DIBATTITO N 4 Gliflozine nel DM1 Accusa. Marco Giorgio Baroni

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1 DIBATTITO N 4 Gliflozine nel DM1 Accusa Marco Giorgio Baroni Endocrinologia e Metabolismo Dipartimento di Medicina Sperimentale Sapienza Università di Roma

2 Il Prof Marco Giorgio Baroni dichiara di aver ricevuto negli ultimi due anni compensi o finanziamenti dalle seguenti Aziende Farmaceutiche e/o Diagnostiche: - Sanofi - Novo Nordisk - Abbott - Takeda Dichiara altresì il proprio impegno ad astenersi, nell ambito dell evento, dal nominare, in qualsivoglia modo o forma, aziende farmaceutiche e/o denominazione commerciale e di non fare pubblicità di qualsiasi tipo relativamente a specifici prodotti di interesse sanitario (farmaci, strumenti, dispositivi medico-chirurgici, ecc.).

3 Outline Abbiamo bisogno di terapie aggiuntive nel diabete di tipo 1? Ruolo SGLT2 inhibitors nel diabete di tipo 1 Problemi aperti e richiesta alla corte

4 Abbiamo bisogno di terapie aggiuntive nel diabete di tipo 1? Problemi aperti della terapia insulinica nel Diabete tipo 1

5 Annali AMD 2012 Target glicemico nel diabete di tipo 1

6 Current State of Type 1 Diabetes Treatment in the U.S.: Updated Data From the T1D Exchange Clinic Registry Miller KM et al. Diabetes Care 2015;38: Target glicemico nel Diabete tipo 1 Mean 22.5%

7 Severe Hypoglycemia and A1C: DCCT (1993), JDRF (2008), and STAR 3 (2010) Studies DCCT (intensive therapy): 62 per 100 pt-yrs, A1C(6.5 yr): 9.0% 7.2% JDRF CGM (adults, 1 subject excluded): 20.0 per 100 pt-yrs; A1C (6 mo): 7.5% 7.1% STAR 3 SAP (all ages): 13.3 per 100 pt-yrs; A1C (1 yr): 8.3% 7.5% DCCT. N Engl J Med. 1993;329: JDRF CGM Study Group. N Engl J Med. 2008;359: Bergenstal RM, et al. N Engl J Med. 2010;363:

8 Conway B et al. Diabetic Medicine 2010

9 Temporal patterns in overweight and obesity in Type 1 diabetes Conway B et al. Diabetic Medicine 2010

10 Variabilità glicemica in Diabetici Tipo 1 ben controllati JDRF-CGM. Diabetes Care 32 (8), 2009

11 Oral glucose tolerance test in T1DM Greenbaum et al Diabetes 2002

12 Problemi aperti della terapia del Target glicemico Ipoglicemie Aumento di peso Variabilità glicemica Iperglucagonemia diabete di tipo 1 Compliance (dosi ritardate/mancate/inerzia)

13 SGLT2i in type 1 diabetes Sodium-glucose co-transporter-2 (SGLT2) inhibitors impair renal glucose reabsorption, causing a substantial excretion of glucose in urine. Since the mechanism of action of SGLT2 inhibitors is insulin-independent, a significant effect of these drugs on glucose control should be expected if used in patients with type 1 diabetes. The glucosuria and osmotic diuresis induced by these drugs are associated in type 2 diabetic patients with weight loss and blood pressure lowering of 2 4 mm Hg.

14 Potential effects og SGLT2i in type 1 diabetes Reduction in HbA1c without increasing insulin doses Weight reduction Blood pressure reduction Protective effects on the kidney and cardiovascular system? Hypoglycemia? DKA?

