Janssen Comments On Diabetes Article
Thanks for your article, “Look for Patterns To Optimize Insulin Therapy,” in the September issue of Pharmacy Practice News [page 23]. I work with Janssen Pharmaceuticals and wanted to provide some additional perspective and background information on Invokana (canagliflozin), the company’s sodium glucose co-transporter 2 (SGLT2) inhibitor, which the FDA approved earlier this year for adults with type 2 diabetes. The article included commentary from Dr. Eric Ip suggesting [that canagliflozin] produces only modest reductions in A1c. In fact, results across the global Phase III clinical program showed that both doses of [canagliflozin], when used as monotherapy or as combination therapy with other glucose-lowering medications, significantly improved glycemic control. For example, when used as monotherapy, [canagliflozin] 100 and 300 mg reduced A1c by 0.91% and 1.16%, respectively, compared with placebo. Furthermore, comparative studies have shown the [canagliflozin] 300-mg dosage provided greater improvements in blood glucose control compared with the commonly prescribed therapies glimepiride or sitagliptin. As briefly noted in the article, in addition to improved glycemic control, both doses of [canagliflozin] also produced significant reductions in the prespecified secondary end points of body weight and systolic blood pressure. For additional information on [canagliflozin’s] clinical results, please see http://www.multivu.com/players/English/60562-janssen-invokana/links/60562-K02CAN13156A-INVOKANA-Media-Fact-Sheet.pdf and Invokana safety information.
Chandler Chicco Agency, on behalf of
Janssen Pharmaceuticals, Inc.
Canagliflozin is a SGLT2 inhibitor, a novel class of medications used to treat type 2 diabetes mellitus and improve glycemic control.1 Canagliflozin lowers blood glucose levels by blocking the reabsorption of glucose in the kidneys.1 Although it has been shown to lower A1c levels,1 this reduction is relatively modest compared with that seen with other antihyperglycemic agents. According to the 2012 position statement regarding the management of hyperglycemia in patients with type 2 diabetes from the American Diabetes Association and the European Association for the Study of Diabetes, the therapeutic agents that have a “high” glucose-lowering effect include metformin, sulfonylureas, thiazolidinediones, GLP [glucagon-like peptide]-1 agonists and insulin.2 Metformin is considered the first-line oral medication for the treatment of type 2 diabetes2 and has proven to lower A1c levels by approximately 1.5% to 2%.3-8 The sulfonylureas include the agents glipizide, glyburide and glimepiride. Glipizide and glyburide decrease A1c by approximately 1.5% to 1.9%,9-11 whereas glimepiride was shown to lower A1c levels by approximately 1.1%.12 The thiazolidinedione pioglitazone was shown to lower A1c by 0.53% to 1.6%,13-21 with a majority of patients showing a decrease greater than 1%.13-18 The GLP-1 agonist liraglutide was shown to decrease A1c by 0.30% to 1.56%, with a majority of patients achieving greater than 1%.22-27 Finally, multiple studies have shown an A1c reduction of 1% to 2% for basal insulin in individuals with type 2 diabetes.10,27-32 Thus, metformin, sulfonylureas, thiazolidinediones, GLP-1 agonists and insulin are considered to have “high” A1c-lowering potential because most studies demonstrate an A1c lowering of at least 1%.
In comparison, canagliflozin was shown to decrease A1c levels, but not to the same consistent magnitude as metformin, sulfonylureas, pioglitazone, liraglutide and basal insulin. When used as monotherapy or as add-on therapy, canagliflozin was shown to reduce A1c by 0.60% to 1.03%.1,33-36 However, all but one study demonstrated an A1c reduction below 1%.1,33-36 Thus, because the A1c-lowering effect generally is between 0.5% and 1.0%, canagliflozin may be grouped into the “generally lower” A1c-reducing antihyperglycemic medications, along with meglitinides, DPP-4 inhibitors, α-glucosidase inhibitors, colesevelam and bromocriptine.2,33-36 Because canagliflozin is relatively new on the market, further data are needed to evaluate its long-term safety and to determine its place in type 2 diabetes management.
- Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2012;35(6):1364-1379.
- DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541-549.
- Setter SM, Iltz JL, Thams J, Campbell RK. Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a clinical review with a focus on dual therapy. Clin Ther. 2003;25(12):2991-3026.
- Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care. 1996;19(1):64-66.
- Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997;103(6):491-497.
- Fujioka K, Brazg RL, Raz I, et al. Efficacy, dose-response relationship and safety of once-daily extended release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Diabetes Obes Metab. 2005;7(1):28-39.
