Currently Viewing:
Supplements Real-World Evidence in Type 2 Diabetes: Focus on SGLT2 inhibitors and GLP-1 Receptor Agonists
A Retrospective Real-World Study of Dapagliflozin Versus Other Oral Antidiabetic Drugs Added to Metformin in Patients with Type 2 Diabetes
Huan Huang, PhD; Kelly F. Bell, PharmD, MSPhr; Ray Gani, PhD; Cathy W. Tugwell, RN, BSN; James M. Eudicone, MS, MBA; and Michelle R. Krukas-Hampel, MA
Currently Reading
Eligibility Varies Among the 4 Sodium-Glucose Cotransporter-2 Inhibitor Cardiovascular Trials: Implications for the General Type 2 Diabetes US Population
Eric T. Wittbrodt, PharmD, MPH; James M. Eudicone, MS, MBA; Kelly F. Bell, PharmD, MSPhr; Devin M. Enhoffer, PharmD; Keith Latham, PharmD; and Jennifer B. Green, MD
Comparison of Low-Dose Liraglutide Use Versus Other GLP-1 Receptor Agonists in Patients Without Type 2 Diabetes
Eric T. Wittbrodt, PharmD, MPH; James M. Eudicone, MS, MBA; Sepehr Farahbakhshian, MS; and Carrie McAdam-Marx, PhD, MSCI, RPh
Real World Evidence in Type 2 Diabetes: Focus on SGLT2 Inhibitors and GLP-1 Receptor Agonist Participating Faculty

Eligibility Varies Among the 4 Sodium-Glucose Cotransporter-2 Inhibitor Cardiovascular Trials: Implications for the General Type 2 Diabetes US Population

Eric T. Wittbrodt, PharmD, MPH; James M. Eudicone, MS, MBA; Kelly F. Bell, PharmD, MSPhr; Devin M. Enhoffer, PharmD; Keith Latham, PharmD; and Jennifer B. Green, MD
Discussion

This retrospective study assessed the extent to which the results of completed or ongoing (at the time of the analysis) studies of CV safety for the SGLT2 inhibitor class of antihyperglycemic medications could be generalized to adults in the United States with T2D. Data for this study were derived from the NHANES, which is a nationally representative survey of health in the United States.32 The calculated prevalence of T2D of 11.8% was similar to that reported by the CDC for 2015 (9.4% of US adults with diagnosed diabetes, with virtually all of these having T2D).1 The slight disparity in prevalence observed could be due to various factors, such as the requirement for data on key eligibility criteria for those patients included in the denominator population in the present study.

This study found substantial differences in the extent to which the eligibility criteria, and hence the CV findings, of these CVOTs could be generalized to a real-world adult T2D patient population. Approximately 40% of the US adult T2D population identified via the weighted analysis of the NHANES data would have been eligible to participate in at least 1 of these 4 studies, but only the DECLARE-TIMI 58 study of dapagliflozin31,41 had eligibility criteria that would have included more than 10% of this population.

The 2008 FDA Guidance for Industry recommends that CV safety studies of novel T2D therapies include patients who are representative of those likely to receive the agent being investigated.14 It is recommended that participants include those at higher risk of CV events, including the elderly, and those with relatively advanced T2D or with some level of renal impairment.14 This is important, as patients with T2D are at a disproportionately high risk of death from CVD, with more than two-thirds of those at least 65 years of age dying from heart disease and approximately 15% from stroke,2,42 and they are also more likely than the general population to have risk factors for CVD, such as hypertension, dyslipidemia, or chronic kidney disease, in addition to diabetes.43 However, when CVOTs in T2D are planned, ideally the inclusion criteria should not be so restrictive as to jeopardize the applicability of findings from the study to patient populations that are encountered in real-world clinical practice.

