Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial

Dandona, Paresh; Mathieu, Chantal; Phillip, Moshe; Hansen, Lars; Griffen, Steven C.; Tschöpe, D; Thorén, Fredrik; Xu, John; Langkilde, Anna Maria; Proietto, Joseph; Stranks, Stephen N; Chen, Roger; O’Neal, David N; Pape, Alexia; Forbes, Mark; Morbey, Claire; Luger, Anton; Hanusch, Ursula; Schnack, Christoph; Fliesser-Goerzer, Evelyn; Hoelzl, Bertram; Ebenbichler, Christoph; Prager, Rudolf; Gaal, Luc Van; Vercammen, Chris; Scheen, André; Duyck, Francis; Nobels, Frank; Ruige, Johannes; Aggarwal, Naresh; Woo, Vincent; St-Pierre, Bruno; Dumas, R; Hramiak, Irene; Elliott, Thomas; Hansen, Troels Krarup; Henriksen, Jan Erik; Gram, Jeppe; Lihn, Aina S.; Bruun, Jens Meldgaard; Saltevo, Juha; Taurio, Jyrki; Strand, Jorma; Valle, Timo T.; Nieminen, Sakari; Pietiläinen, Kirsi H.; Guerci, Bruno; Hadjadj, Samy; Cariou, Bertrand; Vergès, Bruno; Borot, Sophie; Penfornis, A.; Schaum, Thomas; Tschöepe, Diethelm; Marck, Cornelia; Horacek, Thomas; Rose, Ludger; Klausmann, Gerhard; Luedemann, Joerg; Appelt, Steffi; Aigner, Ulrich; Goebel, R; Behnke, Thomas; Ziegler, Anette‐Gabriele; Péterfai, É.; Kerenyi, Zsuzsanna; Oroszlán, Tamás; Kiss, G; Könyves, L.; Piros, Gyorgyi; Mosenzon, Ofri; Shehadeh, Naim; Adawi, Faiad; Wainstein, Julio; Dotta, Francesco; Piatti, PierMarco; Genovese, Stefano; Consoli, Agostino; Bartolo, Paolo Di; Mannucci, Edoardo; Giordano, Carla; Lapolla, Annunziata; Aguilar, Carlos Montoya; Esteban, Alberto; Ruiz, Bazzoni; Ramirez, Guillermo Mondragon; Orozco, Emilia Pelayo; Alejandro, Carlos; Alba, Stobschinski de; Pech, Carlos Medina; Ruiz, Jose Garza; Reyna, Leobardo Sauque; Esperón, Guillermo Llamas; Ruiz, Luis Alejandro Nevarez; Velázquez, Maricela Vidrio; Lozano, Fernando Flores; González, José Gerardo González; García-Hernández, Pedro Alberto; Araujo-Silva, Roberto; Espinosa, Efrain Villeda; Mistodie, Cristina; Popescu, Daniela; Constantin, Ciprian; Nicolau, Alina; Popa, Bogdan; Timar, Romulus; Serafinceanu, Cristian; Pintilei, Ella; Soto, Alfonso; Giménez, Margarita; Merino-Torres, Juan Francisco; Morales, Cristóbal; Mezquita, P.; Jendle, Johan; Tengmark, Bengt-Olov; Eriksson, Jan W.; Löndahl, Magnus; Eliasson, Björn; Gunstone, Anthony; Heller, Simon; Darzy, Ken; Mansell, Peter; Davies, Melanie; Reed, Rory; Browne, Duncan L.; Courtney, Hamish; Turner, Wayne M.; Blagden, Mark; McCrimmon, Rory J.; Bergenstal, Richard M.; Lane, Wendy; Lucas, Kathryn; White, Alexander; Bao, Shichun; White, Judith L.; Jantzi, Curtis; Rasouli, Neda; Ervin, William; Lewy-Alterbaum, Lorena; Handelsman, Yehuda; Miranda-Palma, Bresta; Cleland, Alan; Fink, Raymond; Rodbard, Helena W.; Nakhle, Samer; Greenberg, Craig; Schorr, Alan B.; Bays, Harold; Simmons, Debra L.; Klein, E.; Kane, Laurie A.; Fishman, Norman; Ipp, Eli; Garg, Satish K.; Bhargava, Anuj; Singh, Michelle Zaniewski; Rosenstock, Julio; Thrasher, James; Warren, Mark; Young, Laura; Aroda, Vanita R.; Pettus, Jeremy; Liljenquist, David R.; Busch, Robert S.; Wise, Jonathan; Kayne, David; Biggs, William C.

doi:10.1016/s2213-8587(17)30308-x

Cited by 248 publications

(388 citation statements)

References 34 publications

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“…Of the 12 adjudicated definite events, 10 were also reported as serious adverse events (Table 4) [46]. The percentage of time in range for placebo was unchanged while it increased from 43.2% to 52% and from 44.6% to 54.6% in dapagliflozin 5 mg and 10 mg, respectively.…”

Section: Sodium-glucose Co-transporter-2 Inhibitorsmentioning

confidence: 99%

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

Wright

Hirsch

2019

Diabet. Med.