- Hermann LS, Kalen J, Katzman P, et al. Long-term glycaemic improvement after addition of metformin to insulin in insulin-treated obese type 2 diabetes patients. Diabetes Obes Metab. 2001;3(6):428-434.
- Simonson DC, Kourides IA, Feinflos M, Shamoon H, Fischette CT. Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicenter, randomized, placebo-controlled trials. The Glipizide Gastrointestinal Therapeutic System Study Group. Diabetes Care. 1997;20(4):597-606.
- Abraira C, Henderson WG, Colwell JA, et al. Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes. VA feasibility study on glycemic control and complications (VA CSDM). Diabetes Care. 1998;21(4):574-579.
- Berelowitz M, Fischette C, Cefalu W, Schade DS, Sutfin T, Kourides IA. Comparative efficacy of a once-daily controlled-release formulation of glipizide and immediate-release glipizide in patients with NIDDM. Diabetes Care. 1994;17(12):1460-1464.
- Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year, randomized, double-blind assessment of metabolic parameters and cardiovascular risk factors. Clin Ther. 2003;25(2):472-484.
- Wainstein J, Katz L, Engel SS, et al. Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2012;14(5):409-418.
- Charbonnel BH, Matthews DR, Schernthaner G, Hanefeld M, Brunetti P, QUARTET Study Group. A long-term comparison of pioglitazone and gliclazide in patients with type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial. Diabet Med. 2005;22(4):399-405.
- Rajagopalan R, Perez A, Ye Z, Khan M, Murray FT. Pioglitazone is effective therapy for elderly patients with type 2 diabetes mellitus. Drugs Aging. 2004;21(4):259-271.
- Scherbaum WA, Goke B; German Pioglitazone Study Group. Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study. Horm Metab Res. 2002;34(10):589-595.
- Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improved glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care. 2000;23(11):1605-1611.
- Rosenstock J, Kim SW, Baron MA, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9(2):175-185.
- Temboonkiat S, Satyapan N, Benjasuratwong Y, et al. Clinical efficacy of pioglitazone: generic vs. original product. J Med Assoc Thai. 2012;95(suppl 5):s58-s62.
- Perez A, Zhao Z, Jacks R, Spanheimer R. Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Curr Med Res Opin. 2009;25(12):2915-2923.
- Charbonnel B, Schernthaner G, Brunetti P, et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia. 2005;48(6):1093-1104.
- Garber A, Henry RR, Ratner R, et al. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13(4):348-356.
- Garcia-Hernandez P, Arechavaleta-Granell Mdel R, Yamamoto J, Falahati A, Gonzalez-Galvez G, Grupo de Investgadores de LEAD-3 en Mexico. [Liraglutide and glimepiride on glycaemic control in type 2 diabetes in the Mexican cohort (LEAD 3)]. Rev Med Inst Mex Sequro Soc. 2010;48(5):543-548.
- Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473-481.
- Zinman B, Gerich J, Buse JB, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009;32(7):1224-1230.
- Russel-Jones D, Vaag A, Schmitz O, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52(10):2046-2055.
- Kaku K, Rasmussen MF, Clauson P, Seino Y. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2010;12(4):341-347.
- Heise T, Tack CJ, Cuddihy R, et al. A new-generation ultra-long-acting basal insulin with a bolus boost compared with insulin glargine in insulin-naïve people with type 2 diabetes: a randomized, controlled trial. Diabetes Care. 2011;34(3):669-674.
- Ligthelm RJ, Gylvin T, DeLuzio T, Raskin P. A comparison of twice-daily biphasic insulin aspart 70/30 and once-daily insulin glargine in persons with type 2 diabetes mellitus inadequately controlled on basal insulin and oral therapy: a randomized, open-label study. Endocr Pract. 2011;17(1):41-50.
- Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets-the TITRATE study. Diabetes Obes Metab. 2009;11(6):623-631.
- Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28(2):260-265.
- Janka HU, Plewe G, Riccle MC, Kliebe-Frisch C, Schweitzer MA, YKi-Jarvinen H. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care. 2005;28(2):254-259.
- Devineni D, Morrow L, Hompesch M, et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012;14(6):539-545.
- Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Prac (1995). 2013;41(2):72-84.
- Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232-1238.
- Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomized, double-blind, phase 3 non-inferiority trial. Lancet. 2013;382(9896):941-950.
Amber A. Mann, PharmD/MPH Candidate, 2015
Touro University California College of Pharmacy
Eric J. Ip, PharmD, BCPS, CSCS, CDE
Associate Professor and Chair, Pharmacy Practice Department
Touro University California College of Pharmacy
Diabetes Specialist/Clinical Pharmacist
Kaiser Permanente Mountain View Clinics
Mountain View, California