Trending Topic

3 mins

Trending Topic

Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

It is with great pleasure that we present this latest issue of touchREVIEWS in Endocrinology, which brings together a diverse array of high-quality articles focused on the evolving landscape of endocrine disorders. The importance of patient-centred care is exemplified in the commentary by Bharti Kalra et al., which discusses the international guidelines for polycystic ovary […]

5 mins

Insulin Therapy in Type 2 Diabetes

Etie Moghissi
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Published Online: Jun 10th 2013 US Endocrinology, 2013;9(1):6-12 DOI: http://doi.org/10.17925/USE.2013.09.01.6
Select a Section…
1

Abstract

Overview

Due to the progressive nature of Type 2 diabetes, insulin therapy is often required to achieve glycemic control. When lifestyle modifications and treatment with metformin with or without other oral antidiabetic drugs (OADs) have failed to achieve normoglycemia, timely initiation of singledose basal insulin treatment is a convenient, effective, and recommended strategy. The development of the long-acting basal insulin analogs, insulin detemir (IDet) and insulin glargine (IGlar), has resulted in significant improvements in the management of Type 2 diabetes, and specifically, in reducing rates of hypoglycemia. However, hypoglycemia still remains a limiting factor in the intensification of insulin therapy. Combination regimens involving insulin and incretin-based therapies have resulted in improved glycemic control with a similar rate of hypoglycemia compared with insulin alone. Novel basal insulin analogs may also help address the unmet needs associated with basal insulin therapy. Insulin degludec (IDeg) is a basal insulin analog that offers an ultra-long duration of action of more than 42 hours in adults, more flexibility compared with other long-acting insulin analogs in terms of daily dosing times, and reduced rates of hypoglycemia. Pegylated (PEG) lispro, an agent that is currently in clinical development, also offers an extended duration of action. The potential for fewer hypoglycemic episodes offered by combined regimens and new agents may improve adherence to insulin regimens.

Support: The publication of this article was supported by Novo Nordisk Inc. The views and opinions expressed are those of the author and not necessarily those of Novo Nordisk Inc.

Keywords

Basal insulin analog, degludec, incretin therapy, Type 2 diabetes mellitus

2

Article

The effective management of diabetes requires meticulous glycemic control. The long-term complications resulting from poor glycemic control contribute substantially to the morbidity, mortality, and economic burden of diabetes.

The effective management of diabetes requires meticulous glycemic control. The long-term complications resulting from poor glycemic control contribute substantially to the morbidity, mortality, and economic burden of diabetes. Hyperglycemia in Type 2 diabetes worsens over time as a result of the decline in pancreatic β-cell function, increasing insulin resistance, and the increased hepatic glucose production associated with inappropriately high levels of glucagon and reduced glucagon-like peptide-1 (GLP-1) production.1 Consequently, a substantial number of patients need insulin therapy after nine or more years of disease.2

Advances in insulin therapy and other medications for the management of Type 2 diabetes have resulted in substantial improvements in glycemic control. However, these advances have not eliminated the psychologic and social burdens of the disease, such as fear of future complications and of hypoglycemia.3 While the patient’s attitude toward managing their treatment regimen is crucial to maintaining glycemic control,4,5 adherence to insulin, in particular, is poor in Type 2 diabetes.6 The requirement to inject current formulations of basal insulin analogs at a fixed time each day may negatively affect treatment adherence and patients’ quality of life (QoL) due to the complexity of the insulin regimen, needle phobia, the social stigma of having to inject insulin in public, and the risk for hypoglycemia.7–10 The American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) consensus panel has recommended that hypoglycemia be avoided where possible.11 The need remains for advances in current diabetes therapies that provide effective glucose control, maintain a stable glucose profile, and allow for more flexible treatment regimens that minimize side effects, particularly the risk for hypoglycemia.

This article aims to highlight advances in insulin therapy that aim to address the challenge of hypoglycemia in Type 2 diabetes, including combination therapies involving GLP-1 agonists, and two novel insulin analogs in clinical development: insulin degludec (IDeg) (Tresiba®, Novo Nordisk) and PEGylated insulin lispro ([LY2605541], Eli Lilly & Co).