As estimated by analyses of the NHANES data, the inclusion criteria in 3 of the studies were applicable to less than 10% of the US adult T2D population. All 3 of these CVOTs focused on patients who had a history of prior CVD or were considered to be at high risk of CV events (Table 1).29,30,33 The original CANVAS study included 2 subgroups of patients, one  in those at least 30 years of age with a history of symptomatic atherosclerotic vascular disease and one in those at least 50 years of age without a history of known CVD, but with 2 or more prespecified risk factors in addition to T2D.30 More than 10,000 adults (mean age, 63 years) were included in the combined CANVAS and CANVAS-R analysis,31 of whom 66% had a history of macrovascular atherosclerotic disease before the study.32 Adults aged at least 18 years could participate in the EMPA-REG OUTCOME trial, but only if they were at a high risk of CV events, which were defined by various criteria (including a history of myocardial infarction, and the presence of multivessel coronary artery disease [CAD] or of single-vessel CAD plus evidence, for example, of prior unstable angina, stroke, or peripheral artery disease).29 The study included more than 7000 patients at high risk of CV events with a mean age of 63 years.16,29 The VERTIS-CV Study included patients with T2D at least 40 years of age, but again with specific CVD-related criteria, which specified a history of coronary, cerebral, or peripheral atherosclerotic disease;33,37 data for the recruited patient population were not available at the time of writing this paper. By contrast, DECLARE-TIMI 58 included 2 subgroups, 1 of patients at least 40 years of age with a high risk of CV events because of a history of heart disease or stroke, and a broader subgroup group of women at least 60 years of age and men at least 55 years of age without a known history of CVD, but with at least 1 risk factor (dyslipidemia, hypertension, or tobacco smoking) in addition to T2D.31,40 More than 17,000 patients (mean age, 64 years) were randomized for this study; of these, almost 7000 (41%) had established CVD prior to enrollment, and the remainder had multiple CV risk factors.40 In DECLARE-TIMI 58, the definition of a T2D diagnosis was also broader than that in the other 3 studies (see Table 1). Patients were required to have been told by a physician that they had T2D and an A1C level of 6.5% to 12.0%.32 However, participation in the EMPA-REG OUTCOME trial required patients to have an A1C level of 7.0% to 9.0% if T2D-treatment–naïve or 7.0% to 10.0% if they were already taking antihyperglycemic medication,16 and for both CANVAS and VERTIS-CV, an A1C value of  7.0% to 10.5% was stipulated (Table 1).20,37 Therefore, the DECLARE-TIMI 58 study population comprised a broad population of middle-aged and older adults with T2D, including patients with established CVD or CVD risk factors.

The present analysis included available data for key study criteria from a representative sample of the US population. The results demonstrated that broader patient selection criteria allow enrollment of a study population that is more generalizable to a substantial proportion of US adults with T2D.

Study Limitations

As a retrospective database analysis, this study had a number of limitations. A selection bias of patients who volunteered to participate in the survey, who may not be representative of the general US patient population, could have resulted in inaccurate estimation of T2D prevalence in this analysis of the NHANES data. Although the present analysis excluded patients who were pregnant, and therefore those who could have currently had gestational diabetes, it did not exclude patients who might have had gestational diabetes during a previous pregnancy. Data on CHF were extracted from the present analysis as it can be indicative of CVD; however, this could have also captured CHF unrelated to CVD, although this would have probably impacted findings on generalizability equally across all 4 trials. Furthermore, diabetes diagnoses were allocated from self-reported data rather than from diagnosis or confirmation by treating physicians, and application of the trial definitions of T2D to the NHANES data may also have been imprecise (eg, where there were differences in the criteria used in each CVOT to define T2D and the data collected for the NHANES).

Data on some study eligibility criteria were not available from the NHANES, and guidelines for resolving issues of missing or differing ways of defining/recording criteria were therefore included in the analysis protocol (Appendix 2). However, in such cases, the omission or estimation of certain criteria using data acquired in other formats or from other survey responses would be expected to give only approximations for the numbers meeting the CVOT criteria in question. It is likely that such an approach would have had disproportionate effects on estimation of those meeting key CV eligibility criteria. Finally, this analysis did not consider differences in CVOT size, duration, or design.

Conclusions

There were considerable differences among the 4 SGLT2 inhibitor CVOTs in the proportions of patients in the US adult T2D population who would have met the eligibility criteria and, therefore, in the generalizability and applicability of these trials. The DECLARE-TIMI 58 trial was by far the most generalizable, with approximately 40% of this population potentially being eligible for inclusion; however, only 12% of US adult T2D patients would have been eligible for inclusion in any of the other trials. This analysis shows that it is important to bear in mind the differences in eligibility criteria when considering the generalizability and applicability of CVOTs for T2D medications to real-world populations.

