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Role of Injectable Medications in Type 2 Diabetes Treatment.

The treatment of patients with diabetes mellitus took a huge leap forward a century ago with the discovery of insulin. Over the next 5 decades, insulin was used primarily in patients with type 1 diabetes mellitus (T1DM). As the supply of insulin grew, and with the advent of human insulin, the use of insulin in patients with type 2 diabetes mellitus (T2DM) became more common. Improving upon earlier insulin formulations, the development of analog insulins shifted the risk: benefit ratio by enabling better targeting of basal and prandial glucose requirements, as well as improved safety and tolerability. The availability of medications, most recently the glucagon-like peptide-1 receptor agonists (GLP-1 RAs), as well as oral agents such as the dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium glucose cotransporter-2 inhibitors (SGLT-2is), also provides opportunities to target treatment.

This article describes the roles of injectable glucose-lowering medications, specifically basal insulin and GLP-1 RAs, as recommended in current guidelines and the evidence supporting these recommendations. More detailed discussion of basal insulin and GLP-1 RAs can be found later in this supplement.


In 2006, the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) published the first algorithm for the metabolic management of patients with T2DM. (1) This consensus algorithm recommended lifestyle intervention and metformin as first-line therapy with insulin, sulfonylureas, and thiazolidinediones as second-line therapy. Insulin was preferred for patients with glycated hemoglobin (HbAlc) >8.5% or with symptoms secondary to hyperglycemia. Generally similar recommendations were provided in the 2007 guidelines issued by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) except that insulin should be added in patients with HbAlc 6.5% to 8.5% despite maximally tolerated combination therapy. (2) Despite the recommendation for insulin as second-line therapy, most primary care physicians avoided the use of insulin for patients with T2DM, instead preferring combinations of multiple oral medications. (3,4)

Jump ahead to 2017 and the role of insulin in T2DM has expanded. According to the ADA/EASD algorithm, basal insulin can be used in combination with metformin or as part of triple therapy in combination with metformin and either a sulfonylurea (SU), thiazolidinedione (TZD), DPP-4i, SGLT-2i, or GLP-1RA. (5) Also, insulin in combination with other agents should be considered when hyperglycemia is severe, particularly if the patient is symptomatic or exhibits catabolic features such as weight loss or ketosis. According to the ADA/ EASD algorithm, initiating combination insulin injectable therapy should be considered when the blood glucose is [greater than or equal to] 300 mg/dL or HbA1c is [greater than or equal to] 10% or if the patient has symptoms of hyperglycemia (ie, polyuria, polydipsia). (5) It is important to note that, in contrast to the 2006 ADA/EASD algorithm, there is no recommended HbA1c threshold for the use of insulin in combination with oral therapy in the 2017 algorithm. (5)

The 2017 AACE/ACE algorithm also indicates that insulin can be used as part of dual or triple therapy for patients with HbA1c [greater than or equal to] 7.5% (FIGURE). (6) In addition, insulin can be used alone or with other glucose-lowering agents for patients with an initial HbAlc >9.0%.


Much occurred from 2006 to 2017 that contributed to the expanded role of insulin in patients with T2DM. First, T2DM is now recognized as being a progressive disease such that the average patient with T2DM has only approximately 20% of pancreatic [beta]-cell function remaining at the time of diagnosis. (7) Consequently, treatment intensification is generally required. (5,6) Yet, because many noninsulin medications lower blood glucose by stimulating insulin secretion from the pancreas, glycemic durability is only a few years with most noninsulin medications. (8) Moreover, the glycemic-lowering efficacy of oral medications is limited. The addition to metformin of oral medications such as SUs and TZDs results in a maximum additional HbAlc reduction of approximately 1%. (9) Insulin, on the other hand, has no theoretical limit to its glucose-lowering capacity.