Advances in Basal Insulin Analog Therapy
A summary of insulin analogs currently in use for glycemic control in Type 2 diabetes is shown in Table 1. Prior to the development of basal insulin analogs, neutral protamine Hagedorn (NPH), a suspension of crystalline zinc insulin combined with the positively charged polypeptide, protamine, was commonly used to provide basal glucose control. It has an onset of action beginning about 2 hours following injection, with a peak effect 4–6 hours after injection, and a duration of action of more than 12 hours. The resulting ‘dome-shaped’ basal plasma profile confers a risk for hypoglycemia at the peak insulin concentration and hyperglycemia at the trough.12

Long-acting basal insulin analogs have become important treatment options in Type 2 diabetes. The aim in developing such analogs has been to prolong the absorption kinetics to produce an absorption profile similar to that of endogenous basal insulin secretion. The flatter pharmacodynamic profile promotes a lower peak, a prolonged duration of action, and a slow and continuous absorption of insulin in the body that results in significant benefits in terms of glycemic control, flexibility of administration, and a reduced incidence of hypoglycemia compared with NPH (see Figure 1).13–15 Long-acting insulin analogs also have the advantage of providing a more consistent glucose-lowering effect throughout the day compared with shorter-acting insulin analogs.

The first long-acting insulin analog, insulin glargine ([IGlar], Lantus®), was introduced in 2002. Several studies have reported similar or slightly improved glycemic control with IGlar compared with once- or twice-daily NPH, with IGlar demonstrating a duration of action of up to 24 hours, and fewer episodes of nocturnal hypoglycemia.16–18 Another long-acting basal insulin analog, insulin detemir (IDet) (Levemir®, Novo Nordisk), was introduced in 2004, and comprises insulin linked to a fatty acid (myristic acid). In clinical studies, IDet provided predictable glycemic control with fewer hypoglycemic events (HEs) than NPH, but similar to glargine, and less weight gain compared with both NPH and glargine.19,20

Other advances include biphasic insulin analogs, which consist of a mixture of a soluble and a protaminated form of the rapid-acting analog, have shown improved postprandial glucose (PPG) control and a reduced risk for hypoglycemia compared with human premix formulations.21

Limitations of Basal Insulin Analog Therapy
Despite the reduced frequency of hypoglycemia associated with long-acting basal insulin analog therapy, hypoglycemia remains the major limiting factor in the treatment of Type 2 diabetes.22 The fear of hypoglycemia can delay the initiation of insulin;23 nocturnal hypoglycemia is of particular concern because many episodes are asymptomatic and may remain undetected until they become severe, which may lead to unconsciousness and even death.24 A recent survey of patients with Type 2 diabetes using basal insulin analogs (n=3,042) found that more than a third (36 %) had experienced HEs during the previous 30 days.25

Nonsevere HEs (NSHEs) may invoke a considerable economic burden for employers and patients, in addition to negatively impacting sleep quality, daytime functioning, and diabetes management among patients.26 A survey conducted in the US, UK, Germany and France (n=1,404) found that NSHEs were responsible for 8.3 to 15.9 hours of lost work time per month. Among respondents reporting an NSHE at work (n=972), 18.3 % missed work for an average of 9.9 hours (standard deviation [SD] 8.4); of those experiencing an NSHE outside working hours (including nocturnal), 22.7 % arrived late for work or missed a full day. Productivity loss was highest for NSHEs occurring during sleep, with an average of 14.7 (SD 11.6) working hours lost.27 Another survey (n=6,756) found that more than a third of respondents (36.1 %) reported a daytime NSHE in the past month. These occurred while active (e.g. running errands [45.1 %]), not active (e.g. watching TV [29.6 %]), and at work [23.8 %]). Patients took an average of half a day to respond to and recover from an NSHE, and monitored their glucose an average 5.7 extra times over the following week.28


