Glimepiride not inferior to linagliptin? No, even superior from a public health perspective

In issue 42 of Diabetes Care released on December 2019, Matthew C. Riddle wrote the article “A Verdict for Glimepiride: Effective and Not Guilty of Cardiovascular Harm”.¹

Riddle points out that the cardiovascular safety of sulfonylureas has been debated for nearly 50 years. He notes that, now, two convincing comparisons showed the former “neither an increase nor a decrease of risk with linagliptin versus placebo”, the second “the lack of excess cardiovascular risk with glimepiride versus linagliptin”. Taken together, these results “strongly suggests a neutral [cardiovascular] effect overall for glimepiride”.¹

Correctly, he notes that, though glimepiride gave more hypoglycemia than linagliptin, “the frequency of hypoglycemia accompanying use of glimepiride […] cannot reliably be extrapolated to routine clinical practice. Because […] many participants had HbA1c 7.0% (53 mmol/mol) at entry yet were assigned an aggressive titration regimen. […] In clinical practice, an additional oral therapy is likely to be added only when HbA1c is at least 7.0%. […] With the less aggressive dosing generally used […] in clinical practice, the frequency of hypoglycemia with glimepiride is likely to be substantially lower”.

Note that the aggressive hypoglycemic treatment in the CAROLINA trial² (mean baseline HbA1c 7.2%) is questionable, because a target of HbA1c <7% is associated with an increase in mortality,^3,4 without convincing benefits.⁵

Riddle’s conclusions are: “high tolerability and safety were confirmed for both glimepiride and linagliptin, supporting the use of either as a second agent following metformin when maintaining glycemic control to prevent complications of diabetes is the main goal.”

However, we think that there are two reasons to choose glimepiride over linagliptin (or other DPP-4 inhibitors). The first is the opportunity cost (e.g., in Italy linagliptin costs nearly 19 times more than glimepiride). Decision-makers at the macrolevel and clinicians at the microlevel should consider the net results of any allocative or prescribed intervention, deducting from the expected benefits the harms of displacing equivalent resources that could be used for other cost-effective interventions. There are many underused interventions for diabetic patients’ health with low costs per Quality Adjusted Life Years (QALY) that could be considered before choosing a DPP-4 inhibitor. For example, a motivational interview or exercise prescription to increase physical activity6 or a 5-minutes brief intervention plus self-help for smoking cessation⁶ are much less expensive per QALY than a costly drug.

The second reason is the uncertainty of the results. Indeed, the two fundamental trials about linagliptin are industry funded, and metaepidemiological research showed that industry-sponsored studies more often had favourable efficacy results (relative risk – RR 1.27; 95%CI 1.17-1.37) and favourable conclusions (RR 1.34; 95%CI 0.64-2.93) compared with non-industry-sponsored studies.⁷ Industry-sponsored studies also showed a tendency of similar magnitude towards more favourable harm results (RR 1.37; 95%CI 0.64-2.93).7 Moreover, financial ties of principal investigators to the manufacturer of a study drug were associated with positive outcomes (odds ratio 3.57; 1.7-7.7),⁸ and both the principal investigators and the other authors of the two cited trials about linagliptin^2,9 were in ties with linagliptin manufacturers or employed by one of them.

Each of the above-mentioned characteristics can reduce the confidence in their favourable/non-inferior results. An indication of the presence of such possible bias is the choice of a less appropriate comparator.¹⁰ At the time of the design of CAROLINA trial,² a gold standard comparator should have been preferably gliclazide, with relative rates of hypoglycaemia and severe hypoglycaemia of 4.6% and 0.85/1,000 person years respectively, versus 11.5% and 0.86/1,000 person years for glimepiride,¹¹ and with robust safety results in one of the larger diabetes trial.¹²

Conflicts of interest: none declared.

References

1. Riddle MC. A Verdict for Glimepiride: Effective and Not Guilty of Cardiovascular Harm. Diabetes Care. Diabetes Care 2019;42(12):2161-63.
2. Rosenstock J, Kahn SE, Johansen OE, et al. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA 2019;322(12):1155-66.
3. Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 2010;375(9713):481-89.
4. Nichols GA, Joshua-Gotlib S, Parasuraman S. Glycemic control and risk of cardiovascular disease hospitalization and all-cause mortality. J Am Coll Cardiol 2013;62(2):121-27.
5. Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev 2013;(11):CD008143.
6. Owen L, Morgan A, Fischer A, Ellis S, Hoy A, Kelly MP. The cost-effectiveness of public health interventions. J Publ Health (Oxf) 2012;34(1):37-45.
7. Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev 2017;(2):MR000033.
8. Ahn R, Woodbridge A, Abraham A, et al. Financial ties of principal investigators and randomized controlled trial outcomes: cross sectional study. BMJ 2017;356:i6770.
9. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA 2019 Jan 1;321(1):69-79.
10. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326(7400):1167-70.
11. Tayek J. SUR receptor activity vs. incidence of hypoglycaemia and cardiovascular mortality with sulphonylurea therapy for diabetics. Diabetes Obes Metab 2008;10(11):1128-29; author reply 1129-30.
12. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358(24):2560-72.