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Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes-related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA 1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon-like peptide-1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium-glucose co-transporter-2 and dual sodium-glucose co-transporter-2 and -1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis-related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.

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Section: Sodium-glucose Co-transporter-2 Inhibitorsmentioning

confidence: 99%

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

Wright

Hirsch

2019

Diabet. Med.

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“…After 24 weeks of treatment, both doses of dapagliflozin significantly and to a similar extent reduced HbA1c levels compared to placebo: a 0.42% and a 0.45% reduction in the 5 and 10 mg dapagliflozin arms, respectively. Total daily insulin dose and body weight were likewise significantly reduced in the treatment arms compared to placebo [17]. …”

Section: Use Of Sglt2 Inhibitors In Type 1 Diabetic Patients: Effectsmentioning

confidence: 99%

“…However, of the 18 patients who had possible DKA, only 4 sought treatment for it at a medical facility. Of those 4, two did not meet the classical laboratory criteria for DKA and the other two did not have laboratory values available [17]. In the inTandem3 trial, there was a significantly higher rate of volume depletion, genital infection, urinary tract infection and serious/non-serious DKA in the sotagliflozin versus placebo group.…”

Section: Use Of Sglt2 Inhibitors In Type 1 Diabetic Patients: Safety mentioning

confidence: 99%

The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

Fattah

Vallon

2018

Drugs

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Type 1 diabetes mellitus is a difficult disease to treat due to the relative paucity of therapeutic options other than injectable insulin. The latter, however, can induce hypoglycemia, which has been linked to enhanced cardiovascular risk. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti-hyperglycemic medications that do not increase the hypoglycemia risk and are US Food and Drug Administration (FDA) approved in type 2 diabetes mellitus. SGLT2 inhibitors may also be of benefit in type 1 diabetic patients, in addition to insulin, although they have not yet been approved for this indication. By blocking SGLT2 in the early proximal tubules of the kidney, these drugs decrease renal glucose retention, which is enhanced in hyperglycemia, thereby improving blood glucose control, in type 1 and type 2 diabetic patents. Their low hypoglycemia risk is due to the compensating reabsorption capacity of another glucose transporter, SGLT1, in the downstream late proximal tubule and the body's metabolic counter-regulation, which remains intact during SGLT2 inhibition. When insulin dosage is lowered too much, SGLT2 inhibitors can enhance ketogenesis to the extent that the risk of diabetic ketoacidosis increases, particularly in type 1 diabetic patients. SGLT2 inhibitors improve the renal and cardiovascular outcome in type 2 diabetic patients. The mechanisms likely include a reduction in glomerular hyperfiltration, blood pressure, volume overload, and body weight, as well as lowering blood glucose without increasing the hypoglycemia risk. The same mechanistic effects are induced in type 1 diabetic patients. More studies are needed with SGLT2 inhibitors in type 1 diabetic patients, including renal and cardiovascular clinical outcome trials, to fully evaluate their therapeutic potential in this specific population.

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“…The incidence of hypoglycaemia was similar in dapagliflozin-treated and placebo groups and diabetic ketoacidosis occurred in 1%, 2% and 1% of patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. 25,26 Sotagliflozin is in phase 3 development, and this agent has notable SGLT1 and well as SGLT2 inhibitory activity. In the inTANDEM study, addition of sotagliflozin (400 mg) for 24 weeks reduced HbA1c (p<0.0001); the incidence of severe hypoglycaemia was similar in the treated (3%) and placebo (2.4%) groups and diabetic ketoacidosis occurred in 3% of patients receiving sotagliflozin and 0.4% of patients in the placebo group.…”

Section: … Newer Agentsmentioning

confidence: 99%

Impressions from EASD 2017

Day

2017

Br J Diabetes

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Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial

Cited by 248 publications

References 34 publications

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

Impressions from EASD 2017

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