Unlike the crude animal-derived formulation first injected into humans, the insulin formulations now available are synthetic and highly purified biologies. This has resulted in more predictable pharmacokinetics and pharmacodynamics enabling once-daily dosing and minimizing the risk of hypoglycemia. Moreover, insulin is a natural hormone and administration of insulin serves to address a pathophysiologic defect in T2DM by offsetting what the body no longer adequately produces. The magnitude of the glucose-lowering effect of insulin is dependent on dose, influenced by insulin resistance, and constrained by the risk of hypoglycemia.

The early use of insulin has been shown to offer several benefits. In a meta-analysis of 928 patients with a mean HbAlc of 8.69%, the likelihood of achieving the HbA1c target and reducing hypoglycemia risk was significantly greater with the earlier addition of insulin glargine to baseline metformin monotherapy compared with later addition of insulin glargine to metformin plus sulfonylurea (odds ratio (OR), 0.738; 95% confidence interval (CI), 0.218 to 1.258; P=.005). (10)


Since the introduction of exenatide twice-daily in 2005, five other GLP-1 RAs have been approved for use in the United States: liraglutide, exenatide once-weekly, albiglutide, dulaglutide, and lixisenatide. In the 2009 ADA/EASD algorithm, a GLP-1RA was recommended as a 'less well validated' tier 2 medication as an alternative to a TZD and after metformin, insulin, and an SU.U In the 2012 ADA/EASD update, a GLP-1RA was on an equal footing as basal insulin, SU, TZD, and a DPP-4i as one of 5 medication classes recommended for use in combination with metformin. (12) This same algorithm is recommended in the 2017 ADA Standards of Medical Care, with the only exception being an SGLT-2i as another option for use in combination with metformin. (5)

The AACE/ACE 2017 algorithm goes beyond the ADA/ EASD 2017 recommendations and lists a GLP-1RA at the top of the 'suggested hierarchy of usage' for use in combination with metformin, while acknowledging the importance of individualizing therapy (figure). (6)

Both the 2017 ADA standards and 2017 AACE/ACE recommendations note the cardiovascular benefits of liraglutide and empagliflozin based on the results of recently published cardiovascular outcomes trials. (See Gluagon-Like Peptide-1 Receptor Agonists on page 12.)


The clinical pharmacology, safety, and efficacy of GLP-lRAs have been investigated in more than 500 trials. The clinical efficacy and safety trials were included in the database of studies used for the systematic review "Diabetes Medications for Adults with Type 2 Diabetes: An Update" prepared for the Agency for Healthcare Research and Quality in 2016. (9) This review reported the following mean outcomes with the combination of a GLP-IRA and metformin compared with metformin monotherapy:

* additional 0.5% to 1.3% HbAlc reduction

* additional 2.0 kg weight reduction

* additional 3.1 mmHg systolic blood pressure reduction.

With respect to hypoglycemia, the systematic review found that the data did not favor either treatment (metformin monotherapy vs metformin + GLP-IRA) for mild, moderate, severe, or total hypoglycemia. This suggests a minimal added risk for hypoglycemia when a GLP-IRA is added to metformin.

GLP-1RAs have been reported to improve various markers of [beta]-cell function in patients with T2DM, suggesting that GLP-1RAs may remain effective in lowering blood glucose over time. (13,14) A recent meta-analysis estimated ORs for treatment failure with dual therapy in combination with metformin. Using SU as the reference, ie OR=1, the ORs were (least likely to fail to most likely to fail): basal insulin (0.10; 95% CI, 0.01 to 1.89), SGLT-2i (0.68; 95% CI, 0.48 to 0.96), GLP-IRA (0.84; 95% CI, 0.54 to 1.30), TZD (1.18; 95% CI, 0.70 to 1.98), and DPP-4i (1.37; 95% CI, 1.07 to 1.76), indicating that treatment failure with a GLP-IRA is less likely than with several commonly utilized oral medications. (15) Another potential benefit of GLP-lRAs is a reduction in the blood triglyceride level, albeit over a wide range (2 mg/dL to 73 mg/dL). (16-18) Finally, clinical trial data are beginning to demonstrate the cardiovascular safety and, in some cases, cardiovascular benefit, with the GLP-lRAs. (19-21)


Current treatment guidelines for patients with T2DM recommend key roles for basal insulin and GLP-1RAs across the spectrum of the disease. These recommendations are based on efficacy and safety data as well as other benefits observed in clinical trials.