In addition to its effect on day-to-day living, hypoglycemia can also have serious health consequences. Acute hypoglycemia causes the brain to become neuroglycopenic and promote secretion of counter-regulatory hormones – primarily adrenaline and norepinephrine. In healthy young adults, these effects are transient and have no obvious detrimental consequences. However, people with endothelial dysfunction are at an increased risk for localized tissue ischemia, which can alter a patient’s


cardiovascular (CV) risk profile.29–31 HEs (identified by the presence of an outpatient medical claim with an International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnosis code) have been correlated with an increased risk for acute CV events (ACVEs) in patients with Type 2 diabetes,32 and severe hypoglycemia (defined as a blood glucose concentration of <2.8 mmol/l) was associated with increased mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.33 HEs also result in impaired nutrient delivery to the brain, and may downregulate markers of neuronal plasticity and increase levels of neurotoxic glutamate, increasing the risk for dementia. A history of severe HEs has been associated with an increased risk for dementia in older patients with Type 2 diabetes.34 In summary, it is clear that hypoglycemia remains a serious challenge to patients taking basal insulin analogs, which highlights the need for basal insulin therapies that offer effective glycemic control while minimizing the risk for hypoglycemia.

Recent Advances in Managing Hypoglycemia in Type 2 Diabetes with Combination Regimens Involving Basal Insulin Analogs
Incretin-based therapies offer an effective new approach to the management of diabetes: GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. Because of their glucose-dependent mechanism of action – they stimulate insulin secretion only during hyperglycemia – incretin-based therapies have a low hypoglycemia risk.

As a result of their complementary mechanisms of action, basal insulin analogs are increasingly used in combination with GLP-1 receptor agonists.35 Two GLP-1 receptor agonists are currently approved by the US Food and Drink Administration (FDA): exenatide (Byetta®, Bydureon®, Amylin Pharmaceuticals),36 and liraglutide, (Victoza®, Novo Nordisk).37 Several studies have investigated the efficacy and safety of the combination of GLP-1 receptor agonists and basal insulin; a summary appears in Table 2. All studies to date have shown that the combination of exenatide and insulin, with or without oral antidiabetes drugs, showed significant improvements in glycemic control with low incidences of hypoglycemia, often leading to dose reduction, or even discontinuation, of insulin. However, it must be noted that most of these studies were small, and most were either observational or retrospective. Increased reports of gastrointestinal (GI) side effects associated with the use of GLP-1 receptor agonists resulted in the discontinuation of a minority of patients in each of the studies.38–40

Although there are limited data comparing the rates of hypoglycemia in combined basal insulin regimens with those in monotherapy, the combination of GLP-1 receptor agonists and basal insulin has been associated with high patient satisfaction and low rates of hypoglycemia.41

Other combined therapeutic regimens that are being studied include the combination of insulin therapy with other incretin-based therapies. DPP-4 inhibitors are oral therapies that improve glycemic control in Type 2 diabetes by blocking the degradation of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Several DPP-4 inhibitors have been approved by the FDA for use in Type 2 diabetes, including sitagliptin (Januvia®, Merck & Co, approved in 2006), saxagliptin (Onglyza®, Bristol- Myers Squibb, AstraZeneca, approved in 2009), linagliptin (Trajenta®, Eli Lilly & Co, approved in 2011), and alogliptin (Nesina®, Takeda Pharmaceutical Co., approved in 2013). Vildagliptin (Zomelis®, Abbott India Ltd, Galvus®, Novartis) has been approved in Europe but is not approved in the US.

A number of clinical studies have shown the efficacy and safety of DPP- 4 inhibitors as part of combined treatment regimens with basal insulin analogs, with low levels of hypoglycemia reported (see Table 2).

As a result of these studies, all FDA-approved GLP-1 receptor agonists and DPP-4 inhibitors have been approved for use as add-on therapy to basal insulin. Although incretin therapies are considered safe, there is a lack of long-term safety data relating to their use. Reports of associations between incretin therapies and acute pancreatitis are being investigated.42 While a large body of clinical data has demonstrated that combined regimens involving incretin-based therapies and basal

insulin analogs offer improved glycemic control with low incidence of hypoglycemia, there is a need for long-term data. It is not known how the efficacy of incretin-plus-insulin regimens will change in the course of the Type 2 diabetes disease process, and how and when doses should be adjusted. Therefore, more clinical trials are required to determine the appropriate use of incretin-based therapies combined with basal insulin.

