Expert guide to universe of choice after metformin – An evidence based approach Dr. A. K. Singh M.D (Medicine), D.M (Endocrinology) Consultant Endocrinologist G D Hospital & Diabetes Institute, Kolkata

Medicine Update Vol. 24; 1449-1457 2014

Choice after metformin failure... Pioglitazone AGI QR Bromo SUs DPP4 Inhibitors SGLT 2 Inhibitors GLP-1 Analogues Basal/premix Insulin How to answer this in evidence based era..? SUs vs DPP4I SUs vs SGLT2I DPP4I vs SGLT2I

Sulfonylureas – lessons learnt so far... Advantage Disadvantage Time tested – Since 1950 Robust glucose reduction in early stage Inexpensive RCT did’nt give bad CV signals “Gluco-centric “ without “Disease-centric” properties Durability – less (ADOPT) Hypoglycemia – major issue Weight gain Possible beta cell apoptosis ? Prevents ischemic preconditioning (Glibenclamide) Observational studies and meta-analysis shows increasingly bad CV signals Singh AK. Indian J Endocr Metab 2014;18:617-23

Gliptins – lessons learnt so far... Advantage Disadvantage A1c reduction at par with Met, SUs and SGLT-2I Minimal hypoglycaemia with weight neutrality or loss Possible pleiotropic benefit and beta cell protection Pancreatitis : not a great concern Bone friendly Meta-analysis of pooled data from phase 2/3 showed CV benefit RCT – TECOS, SAVOR TIMI & EXAMINE suggested CV neutrality Cost Possible off-target side effect Signals of higher CV mortality with VILDA in VIVIDD trial Increased heart failure hospitalisation with SAXA in SAVOR TIMI - ? Play of chance Arthritis - FDA Singh AK. Indian J Endocr Metab 2014;18:617-23

SGLT2I: Lessons learnt so far... Advantage Disadvantage A1c reduction at par with metformin, SU, Gliptins Durability seems superior to SU Wt loss superior to metformin and gliptins BP reduction robust than metformin and gliptins Robust reduction in CV death, hHF, all-cause mortality in EMPA-REG Genital and urinary infection Volume depletion with loop diuretics Postural hypotension with RAAB and diuretics Safety in elderly >75 yr Loosing effectiveness in renal insufficiency Bone health : ↑ PTH (fractures with Cana) EuDKA – very rare Singh AK. Indian J Endocr Metab, 2014;18:617-23

Increases (Tolbutamide) SUs and CV outcome Study comparison Impact on total/CV mortality UGDP Increases (Tolbutamide) UKPDS No Difference RECORD No Difference ADOPT No Difference ACCORD No Difference ADVANCE No Difference VADT No Difference ORIGIN No Difference

Where is the difficulty with SUs? To date, the large CV outcome trials have essentially assessed the impact of multiple combinations of glucose-lowering agents as part of an overall treatment regimen of intensive vs. conventional (e.g. UKPDS, ACCORD, ADVANCE & VADT, ORIGIN) Thus, a comparative understanding of the CV impact of the most widely used diabetes drugs is actually lacking. Discordantly, data from observational studies finds increased mortality with SUs.

Glipizide had intermediate risk Glibenclamide has worst outcome SUs and CV outcome Most neutral CV outcome data lies with Gliclazide followed by Glimepiride Glipizide had intermediate risk Glibenclamide has worst outcome Singh AK. Expert Review of Clinical Pharmacology; 2016

Head-to-head study SUs vs DPP4I SUs vs SGLT2I DPP4I vs SGLT2I

SUs vs Gliptins ( 12 Head-to-head studies) 12 Studies = 5 Sita, 4 Vilda, 1 Saxa, 1 Lina, 1 Alo (n=11000) A1C reduction# A1c <7%* Hypoglycaemia Weight gain Adverse effect CV events reduction Beta cell effect DPP4I produced less A1c reduction by 0.11% 9% less with DPP4I when trial <32 weeks 87% less with DPP4I 1.65 Kg less with DPP4I 21% less total adverse event with DPP4I 47% less with DPP4I Better PI/I ratio & HOMA-IR with DPP4I # DPP4I showed better efficacy when compared to 2nd gen SU and also in CKD patient * Same % of patient had A1C <7% when trial >32 weeks Zhang et al, Diabetes Metab Res Rev. 2013 Oct 5. Singh AK. IJEM, Sept-Oct 2014

