excellence (NICE)7 therefore leaves the choice of second line treatment for most people with type 2 diabetes mellitus to clinicians and patients, which has led to wide variation across groups of primary care providers in England in the proportion of people prescribed each drug class.12 Current NICE (2022) guidelines recommend other antidiabetic treatments, such as insulin based therapy and glucagon-like peptide-1 receptor agonists, only if HbA1c levels are not controlled after second line treatment with oral antidiabetics.7 Hence in many countries, including England, the proportion of people with type 2 diabetes mellitus who are prescribed glucagon-like peptide-1 receptor agonists as second line treatment is low.101213
Limitations of Existing Evidence
Most randomised controlled trials assessing the effectiveness and safety of SGLT-2 inhibitors and DPP-4 inhibitors have randomised groups to an active intervention or placebo comparator.14151617181920212223242526 Therefore, although these trials reported fewer CVD and kidney events in people with and without type 2 diabetes mellitus allocated to SGLT-2 inhibitors, the results are difficult to apply to routine clinical practice, where the relevant populations and comparators differ.161718192021222324
Of the randomised controlled trials with an active comparator, some compared DPP-4 inhibitors with sulfonylureas27282930 or compared SGLT-2 inhibitors with sulfonylureas,31 but none compared all three drug classes. Thus the comparative effectiveness of SGLT-2 inhibitors versus alternative second line oral antidiabetic treatments on outcomes important to people with type 2 diabetes mellitus, particularly reduction in HbA1c level, remains unclear.
Results from previous observational studies comparing these treatments323334 are at risk of bias from residual (unmeasured) confounding. Although a recent observational study35 emulated some of the results of the GRADE (Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness Study) randomised trial,293637 neither the trial nor the observational study considered SGLT-2 inhibitors, which limits the applicability of the results to routine clinical practice.
Leveraging Real-World Data for Comparative Effectiveness Research
Recent advances in real world data combined with developments in quantitative methods offer important opportunities for generating evidence on comparative effectiveness of treatments with direct relevance to clinical practice.35 In this study, we illustrated the potential and challenges of using real world data from Clinical Practice Research Datalink (CPRD) for these purposes.
We emulated the design of a hypothetical pragmatic randomised controlled trial by comparing three antidiabetic drug classes (sulfonylureas, DPP-4 inhibitors, and SGLT-2 inhibitors) of interest to the broad population of people with type 2 diabetes mellitus who, according to current NICE guidelines, are eligible for any of these second line treatments. We considered intermediate metabolic outcomes, particularly HbA1c level, but also kidney and cardiovascular related complications.
To reduce the risk of unmeasured confounding we used prescriber variation as an instrumental variable to estimate treatment effectiveness from routine data.3839 Our study complements a recent target trial emulation that assessed the comparative effectiveness of alternative second line treatments using data from the Department of United States Veterans Affairs,40 but which underrepresented female members of the population (100).3857
Findings from the PERMIT Study
The measured potential confounders were balanced across levels of the tendency to prescribe (assumption 2), aside from time period, which was included within the covariate adjustment of the instrumental variable analysis (see supplementary figures 2A-2C).
The crude change in mean HbA1c level from baseline to one year follow-up among people with observed follow-up measures was greatest for those prescribed sulfonylureas (-18 mmol/mol) compared with DPP-4 inhibitors (-10 mmol/mol) and SGLT-2 inhibitors (-14 mmol/mol; fig 3, also see supplementary figure 3).
The crude changes in mean BMI and systolic blood pressure from baseline were small across all time points (fig 3, also see supplementary figure 3). The crude change in mean eGFR from baseline to one year follow-up was similar across the three second line treatments of interest (-2 mL/min/1.73m2), with smaller decreases in mean eGFR across subsequent follow-up periods among people prescribed SGLT-2 inhibitors rather than sulfonylureas or DPP-4 inhibitors (fig 3, also see supplementary figure 3).
After accounting for confounding and missing data, SGLT-2 inhibitors were more effective in improving BMI and systolic blood pressure (fig 4). People prescribed SGLT-2 inhibitors showed a greater reduction in BMI between baseline and one year, with a mean difference of -1.6 (95% CI -1.7 to -1.4) compared with sulfonylureas and -0.8 (-1.0 to -0.7) compared with DPP-4 inhibitors. For systolic blood pressure, the mean difference was -2.1 mm Hg (95% CI -3.1 to -1.0) compared with sulfonylureas and -1.8 mm Hg (-3.0 to -0.5) compared with DPP-4 inhibitors, with these improvements maintained at two years follow-up.