Future Developments in Insulin Therapy
Recent research in insulin therapy has focused on the development of basal insulin analogs with an ultra-long duration of action. IDeg has a Figure 2: Phase III Trial-confirmed Hypoglycemic Events Comparing Insulins Degludec and Glargine A. Overall confirmed glycemic episodes. B. Nocturnal confirmed glycemic episodes. C. Diurnal confirmed hypoglycemic episodes. D. Cumulative number of hypoglycemic episodes per participant during 24 hours. E. Distribution of confirmed hypoglycemic episodes. Adapted from Figure 3, Garber, 2012.46 duration of action of more than 42 hours in adults.43 The basis for IDeg’s long duration of action lies in its structure: IDeg has the same amino acid sequence as human insulin except for the deletion of threonine in the B30 position and the addition of hexadecanedioic acid to lysine at the B29 position.44 This allows for the formation of multihexameric complexes as the additives in the formulation disperse, resulting in a subcutaneous depot from which IDeg monomers are slowly and continuously released into systemic circulation. The resultant smooth and stable pharmacokinetic profile provides an extended duration of action of up to 42 hours, minimizing the risk for hypoglycemia.
Pharmacokinetic and phamacodynamic studies have found that when administered once daily under steady-state conditions, IDeg has a more stable and consistent glucose-lowering effect than IGlar in Type 2 diabetes.45 This has been confirmed in clinical studies: in a phase III, open-label, treat-to-target, noninferiority trial (n=755), the rates of overall confirmed hypoglycemia were lower with IDeg than IGlar (11.1 and 13.6 episodes per patient–year of exposure [PYE], respectively; p=0.0359), as were the rates of nocturnal confirmed hypoglycemia (1.4 and 1.8 episodes per PYE, respectively; p=0.0399) (see Figure 2).46

A meta-analysis of clinical trials in the IDeg development program confirmed that similar levels of glycemic control were achieved with fewer hypoglycemic episodes, particularly nocturnal episodes, with IDeg compared with IGlar, across a broad spectrum of patients with diabetes.47

Since postprandial hyperglycemia contributes substantially to overall glycemia, initiating basal insulin therapy in combination with a rapid-acting insulin in one injection presents a convenient approach to achieving and sustaining optimal glycemic control. IDeg can be co-formulated with the rapid-acting insulin aspart (IAsp), resulting in the first soluble combination of two insulin analogs. IDegAsp, a co-formulation of IDeg (70 %) and IAsp (30 %), provided similar overall glycemic control to biphasic IAsp 30 with a significantly lower rate of hypoglycemia.48

IDeg has the potential to allow for a flexible, once-daily dosing regimen in which the patient can vary the daily injection time from day to day if needed. This flexibility provides convenience while maintaining glycemic control not only for those who self-administer insulin, but also for patients for whom insulin is administered by a caretaker or a third party who may not be able to visit the patient at the same time every day. Two recent studies investigated the efficacy and safety of IDeg in a flexible dosing regimen in patients with Type 1 and 2 diabetes and found that IDeg can be administered at any time of the day, with a varied injection time (8–40 hour intervals between daily injections), without compromising glycemic control or safety compared with same-time-daily IDeg or IGlar.49,50 IDeg has been approved in the EU, Japan and Mexico and is under review for FDA approval pending additional data.

Representing another recent advancement, insulin lispro has undergone PEGylation to produce a novel insulin analog. PEGylated lispro (LY2605541) comprises a 20 kDa polyethylene glycol (PEG) moiety covalently attached to lysine B28. It is designed to have a large hydrodynamic size that slows absorption and reduces clearance, resulting in therapeutically effective basal insulin activity and a longer duration of action.51 The efficacy of PEGylated lispro has been demonstrated in two phase II clinical trials. In a recent study comparing PEGylated lispro with IGlar, patients receiving the two agents had similar overall rates of hypoglycemia; however, fewer cases of nocturnal hypoglycemia were seen in the PEGylated lispro group.52 In a phase II study involving patients with Type 1 diabetes, PEGylated lispro demonstrated greater improvements in glycemic control compared with IGlar, and also caused weight loss. Mealtime insulin dose was decreased with PEGylated lispro, and increased with IGlar. The total rate of hypoglycemia was higher for PEG lispro (p=0.04), and the nocturnal hypoglycemia rate was lower (p=0.01).53 These results were obtained with a prandial dose of PEGylated lispro that was 24 % lower than the IGlar dose. Further research is required to determine the day-to-day variability of PEGylated lispro at doses relevant to clinical practice.