15 Summary of the efficacy of sodium-glucose co-transporter inhibitors published in clinical trials in type 1 diabetes - 0.5% HbA1c; -1.5 kg weight; to -5 U/die insulin dose Yamada T et al. Diabetes Obes Metab. 2018;20:

16 Garg S et al. NEJM 2018 Glycated hemoglobin level <7.0% at week 24

17 DKA and SGLT2i in type 1 diabetes Perkins et al weeks, open-label with empaglifozin 25 mg, diabetes duration median 18.5 years: 2 cases of DKA (CSII users) Pieber et al weeks, open-label with empaglifozin ( mg), diabetes duration mean 21 years. increases in fasting concentrations of β-hydroxybutyrate with all doses of empagliflozin. Henry et al weeks, with canglifozin 100 mg or 300 mg, diabetes duration 22 years: the incidence of diabetic ketoacidosis (with hospitalization) was increased with both doses of canagliflozin: 4.3% (n=5/117) and 6% (n=7/117), respectively. Between 2004 Q1 to 2016 Q3, among type 1 diabetic individuals with an FDA reported adverse event listing an SGLT2i as suspect or concomitant, 67.1% had a report for DKA, compared with 1.2% among T1D individuals with a report filed for other drugs (Fadini et al 2017)

18 edka DKA is traditionally defined by the triad of hyperglycemia (250 mg/dl), anion-gap acidosis, and increased plasma ketones Euglycemic DKA (edka), defined as DKA without marked hyperglycemia (>200 mg/dl), is classically considered rare but this is perhaps a result of underrecognition and underreporting

19 Peters AL et al. Diabetes Care 2015 Casi di edka in DT1

20 Summary of the side effects of sodium-glucose co-transporter inhibitors published in clinical trials in type 1 diabetes Incidence rates of DKA are dose-dependent - Dapa: 1% 5 mg, 2% 10mg - Cana: 4.3% 100 mg, 6% 300 mg - Empa: increases in fasting β-hydroxybutyrate with all doses - Sota: 2.3% 200mg, 3.4% 400mg Yamada T et al. Diabetes Obes Metab. 2018;20:

21 HbA1c and Hypoglycemia Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European intandem2 Study) Danne T et al. Diabetes Care 2018

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23 Potential mechanisms of adjunctive therapy with SGLT2 inhibitors to promote ketosis and increase the risk of ketoacidosis in T1D patients

24 Bonner C et al Nat Med 2015

25 In Acromegaly a shift from glucose to fatty acid oxidation after enhanced GHinduced lipolysis is a hallmark pathogenic feature SGLT2i increase plasma ketone levels through enhanced fat oxidation and increased synthesis as a result of an increased glucagon-to-insulin ratio Above the enhanced free fatty acid flux through GH induced lipolysis, the addition of empagliflozin further promoted hepatic ketogenesis due to increased glucagon-to-insulin ratio and decreased renal clearance of ketone bodies, resulting in euglycemic ketoacidosis Ketaoacidosis is determined by the additive effects of both conditions (i.e., uncontrolled GH excess and SGLT2 inhibition) on free fatty acid and ketonebody metabolism.

26 Possible causes of DKA with SGLT2i in T1DM Insulin dose reduction SGLT2 is expressed in pancreatic alpha-cells, and SGLT2 inhibitors promote glucagon secretion A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels In the presence of risk factors (e.g., pump malfunctions, carbohydrate restriction, increased alcohol consumption), reductions in the insulin-to-glucagon ratio in patients treated with SGLT2 inhibitors may increase susceptibility to DKA

27 Henry RR, Diabetes Obes Metab. 2017

28 Henry RR, Diabetes Obes Metab. 2017

29 Conclusioni su SGLT2i nel T1DM Il ruolo degli inibitori del SGLT2 come terapia add-on in pazienti con diabete di tipo 1 è promettente, ma persistono questione aperte La relazione tra l uso di SGLT2 inibitori e lo sviluppo di DKA nel DT1 deve essere valutata attentamente: Serve un punto di equilibrio quando si decide di aggiustare la dose insulinica in un paziente con DT1 che inizi SGLT2-i. Il monitoraggio dei corpi chetonici deve essere considerato in pazienti che hanno sintomi di DKA o sono in condizioni cliniche predisponenti (affaticamento, dolori addominali, digiuno, vomito, attività fisisca, uso di alcool, febbre, riduzione della terapia insulinica). Si deve assicurare un adeguata dose insulinica con algoritmi clinici sul monitoraggio dei corpi chetonici, indipendentemente dalla glicemia

30 Richiesta di Sentenza Si chiede la condanna degli inibitori del SGLT2: ad anni 3 di ulteriori studi sugli effetti collaterali ad attività educazionale dedicata allo sviluppo di algoritimi di terapia insulinica dedicati