Inhaled insulin therapy: where are we heading?

Inhaled insulin therapy: where are we heading?

Stephen Gough

The availability of insulin for the treatment of diabetes has transformed the care of people with this life-long chronic condition. Following the first use of animal insulin in 1922 there have been a series of significant developments both in terms of the type of insulin used and the method of administration. These have included the widespread availability of human insulin in 1978, the introduction of the insulin pen delivery system in 1986 and the arrival of the first analogue insulins in 1996.

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Recently the first commercially available inhaled insulin has become a reality, with Exubera being launched by Pfizer. Based on clinical trial data Exubera was granted a licence in early 2006 for use in certain adults with type 1 or type 2 diabetes; and later in the year guidance was also provided by NICE under a technology appraisal (NICE, 2006).

While insulin has undoubtedly saved the lives of thousands of people with diabetes over the last 85 years, today’s greatest personal and financial burden of diabetes is the associated long-term complications including heart disease, end-stage renal disease, stroke, eye disease and lower limb complications.

Although blood glucose concentration is only one of a number of modifiable risk factors for the development of diabetes-related complications, in many individuals it remains, unfortunately, sub-optimal. The reasons for this are clearly multifactorial, but the initiation of insulin in people with type 2 diabetes and subsequent intensification onto an appropriate insulin regimen is certainly one of the barriers to achieving better glycaemic control. Attempts to understand why this particular barrier exists have also pointed to multifaceted causes including a sense of self-failure on the part of the individual, weight gain, hypoglycaemia and even clinical inertia (Hunt et al, 1997; Peyrot et al, 2005; Ziemer et al, 2005). Although true needle phobia may be uncommon there is no doubt that a large number of people with diabetes are reluctant to change to a treatment regimen that involves multiple daily injections (Peyrot et al, 2005).

For some individuals, the advent of inhaled insulin provides an exciting new alternative to delivering insulin via injection that will aid them in overcoming at least one of the barriers to using insulin. The NICE guidance on inhaled insulin identifies specific groups of patients who may benefit from inhaled insulin (NICE, 2006). One of these groups is defined as those people with: ‘A marked and persistent fear of injections that meet DSM-IV criteria for specific phobia ‘blood injection injury type’ diagnosed by a diabetes specialist or mental health professional.’

However, this can be difficult to accurately diagnose and, in some situations, to differentiate from significant needle aversion.

For example, an individual with type 2 diabetes that is inadequately controlled with maximal oral therapy may refuse insulin therapy for a number of years. This is despite an unacceptably high Hb[A.sub.1c] and the knowledge that this decision is putting them at an increased risk of morbidity and mortality. In this situation, it is fair to conclude that the individual has an unreasonable fear or anxiety and is avoiding the potentially stressful situation of initiating subcutaneous insulin therapy.

Inhaled insulin may help people with type 2 diabetes to start or intensify insulin treatment earlier and benefit from a significant improvement in glycaemic control (as assessed by a reduction in Hb[A.sub.1c]) over the ensuing months. Optimising insulin therapy may help to reduce the probability of developing vascular events. When assessed in terms of an incremental cost effectiveness per quality-adjusted life year, in some people with diabetes inhaled insulin would be considered to be cost effective based upon accepted national thresholds (NICE, 2006).

Those of us who have started to prescribe inhaled insulin in our clinics in cases of type 2 diabetes where insulin initiation or intensification has been delayed owing to needle phobia or aversion have seen impressive responses. This has been measured in terms of patient satisfaction, acceptance of an easy-to-use device and improvements in glycaemic control that reflect the findings of earlier clinical trials (such as: Rosenstock et al, 2004; Rosenstock et al, 2005).

The type of situations in which inhaled insulin is used are varied. Some people may be completely new to insulin therapy and are taking prandial inhaled insulin with continued oral therapy. Others, who have coped with only one basal injection per day, have been able to intensify their regimen with prandial inhaled insulin. It is interesting that self monitoring of blood glucose has generated much less of an anxiety in these individuals than the injection of insulin.

Although clinics may often be consultant led and based within the Diabetes Centre in a hospital setting, much of the education has been coordinated by diabetes specialist nurses, as has the monitoring of lung function via handheld spirometry. The education addresses issues surrounding the inhaler device, insulin initiation and dose titration.

As with all new medicines it is important to practice a high level of surveillance and vigilance (Gough, 2005). We have seen very recently the importance of collecting and reporting side effects of all medicines that we use, including those that may have been around for a number of years (Nissen and Wolski, 2007). Inhaled insulin is no exception and we need to follow the very simple and clear advice given in the product information.

Unfortunately, increasing evidence, including that from the UK, suggests that many people with type 2 diabetes still have poor glycaemic control to the extent that they may have Hb[A.sub.1c] values of 8.0% and above for 5 years or more before subcutaneous insulin is initiated (Brown et al, 2004; Fox et al, 2006; Rubino et al, 2007).

Concluding point

As discussed, the reasons for poor glycaemic control are complex, but the availability of inhaled insulin offers an alternative to insulin injections that has the potential to improve glycaemic control in a number of individuals where patients and doctors have been delaying initiation of appropriate insulin therapy.

Brown JB, Nichols GA, Perry A (2004) The burden of treatment failure in type 2 diabetes. Diabetes Care 27: 1535-40

Fox KM, Gerber Pharmd RA, Bolinder B et al (2006) Prevalence of inadequate glycemic control among patients with type 2 diabetes in the United Kingdom general practice research database: A series of retrospective analyses of data from 1998 through 2002. Clinical Therapeutics28: 388-95

Gough S (2005) Post-marketing surveillance: a UK/European perspective. Current Medical Research and Opinion 21: 565-70

Hunt LM, Valenzuela MA, Pugh JA (1997) NIDDM patients’ fears and hopes about insulin therapy. The basis of patient reluctance. Diabetes Care 20: 292-8

NICE (2006) NICE Technology Appraisal Guidance 113. Inhaled insulin for the treatment of type 1 and type 2 diabetes. NICE, London

Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine 356: 2457-71

Peyrot M, Rubin RR, Lauritzen T et al (2005) Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 28: 2673-9

Rosenstock J, Cappelleri JC, Bolinder B, Gerber RA (2004) Patient satisfaction and glycemic control after 1 year with inhaled insulin (Exubera) in patients with type 1 or type 2 diabetes. Diabetes Care27: 1318-23

Rosenstock J, Zinman B, Murphy LJ et al (2005) Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Annals of Internal Medicine 143: 549-58

Rubino A, McQuay LJ, Gough SC et al (2007) Delayed initiation of subcutaneous insulin therapy after failure of oral antidiabetic agents in patients with type 2 diabetes: A population-based analysis in the United Kingdom. Diabetic Medicine. In Press (accepted June 2007)

Ziemer DC, Miller CD, Rhee MK et al (2005) Clinical inertia contributes to poor diabetes control in a primary care setting. The Diabetes Educator 31: 564-71

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Stephen Gough is Professor of Medicine and Consultant Physician at the University of Birmingham and University Hospital Birmingham NHS Foundation Trust.

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