Summary and Concluding Remarks
Hypoglycemia remains the primary challenge in achieving and maintaining glycemic control with insulin therapy. The development of the long-acting analogs, IDet and IGlar, has resulted in improvements in the overall management of Type 2 diabetes, and specifically in reducing the rates of hypoglycemia, However, hypoglycemia remains a limiting factor in the intensification of insulin therapy.

Recent advances in the treatment of Type 2 diabetes include the combined use of incretin-based therapies with basal insulin analogs, a combination that has demonstrated improved glycemic control with the potential for reduced insulin dosing. Future advances are aimed at further reducing the risk for hypoglycemia through such novel insulin analogs as IDeg and PEGylated lispro, with studies showing that both agents have the potential to offer better glycemic control with less risk for nocturnal hypoglycemia compared with currently available basal insulin analogs. Moreover, IDeg offers patients the flexibility to vary the time of day at which the basal insulin can be administered when consistent timing of insulin administration is not possible or is impractical. The potential for fewer hypoglycemic episodes offered by combined regimens and new agents may bolster patients’ confidence in their ability to improve adherence to insulin regimens and maintain tighter glycemic control.

2

References

1. Freeman JS, A physiologic and pharmacological basis for implementation of incretin hormones in the treatment of type 2 diabetes mellitus, Mayo Clin Proc, 2010;85:S5–S14.
2. Turner RC, Cull CA, Frighi V, et al., Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group, JAMA, 1999;281:2005–12.
3. Giordano C, Insulin therapy: unmet needs and new perspectives, Minerva Endocrinol, 2013;38:95–102.
4. Rubin RR, Peyrot M, Psychological issues and treatments for people with diabetes, J Clin Psychol, 2001;57:457–78.
5. Kunt T, Snoek FJ, Barriers to insulin initiation and intensification and how to overcome them, Int J Clin Pract Suppl, 2009;(164):6–10.
6. Donnelly LA, Morris AD, Evans JM, Adherence to insulin and its association with glycaemic control in patients with type 2 diabetes, QJM, 2007;100:345–50.
7. Peyrot M, Rubin RR, Kruger DF, et al., Correlates of insulin injection omission, Diabetes Care, 2010;33:240–45.
8. Peyrot M, Rubin RR, Khunti K, Addressing barriers to initiation of insulin in patients with type 2 diabetes, Prim Care Diabetes, 2010;4 Suppl. 1:S11–18.
9. Polonsky WH, Fisher L, Guzman S, et al., Psychological insulin resistance in patients with type 2 diabetes: the scope of the problem, Diabetes Care, 2005;28:2543–5.
10. Currie CJ, Morgan CL, Poole CD, et al., Multivariate models of health-related utility and the fear of hypoglycaemia in people with diabetes, Curr Med Res Opin, 2006;22:1523–34.
11. Rodbard HW, Jellinger PS, Davidson JA, et al., Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control, Endocr Pract, 2009;15:540–59.
12. Peterson GE, Intermediate and long-acting insulins: a review of NPH insulin, insulin glargine and insulin detemir, Curr Med Res Opin, 2006;22:2613–19.
13. Gough SC, A review of human and analog insulin trials, Diabetes Res Clin Pract, 2007;77:1–15.
14. Mavrogiannaki AN, Migdalis IN, Long-acting basal insulin analogs: latest developments and clinical usefulness, Ther Adv Chronic Dis, 2013;3:249–57.
15. Riddle MC, Rosenstock J, Gerich J, The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients, Diabetes Care, 2003;26:3080–86.
16. Rosenstock J, Park G, Zimmerman J, Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. U.S. Insulin Glargine (HOE 901) Type 1 Diabetes Investigator Group, Diabetes Care, 2000;23:1137–42.
17. Rosenstock J, Schwartz SL, Clark CM, Jr., et al., Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin, Diabetes Care, 2001;24:631–6.
18. Yki-Jarvinen H, Dressler A, Ziemen M, Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group, Diabetes Care, 2000;23:1130–36.
