The choice of medication for dual-combination therapy when the treatment with metformin alone is inadequate: DiaSTATUS-2 trial outcomes

Czech version

Authors: Emil Martinka
Authors‘ workplace: Národný endokrinologický a diabetologický ústav, n. o., Ľubochňa
Published in: Forum Diab 2019; 8(2): 117-127
Category: Review Article

Overview

The DiaSTATUS-2 trial was a randomized, multicentric, non-interventional, cross-sectional, retrospective study in patients with type 2 diabetes mellitus to determine the status of glycemic control at the time of intensification of the previous metformin monotherapy and the most common choice of another group of antidiabetic agents for a combination at the time of intensification, in the routine clinical practice at diabetic outpatient clinics across Slovakia, with a balanced representation of individual regions. A parallel question was to find out whether these parameters differ with respect to the presence of cardiovascular disease, the HbA_1c value, and the duration of type 2 diabetes mellitus. As in other countries, the study pointed to a significant clinical inertia in the process of intensification of metformin therapy. The average HbA_1c value at the time of intensification was HbA_1c 8.06 ± 0.98 %, while HbA_1c values averaged > 7.35 % for more than a year before intensification. In selecting the second drug, sulfonylurea-based drugs, followed by DPP4i and insulin, were most commonly used. For CVD-free patients, who were nearly 69.1%, this choice is acceptable, especially if the preferred sulfonylurea formulation was Gliclazide MR which presents a risk of hypoglycaemia and weight gain comparable to DPP4i, and therefore is the preferential choice for sulfonylurea-based therapy in other countries and in several therapeutic recommendations. On the other hand, in patients with cardiovascular disease (CVD⁺), who were 30.9%, no essential difference was found compared to CVD-free patients with regard to choosing pharmacotherapy, including cardioprotective SGLT2 and GLP1Ra, although their preference is recommended. While the use of SGLT2i in a dual combination with metformin is still limited by the wording of the indication limitations (ILs), also GLP1Ra are only minimally used, although IOs allow such choice. Conversely, also in the CVD⁺ group, sulfonylurea was still very frequently used in a dual combination, although its cardiovascular safety (with the exception of Gliclazide MR) is being discussed until now. Also in the DIASTATUS-2 study, Gliclazide MR0 which has an EBM confirmed cardiovascular safety and renal benefit, predominated among the sulfonylurea preparations. The DIASTATUS-2 study mainly pointed to the persistent clinical inertia which, similarly to patient adherence, is a significant factor affecting both medical and economic efficacy of the treatment outcomes, in this country as well as abroad. Therefore this issue should be systematically addressed.

Keywords:

choice of treatment after metformin – type 2 diabetes

Sources

Patel A, MacMahon S, Chalmers J et al. [ADVANCE Collaborative Group]. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24): 2560–2572. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa0802987>.
[American Diabetes Association]. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes. 2018 Diabetes Care 2018; 41(Suppl 1): S73–S85. Dostupné z DOI: <https://doi.org/10.2337/dc18-S008>.
Brown JB1, Conner C, Nichols GA. Secondary Failure of Metformin Monotherapy in Clinical Practice. Diabetes Care 2010; 33(3): 501–506. Dostupné z DOI: <http://dx.doi.org/10.2337/dc09–1749>.
Calvert MJ, McManus RJ, Freemantle N et al. Management of type 2 diabetes with multiple oral hypoglycaemic agents or insulin in primary care: retrospective cohort study. Br J Gen Pract 2007; 57(539): 455–460
Carls G, Huynh J, Tuttle E et al. Achievement of Glycated Hemoglobin Goals in the US Remains Unchanged Through 2014. Diabetes Ther 2017; 8(4): 863–873. Dostupné z DOI: <http://dx.doi.org/10.1007/s13300–017–0280–5>.
Davies MJ, D’Alessio DA, Walter JF et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018; 61(12): 2461–2498. Dostupné z DOI: <https://doi.org/10.1007/s00125–018–4729–5>.
[Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group]. Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT/EDIC Study 30-year follow-up. Diabetes Care 2016; 39(5): 686–693. Dostupné z DOI: <http://dx.doi.org/10.2337/dc15–1990>.
Desai U, Kirson NY, Kim J et al.Time to Treatment Intensification After Monotherapy Failure and Its Association With Subsequent Glycemic Control Among 93,515 Patients With Type 2 Diabetes. Diabetes Care 2018; 41(10): 2096–2104. Dostupné z DOI: <https://doi.org/10.2337/dc17–0662>.
Esposito K, Chiodini P, Bellastella G et al. Proportion of patients at HbA1c target <7% with eight classes of antidiabetic drugs in type 2 diabetes: systematic review of 218 randomized controlled trials with 78 945 patients. Diabetes Obes Metab 2012; 14(3): 228–233. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1463–1326.2011.01512.x>.
Folse HJ, Mukherjee J, Sheehan JJ et al. Delays in treatment intensification with oral antidiabetic drugs and risk of microvascular and macrovascular events in patients with poor glycaemic control: an individual patient simulation study. Diabetes Obes Metab 2017; 19(7): 1006–1013. Dostupné z DOI: <http://dx.doi.org/10.1111/dom.12913>.
Fu AZ, Qiu Y, Davies MJ et al. Treatment intensification in patients with type 2 diabetes who failed metformin monotherapy. Diabetes Obes Metab 2011; 13(8): 765–769. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1463–1326.2011.01405.x>.
Cathelineau G, de Champvallins M, Bouallouche A et al. Management of newly diagnosed non-insulin-dependent diabetes mellitus in the primary care setting: effects of 2 years of gliclazide treatment— the diadem study. Metabolism 1997; 46(12 Suppl 1): 31–34. Dostupné z DOI: <https://doi.org/10.1016/S0026–0495(97)90314–0>.
Harris MI, Klein R, Welborn TA et al. Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 1992; 15(7): 815–819.
Hillier TA, Pedula KL. Characteristics of an Adult Population With Newly Diagnosed Type 2 Diabetes. Diabetes Care 2001; 24(9): 1522–1527.
Holman RR, Paul SK, Bethel MA et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15): 1577–1589. Dostupné z DOI: Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa0806470.
Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55(6): 1577–1596. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–012–2534–0>.
Jones S, Benroubi M, Castell C et al. Characteristics of patients with type 2 diabetes mellitus initiating insulin therapy: baseline data from the INSTIGATE study. Curr Med Res Opin 2009; 25(3): 691–700. Dostupné z DOI: <http://dx.doi.org/10.1185/03007990902739669>.
Khunti K, Godec TR, Medina J et al. Patterns of glycaemic control in patients with type 2 diabetes mellitus initiating second‐line therapy after metformin monotherapy: Retrospective data for 10 256 individuals from the United Kingdom and Germany. Diabetes Obes Metab. 2018; 20(2): 389–399. Dostupné z DOI: <http://dx.doi.org/10.1111/dom.13083>.
Khunti K., Wolden ML et al. Clinical Inertia in People With Type 2 Diabetes. A retrospective cohort study of more than 80,000 people. Diabetes Care 2013; 36(11): 3411–3417. <http://dx.doi.org/10.2337/dc13–0331>.
Liebl A, Mata M, Eschwège E. [ODE-2 Advisory Board]. Evaluation of risk factors for development of complications in Type II diabetes in Europe. Diabetologia 2002; 45(7): S23–S28. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–002–0863–0>.
Martinka E, Tkáč I, Mokáň M. Interdisciplinárne štandardy diagnostiky a liečby diabetes mellitus, jeho komplikácií a najvýznamnejších sprievodných ochorení. Forum Diab 2018; 7(2 Suppl 1): S5-S153.
Martinka E. Kardiovaskulárna morbidita a mortalita pacientov s diabetes mellitus 2. typu na Slovensku. Výsledky štúdie NEFRITI II. Edukačný portál SDiA 2019. Dostupné z WWW: <http://lekar.sdia.sk/sdia-lekarske-profesne-zdruzenie-aktuality/170/kardiovaskularna-morbidita-a-mortalita-pacientov-s-diabetes-mellitus-2-typu-na-slovensku-vysledky-studie-nefriti-ii/>.
Martinka E. Spektrum liečby a využívanie kardioprotektívnych molekúl u pacientov s diabetes mellitus 2. typu s prítomným kardiovaskulárnym ochorením na Slovensku. Výsledky štúdie NEFRITI II. Edukačný portál SDiA 2019. Dostupné z WWW: <http://lekar.sdia.sk/sdia-lekarske-profesne-zdruzenie-aktuality/177/spektrum-liecby-a-vyuzivanie-kardioprotektivnych-molekul-u-pacientov-s-diabetes-mellitus-2-typu-s-pritomnym-kardiovaskularnym-ochorenim-na-slovensku-vysledky-studie-nefriti-ii/>.
Martinka E, Plichtová M, Davani A et al. Charakteristiky pacientov s novodiagnostikovaným diabetes mellitus 2. typu na Slovensku. Výsledky prieskumu DiaSTATUS. Diab Obez 2018; 18(36): 9, 11–19.
Marso SP, Daniels GH et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes N Engl J Med 2016; 375: 311–322. Dostupné z WWW: <http://doi: 10.1056/NEJMoa1603827>.
NCZI. Činnosť kardiologických ambulancií v SR 2016. Dostupné z WWW: <http://www.nczisk.sk/Documents/publikacie/2016/sp1705.pdf>.
MZ SR. Zoznam kategorizovaných liekov 1. 5. 2019–31. 5. 2019. Dostupné z WWW: <http://www.health.gov.sk/Clanok?lieky201905>.
Paul SK, Klein K, Thorsted BL et al. Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes. Cardiovasc Diabetol 2015; 14: 100. Dostupné z DOI: <http://dx.doi.org/10.1186/s12933–015–0260-x>.
Ponto KA, Koenig J, Peto T et al. Prevalence of Diabetic Retinopathy in Screening-Detected Diabetes Mellitus: Results From the Gutenberg Health Study (GHS). Diabetologia 2016; 59(9): 1913–1919. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–016–4013–5>.
Rajpathak SN, Rajgopalan S, Engel SS. Impact of time to treatment intensification on glycemic goal attainment among patients with type 2 diabetes failing metformin monotherapy. J Diabetes Complications 2014; 28(6): 831–835. Dostupné z DOI: <http://dx.doi.org/10.1016/j.jdiacomp.2014.06.004>.
Strain WD, Cos X, Hirst M et al.Time to do more: Addresing clinical inertia in tje management of type 2 diabetes mellitus. Diabetes Res Clin Pract 2014; 105(3): 302–312. Dostupné z DOI: <http://dx.doi.org/10.1016/j.diabres.2014.05.005>.
UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance. Diabetologia 1991; 34(12): 877–890.
Watson L, Das R, Farquhar R et al. Consequences of delaying treatment intensification in type 2 diabetes: evidence from a UK database. Curr Med Res Opin 2016; 32(9): 1465–1475. Dostupné z DOI: <http://dx.doi.org/10.1185/03007995.2016.1157462>.
Zafar A, Davies M, Azhar A et al. Clinical inertia in management of T2DM. Prim Care Diabetes 2010; 4(4): 203–207. Dostupné z DOI: <http://dx.doi.org/10.1016/j.pcd.2010.07.003>.
Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes N Engl J Med 2015; 373(22): 2117–2128. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1504720>.