CV Events: SU vs Gliptins (Met-analysis of head-to-head trials) Study (year) Duration (Week) Drug (dose) CV Events (% of patients) Arzona Ferreira et al, 2013 54 wk Sitagliptin (25 mg) 7.8 % Glipizide (2.5-20 mg) 9.2 % Filozof et al, 2010 52 wk Vildagliptin (100 mg) 1.4 % Gliclazide (80-320 mg) 2.4 % Gallwitz et al, 2012 104 wk Linagliptin (5 mg) 1.5 % Glimepiride (1-4 mg) 3.4 % Rosenstock et al, 2013 Alogliptin (25 mg) 0.5 % Glipizide (5-10 mg) 0.9 % Singh AK. IJEM, Sept-Oct 2014 Zhang et al, Diabetes Metab Res Rev. 2013 Oct 5. doi: 10.1002/dmrr.2482. [Epub ahead of print]

SU vs Gliptins – CV outcome 12 head-to-head trials, 5 Sitagliptin, 4 Vildagliptin, 1 Saxagliptin, 1 Linagliptin, 1 Alogliptin (n=11000) 4 looked for CV outcome 47% less with DPP4I Diabetes Metab Res Rev. 2013 Oct 5. doi: 10.1002/dmrr.2482. [Epub ahead of print] Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulphonylureas----A meta-analysis from randomized clinical trials. Zhang Y, Hong J, Chi J, Gu W, Ning G, Wang W.

Summary: SUs or DPP-4I? SUs and DPP-4I are both insulinotropic, but with different mechanisms. SUs may cause (severe) hypoglycamia, whereas DPP-4I don‘t. Whether SUs elicit cardio-vascular problems is still not known. By direct (head-to-head) comparison, DPP-4I are associated with less cardio-vascular events than SUs. Whether this indicates a harm of SUs or a benefit of DPP-4 inhibitors needs to be clarified from further CV outcome studies. CAROLINA may answer or at least enlighten further.

Head-to-head study SUs vs DPP4I SUs vs SGLT2I DPP4I vs SGLT2I

Singh AK. Indian J Endocr Metab 2014; 18(5): 617-623 (updated)

Apostolos et al, EASD Vienna 2013

Head-to-head study SUs vs DPP4I SUs vs SGLT2I DPP4I vs SGLT2I

Singh AK. Indian J Endocr Metab 2014; 18(5): 617-623 (updated)

Apostolos et al, EASD Vienna 2013

Conclusion Currently there is no compelling evidence to suggest that SUs (in particular gliclazide and possibly glimepiride) truely increases CV events. However, it is used primarily beacuse of its low cost. Nonetheless hypoglycemia is a major issue (least with gliclazide MR) Because of their advantages (no hypoglycaemia and no weight gain) and CV neutrality (SITA most neutral) DPP-4I are increasingly used instead of SUs. Undoubtly , DPP-4I are preferble in DKD patients and elderly population over all oral agents. SGLT-2I appears very encouraging in weight loss and BP reduction, apart from moderate efficacy. Robust outcome in EMPA-REG also gave great confidence in using this class as a whole. However, use in elderly and renal insuffiency is a great limitation. EuDKA is possible but rare. Pharmacovigilance is must.

Criteria for ideal oral drug after metformin... Efficacy Safety – short term – hypoglycemia long term – CV, All-cause, Cancer mortality Durability Good partner to insulin (eventually) Corrects the pathogenesis of T2DM – desirable Safe in co-morbid condition – DKD, CLD, IHD, CCF

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