19. Vague P, Selam JL, Skeie S, et al., Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart, Diabetes Care, 2003;26:590–96.
20. Hermansen K, Madsbad S, Perrild H, et al., Comparison of the soluble basal insulin analog insulin detemir with NPH insulin: a randomized open crossover trial in type 1 diabetic subjects on basal-bolus therapy, Diabetes Care, 2001;24:296–301.
21. Cucinotta D, Russo GT, Biphasic insulin aspart in the treatment of type 2 diabetes mellitus, Expert Opin Pharmacother, 2009;10:2905–11.
22. Cryer PE, Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes, Diabetologia, 2002;45:937–48.
23. Nakar S, Yitzhaki G, Rosenberg R, et al., Transition to insulin in Type 2 diabetes: family physicians’ misconception of patients’ fears contributes to existing barriers, J Diabetes Complications, 2007;21:220–26.
24. Brunton SA, Nocturnal hypoglycemia: answering the challenge with long-acting insulin analogs, MedGenMed, 2007;9:38.
25. Brod M, Rana A, Barnett AH, Impact of self-treated hypoglycaemia in type 2 diabetes: a multinational survey in patients and physicians, Curr Med Res Opin, 2012;28:1947–58.
26. Brod M, Christensen T, Bushnell DM, Impact of nocturnal hypoglycemic events on diabetes management, sleep quality, and next-day function: results from a four-country survey, J Med Econ, 2011;15:77–86.
27. Brod M, Christensen T, Thomsen TL, et al., The impact of nonsevere hypoglycemic events on work productivity and diabetes management, Value Health, 2011;14:665–71.
28. Brod M, Christensen T, Bushnell DM, The impact of non-severe hypoglycemic events on daytime function and diabetes management among adults with type 1 and type 2 diabetes, J Med Econ, 2012;15:869–77.
29. Wright RJ, Frier BM, Vascular disease and diabetes: is hypoglycaemia an aggravating factor?, Diabetes Metab Res Rev, 2008;24:353–63.
30. Zoungas S, Patel A, Chalmers J, et al., Severe hypoglycemia and risks of vascular events and death, N Engl J Med, 2010;363:1410–18.
31. Frier BM, Schernthaner G, Heller SR, Hypoglycemia and cardiovascular risks, Diabetes Care, 2011;34 Suppl. 2:S132–7.
32. Johnston SS, Conner C, Aagren M, et al., Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes, Diabetes Care, 2011;34:1164–70.
33. Bonds DE, Miller ME, Bergenstal RM, et al., The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study, BMJ, 2010;340:b4909.
34. Whitmer RA, Karter AJ, Yaffe K, et al., Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus, JAMA, 2009;301:1565–72.
35. Tobin GS, Cavaghan MK, Hoogwerf BJ, et al., Addition of exenatide twice daily to basal insulin for the treatment of type 2 diabetes: clinical studies and practical approaches to therapy, Int J Clin Pract, 2012;66:1147–57.
36. Heine RJ, Van Gaal LF, Johns D, et al., Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial, Ann Intern Med, 2005;143:559–69.
37. Buse JB, Rosenstock J, Sesti G, et al., Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD- 6), Lancet, 2009;374:39–47.
38. Nayak UA, Govindan J, Baskar V, et al., Exenatide therapy in insulin- treated type 2 diabetes and obesity, QJM, 2010;103:687–94.
39. Viswanathan P, Chaudhuri A, Bhatia R, et al., Exenatide therapy in obese patients with type 2 diabetes mellitus treated with insulin, Endocr Pract, 2007;13:444–50.
40. Yoon NM, Cavaghan MK, Brunelle RL, et al., Exenatide added to insulin therapy: a retrospective review of clinical practice over two years in an academic endocrinology outpatient setting, Clin Ther, 2009;31:1511–23.
41. Lind M, Jendle J, Torffvit O, et al., Glucagon-like peptide 1 (GLP-1) analog combined with insulin reduces HbA1c and weight with low risk of hypoglycemia and high treatment satisfaction, Prim Care Diabetes, 2011;6:41–6.
42. Iyer SN, Tanenberg RJ, Mendez CE, et al., Pancreatitis associated with incretin-based therapies, Diabetes Care, 2013;36:e49.
43. Wang F, Surh J, Kaur M, Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review, Diabetes Metab Syndr Obes, 2012;5:191–204.
44. Jonassen I, Havelund S, Hoeg-Jensen T, et al., Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin, Pharm Res, 2012;29:2104–14.