Acknowledgements

Medical writing and editorial support was provided by Annie Rowe, Prime, UK, according to Good Publication Practice guidelines (available at http://annals.org/aim/fullarticle/2424869/good-publication-practicecommunicating-company-sponsored-medical-research-gpp3) and supported by AstraZeneca. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors.


Author affiliations: AstraZeneca, Wilmington, DE (KFB [at time of study], JME, KL, ETW); Rutgers University, Piscataway, NJ (DME); Division of Endocrinology, Duke University Medical Center, Durham, NC (JBG).
Funding source: This study was funded by AstraZeneca.
Author disclosures: Dr Bell reports employment with GlaxoSmithKline. Mr Enhoffer reports no relationships or financial interests with any entity that would pose a conflict of interest with the subject matter of this supplement. Mr Eudicone, Dr Latham, and Dr Wittbrodt report employment with AstraZeneca; the subject matter of this supplement pertains to an AstraZeneca product. Dr Green reports serving as a consultant for Boehringer Ingelheim Pharmaceuticals, Inc; Daiichi Sankyo Company, Limited; Merck Sharpe & Dohme Corp; and Novo Nordisk Inc, and reports receipt of research grants from AstraZeneca; GlaxoSmithKline plc; and Intarcia Therapeutics, Inc. 
Authorship information: Concept and design (KFB, JME, JBG, KL, ETW); acquisition of data (DME, ETW); analysis and interpretation of data (KFB, DME, JME, JBG, KL, ETW); drafting of the manuscript (DME); critical revision of the manuscript for important intellectual content (KFB, DME, JME, JBG, ETW); obtaining funding (KFB); administrative, technical, or logistic support (KL, ETW); supervision (ETW).
Address correspondence to: eric.wittbrodt@astrazeneca.com.
 