SGLT-2 inhibitors led to a slower decline in eGFR at two years follow-up compared with sulfonylureas (mean difference 1.4 mL/min/1.73m2, 95% CI 0.5 to 2.3), but not compared with DPP-4 inhibitors (0.0 mL/min/1.73m2, -1.1 to 1.0).
People prescribed SGLT-2 inhibitors had lower crude rates of all adverse kidney, cardiovascular, and mortality events compared with those prescribed sulfonylureas and DPP-4 inhibitors (see supplementary table 9 and supplementary figures 4-9). After reducing the risk of confounding and addressing the missing data, we found that over two years follow-up (base case), SGLT-2 inhibitors were more effective in preventing a ≥40% decline in eGFR from baseline versus sulfonylureas (hazard ratio 0.42, 95% CI 0.22 to 0.81), but the estimated hazard ratios for SGLT-2 inhibitors compared with DPP-4 inhibitors were highly uncertain (0.64, 0.29 to 1.43) (fig 5).
The rates of admission to hospital for heart failure were lower for SGLT-2 inhibitors compared with sulfonylureas (0.46, 0.20 to 1.05) and with DPP-4 inhibitors (0.32, 0.12 to 0.85). For the other endpoints, we found no evidence of a difference in the comparative effectiveness of the second line antidiabetic treatments (fig 5, also see supplementary table 10).
Implications and Future Research
This study provides evidence that SGLT-2 inhibitors might offer clinically important benefits when provided in routine clinical practice compared with common alternative oral antidiabetic drugs that are added to metformin for people with type 2 diabetes mellitus. These findings apply to a wide range of people with type 2 diabetes mellitus and therefore complement the evidence available from randomised controlled trials161718192021222324 and previous studies that have emulated trials.3540
In recent updated guidelines, NICE and other health technology assessment agencies have published guidance and guidelines that are neutral about the use of SGLT-2 inhibitors versus DPP-4 inhibitors versus sulfonylureas as second line treatments, except for people at high risk of CVD, or for people with pre-existing CVD, including heart failure, or with kidney disease. For these subgroups, SGLT-2 inhibitors are recommended in addition to metformin. Our study reported similar advantages for SGLT-2 inhibitors (compared with sulfonylureas and DPP-4 inhibitors) as second line treatments for people who did not have pre-existing CVD as well as for those who did have CVD before second line treatment. Future guidelines could draw from this study and related evidence to also recommend SGLT-2 inhibitors for those without CVD, including those at relatively low risk of subsequent CVD.
More work is needed to understand the long term effectiveness and cost effectiveness of increasing the use of SGLT-2 inhibitors for people with type 2 diabetes mellitus. Future research can use the information from this study to predict whether SGLT-2 inhibitors can lead to sufficient improvement in long term outcomes—for example, from reduced incidence and costs of complications such as retinopathy, amputation, or end stage kidney disease, to justify any additional costs. Further research is also required to assess the comparative effectiveness of glucagon-like peptide-1 receptor agonists with the three alternative second line oral antidiabetic treatments among people with type 2 diabetes mellitus, and to assess how best to personalise the order in which these treatments are prescribed.
Conclusion
We found that for a broad population of people with type 2 diabetes mellitus, SGLT-2 inhibitors were more effective second line treatments in routine clinical practice compared with DPP-4 inhibitors or sulfonylureas in improving HbA1c levels, BMI, and systolic blood pressure. SGLT-2 inhibitors were also found to be more effective at reducing the hazards of hospital admission for heart failure (compared with DPP-4 inhibitors) and ≥40% decline in eGFR (compared with sulfonylureas). We did not find evidence for differences in the other study endpoints over the two year study period.
The IT Fix blog aims to provide practical, in-depth insights on technology, computer repair, and IT solutions from seasoned professionals. This article on the comparative effectiveness of second line oral antidiabetic medications highlights how real-world data and advanced analytical methods can generate important evidence to guide clinical practice, complementing the insights available from randomized controlled trials. By emulating the design of a target trial, this study overcomes limitations of prior observational research to offer timely, relevant insights on a topic of growing importance as diabetes prevalence rises globally.