45. Heise T, Nosek L, Bottcher SG, et al., Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes, Diabetes Obes Metab, 2012;14:944–50.
46. Garber AJ, King AB, Del Prato S, et al., Insulin degludec, an ultralongacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-totarget non-inferiority trial, Lancet, 2012;379:1498–507.
47. Ratner RE, Gough SC, Mathieu C, et al., Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials, Diabetes Obes Metab, 2012;15:175–84.
48. Niskanen L, Leiter LA, Franek E, et al., Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: a randomised trial, Eur J Endocrinol, 2012;167:287–94.
49. Mathieu C, Hollander P, Miranda-Palma B, et al., Efficacy and Safety of Insulin Degludec in a Flexible Dosing Regimen vs Insulin Glargine in Patients With Type 1 Diabetes (BEGIN: Flex T1): A 26-Week Randomized, Treat-to-Target Trial With a 26-Week Extension, J Clin Endocrinol Metab, 2013;98(3):1154–62.
50. Meneghini L, Atkin SL, Gough SC, et al., The Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Compared With Insulin Glargine and Insulin Degludec Dosed at the Same Time Daily: A 26-week, randomized, open-label, parallel-group, treat-to-target trial in people with type 2 diabetes, Diabetes Care, 2013;36(4):858–64.
51. Pandyarajan V, Weiss MA, Design of non-standard insulin analogs for the treatment of diabetes mellitus, Curr Diab Rep, 2012;12:697–704.
52. Bergenstal RM, Rosenstock J, Arakaki RF, et al., A randomized, controlled study of once-daily LY2605541, a novel longacting basal insulin, versus insulin glargine in basal insulintreated patients with type 2 diabetes, Diabetes Care, 2012;35:2140–47.
53. Rosenstock J, Bergenstal RM, Blevins TC, et al., Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes: A randomized, crossover study, Diabetes Care, 2013;36:522–8.
54. Sheffield CA, Kane MP, Busch RS, et al., Safety and efficacy of exenatide in combination with insulin in patients with type 2 diabetes mellitus, Endocr Pract, 2008;14:285–92.
55. Arnolds S, Dellweg S, Clair J, et al., Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study, Diabetes Care, 2010;33:1509–15.
56. Buse JB, Bergenstal RM, Glass LC, et al., Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial, Ann Intern Med, 2011;154:103–12.
57. Thong KY, Jose B, Sukumar N, et al., Safety, efficacy and tolerability of exenatide in combination with insulin in the Association of British Clinical Diabetologists nationwide exenatide audit*, Diabetes Obes Metab, 2011;13:703–10.
58. DeVries JH, Bain SC, Rodbard HW, et al., Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets, Diabetes Care, 2012;35:1446–54.
59. Fonseca V, Schweizer A, Albrecht D, et al., Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes, Diabetologia, 2007;50:1148–55.
60. Bruttomesso D, Pianta A, Mari A, et al., Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients, Diabetes, 1999;48:99–105.
61. Holleman F, Schmitt H, Rottiers R, et al., Reduced frequency of severe hypoglycemia and coma in well-controlled IDDM patients treated with insulin lispro. The Benelux-UK Insulin Lispro Study Group, Diabetes Care, 1997;20:1827–32.
62. Home PD, Lindholm A, Riis A, et al., Insulin aspart vs. human insulin in the management of long-term blood glucose control in Type 1 diabetes mellitus: a randomized controlled trial, Diabet Med, 2000;17:762–70.
63. Woerle H-J, Neubacher, D, Patel, S, et al., Safety and Efficacy of Linagliptin Plus Basal Insulin Combination Therapy in a vulnerable Population of Elderly Patients (Age ≥70 Years) With Type 2 Diabetes, 48th Annual Meeting of the European Association for the Study of Diabetes, Berlin, Germany, Poster P848, 2012.

3

Article Information

Disclosure

The author has no conflicts of interest to declare.

Correspondence

Etie Moghissi, MD, FACE, 4644 Lincoln Blvd., Suite 409, Marina del Rey, CA 90292. emoghissi@gmail.com

Received

2013-03-22

4

Further Resources

Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Close Popup