1. CDC. National diabetes statistics report, 2017 estimates of diabetes and its burden in the United States. CDC website. cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed March 19, 2018.
2. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-2222. doi: 10.1016/S0140-6736(10)60484-9.
3. Lathief S, Inzucchi SE. Approach to diabetes management in patients with CVD. Trends Cardiovasc Med. 2016;26(2):165-179. doi: 10.1016/j.tcm.2015.05.005.
4. American Diabetes Association. 8. Cardiovascular Disease and Risk Management. Diabetes Care. 2016;39(suppl 1):S60-S71. doi: 10.2337/dc16-S011.
5. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412. doi: 10.1136/bmj.321.7258.405
6. 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):2560-257. doi: 10.1056/NEJMoa0802987.
7. Marx N, Rosenstock J, Kahn SE, et al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res. 2015;12(3):164-174. doi: 10.1177/1479164115570301.
8. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232-242. doi: 10.1056/NEJMoa1501352.
9.Holman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228-1239. doi: 10.1056/NEJMoa1612917.
10. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559. doi: 10.1056/NEJMoa0802743.
11. Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. N Engl J Med. 2013;369(14):1285-1287. doi: 10.1056/NEJMp1309610.
12. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180-1188. doi: 10.1001/jama.298.10.1180.
13. Sardar P, Udell JA, Chatterjee S, Bansilal S, Mukherjee D, Farkouh ME. Effect of intensive versus standard blood glucose control in patients with type 2 diabetes mellitus in different regions of the world: systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2015;4(5): e001577. doi: 10.1161/JAHA.114.001577.
14. FDA. Guidance for Industry. Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. FDA website. www.fda.gov/downloads/Drugs/.../Guidances/ucm071627.pdf. Published December 2008. Accessed March 19, 2018.
15. Hirshberg B, Katz A. Cardiovascular outcome studies with novel antidiabetes agents: scientific and operational considerations. Diabetes Care. 2013;36(suppl 2):S253-S258. doi: 10.2337/dcS13-2041.
16. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.
17. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.
18. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141.
19. Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016;15:37. doi: 10.1186/s12933-016-0356-y.
20. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.
21. Mahaffey KW, Neal B, Perkovic V, et al; CANVAS Program Collaborative Group. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;137(4):323-334. doi: 10.1161/CIRCULATIONAHA.117.032038.
22. Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32(4):515-531. doi: 10.1210/er.2010-0029.
23. Cefalu WT, Stenlöf K, Leiter LA, et al. Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia. 2015;58(6):1183-1187. doi: 10.1007/s00125-015-3547-2.
24. Del Prato S, Nauck M, Durán-Garcia S, et al. Long-term glycaemic response and tolerability of
dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes Metab. 2015;17(6):581-590. doi: 10.1111/dom.12459.
25. Nauck MA, Del Prato S, Durán-Garcia S, et al. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab. 2014;16(11):1111-1120. doi: 10.1111/dom.12327.
26. Weber MA, Mansfield TA, Cain VA, Igbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211-220. doi: 10.1016/S2213-8587(15)00417-9.
27. Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16(10):984-993. doi: 10.1111/dom.12307.
28. Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004-1016. doi: 10.1016/S2213-8587(16)30267-4.
29. Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol. 2014;13:102. doi: 10.1186/1475-2840-13-102.
30. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217-223.e11. doi: 10.1016/j.ahj.2013.05.007.
31. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI 58). Clinicaltrials.gov website. https://www.clinicaltrials.gov/ct2/show/NCT01730534?term=TIMI+declare&rank=1. Accessed March 21, 2018.
32. Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: participants’ baseline characteristics. Diabetes Obes Metab. 2018 [published online January 11, 2018]. doi: 10.1111/dom.13217.
33. Cardiovascular outcomes following ertugliflozin treatment in type 2 diabetes mellitus participants with vascular disease, the VERTIS-CV Study (MK-8835-004). Clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01986881. Accessed March 21, 2018.
34. Schnell O, Standl E, Catrinoiu D, et al. Report from the 1st Cardiovascular Outcome Trial (CVOT) Summit of the Diabetes & Cardiovascular Disease (D&CVD) EASD Study Group. Cardiovasc Diabetol. 2016;15:33. doi: 10.1186/s12933-016-0357-x.
35. Questionnaires, datasets, and related documentation. CDC website. https://wwwn.cdc.gov/nchs/nhanes/Default.aspx. Accessed March 21, 2018.
36. About the National Health and Nutrition Examination Survey. Introduction. CDC website. https://www.cdc.gov/nchs/nhanes/about_nhanes.htm. Accessed March 21, 2018.
37. Cannon CP, McGuire D, Pratley R, et al. Design and baseline characteristics of the evaluation of ertugliflozin efficacy and safety cardiovascular outcomes trial (VERTIS-CV). J Am Coll Cardiol. 2018; 71(11): A1825. doi: 10.1016/S0735-1097(18)32366-0.
38. Mirel LB, Mohadjer LK, Dohrmann SM, et al. National Health and Nutrition Examination Survey:
estimation procedures, 2007-2010. Vital Health Stat 2. 2013(159):1-17.
39. Johnson CL, Paulose-Ram R, Ogden CL, et al. National Health and Nutrition Examination Survey: analytic guidelines, 1999-2010. Vital Health Stat 2. 2013(161):1-24.
40. National Health and Nutrition Examination Survey: analytic guidelines, 2011-2012. CDC website. https://wwwn.cdc.gov/nchs/data/nhanes/2011-2012/analytic_guidelines_11_12.pdf. Published September 30, 2013. Accessed March 21, 2018.
41. Raz I, Bonaca MP, Mosenzon O, et al. DECLARE-TIMI 58: design and baseline characteristics. Poster presented at: 77th Scientific Session of the American Diabetes Association; June 11, 2017; San Diego, CA. http://www.abstractsonline.com/pp8/#!/4297/presentation/44443. Accessed March 21, 2018.
42. Cardiovascular disease & diabetes. American Heart Association website. http://www.heart.org/HEARTORG/Conditions/More/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp/#.WhxMRTenyUk. Accessed March 21, 2018.
43. Fox CS, Golden SH, Anderson C, et al; American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Quality of Care and Outcomes Research; American Diabetes Association. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38(9):1777-1803. doi: 10.2337/dci15-0012.

 
PDF
 
Copyright AJMC 2006-2020 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up