(1.) Nathan DM, Buse IB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006:29(8): 1963-1972.

(2.) Rodbard HW, Blonde L, Braithwaite SS, et al; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(Suppl 1):1-68.

(3.) Hayes RP, Fitzgerald IX lacober SJ. Primary care physician beliefs about insulin initiation in patients with type 2 diabetes. Int J Clin Pract. 2008;62(6):860-868.

(4.) Jabbour S. Primary care physicians and insulin initiation: multiple barriers, lack of knowledge or both? Int J Clin Pract. 2008;62(6):845-847.

(5.) American Diabetes Association. Standards of medical care in diabetes--2017. Diabetes Care. 2017;40(suppl 1):S1-S135.

(6.) Garber AJ, Abrahamson MJ, Barzilay 11, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm--2017 Executive Summary. Endocr Pract. 2017;23(2):207-238.

(7.) DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-795.

(8.) Kahn SE, Haffiier SM, Heise MA, et al; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. NEngl J Med. 2006;355(23):2427-2443.

(9.) Bolen S, Tseng E, Hutfless S, et al. Agency for Healthcare Research and Quality. Diabetes medications for adults with type 2 diabetes: An update. Comparative Effectiveness Review No. 173. diabetes-update-2016-report.pdf. Published April 2016. Accessed October 3,2016.

(10.) Fonseca V, Gill J, Zhou R, Leahy J. An analysis of early insulin glargine added to metformin with or without sulfonylurea: impact on glycaemic control and hypoglycaemia. Diabetes Obes Metab. 2011;13(9):814-822.

(11.) Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(l):193-203.

(12.) Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association; European Association for the Study of Diabetes. Management of hyperglycemia 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) (published correction appears in Diabetes Care. 2013;36(2):490l. Diabetes Care. 2012;35(6):1364-1379.

(13.) Grandy S, Shaunik A, Hardy E. Effects of glucagon-like peptide-1 receptor agonists on beta-cell function in patients with type 2 diabetes. J Diabetes Metab. 2016:7:643.

(14.) Mari A, Del Prato S, Ludvik B, et al. Differential effects of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide and metformin on pancreatic beta-cell and insulin sensitivity during a standardized test meal in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(8):834-839.

(15.) Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. IAMA. 2016;316(3):313-324.

(16.) Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24(1):275-286.

(17.) Pratley R, Nauck M, Bailey T, et al; 1860-L1RA-DPP-4 Study Group. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. Int J Clin Pract. 2011;65(4):397-407.

(18.) Ratner FIE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8(4):419-428.

(19.) Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl] Med. 2016;375(4):311-322.

(20.) Pfeffer MA. Claggett B, Diaz R, et al; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247-2257.

(21.) Matso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375(19):1834-1844.

Eden M. Miller, DO, Executive Director and co-founder Diabetes Nation, High Lakes Health Care, St. Charles Hospital, Bend, Oregon


Dr. Miller discloses that she is on the advisory boards for Abbott; Boehringer-lngelheim GmbH; Eli Lilly and Company; and Omnipod. She is on the speakers' bureaus for AstraZeneca; Becton, Dickinson and Company; Janssen Pharmaceuticals, Inc.; and Novo Nordisk Inc.

Caption: FIGURE 1 AACE/ACE glycemic control algorithm (6)
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Author:Miller, Eden M.
Publication:Journal of Family Practice
Article Type:Report
Geographic Code:1USA
Date:Oct 1, 2017
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