Abstract
Diabetes mellitus affects 23.6 million Americans and its incidence is rapidly increasing, particularly in older, overweight patients. Large-scale studies conclusively show that elevated blood glucose levels are associated with an increased risk for microvascular complications, such as retinopathy and nephropathy. The high rates of morbidity and mortality associated with this disease, and the costs associated with it, underscore the importance of effective glycemic control. Conventional syringe/vial insulin delivery is associated with many barriers for patients with diabetes mellitus and for their healthcare providers. Substantial developments in insulin delivery show promise in overcoming these barriers. New technologies in insulin delivery focus on increasing patient convenience, reducing the frequency of daily injections, and improving glycemic control. This article outlines the challenges associated with conventional insulin delivery and describes recent developments that may help to overcome these barriers and, ultimately, could enhance glycemic control.
Diabetes mellitus affects 23.6 million Americans, or about 8% of the US population.1 This includes nearly 18 million persons with diagnosed disease and about 5.7 million undiagnosed cases. The incidence of type 2 diabetes is rapidly increasing, particularly among older, overweight persons who have concomitant cardiovascular (CV) risks.2 The coexistence of diabetes mellitus and hypertension works synergistically to increase morbidity and mortality, especially renal and CV injury.3 Well-known, large-scale studies, such as the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study, conclusively show that elevated levels of blood glucose are associated with an increased risk of microvascular complications, such as retinopathy and nephropathy.4–6 The high rates of morbidity and mortality associated with diabetes, coupled with the costs of treating these sequelae, underscore the importance of effective glycemic control.
Maintaining optimal glucose control—defined by the American Diabetes Association as a glycosylated hemoglobin level of <7%7—may require multiple daily insulin injections. However, conventional insulin injection techniques are a major cause of reduced patient adherence to treatment.8 Patient medication adherence and satisfaction with treatment regimens are more likely to occur with fewer medication side effects, as well as with reduced patient burden and inconvenience.9,10 Typical side effects of insulin therapy may include weight gain or hypoglycemic events.2,11
Significant advances in insulin delivery have been aimed at improving patient convenience and enhancing glycemic control.12 Alternatives to syringe/vial insulin delivery include:
Insulin pens
Injection ports
Insulin infusion pumps
Transdermal insulin patches
Inhaled insulin.
Some of these methods, however, have not met with great success. Inhalable insulin was available in the United States from September 2006 through October 2007 but was subsequently withdrawn from the market because of poor utilization rates. Other advances currently in development include oral insulin and buccal insulin spray. An international phase 3 clinical trial is ongoing for both types of insulin delivery.
This article reviews the barriers to adherence to conventional therapy and evaluates developments in the management of insulin-requiring diabetes that may help to overcome some of these barriers, as well as improve glycemic control and quality of life for patients with diabetes.
KEY POINTS
-
▸
Nearly 18 million Americans are diagnosed with diabetes, and about 5.7 million have the disease but have not been diagnosed.
-
▸
The high rates of morbidity and mortality associated with diabetes, and the costs associated with its treatment, underscore the importance of effective glycemic control.
-
▸
Conventional syringe/vial insulin delivery is associated with patient and physician barriers, such as psychological insulin resistance, patients' fear of insulin side effects and complications, and required lifestyle changes/restrictions.
-
▸
Despite evidence that many patients with type 2 diabetes do not achieve glycemic control with oral therapy alone, some physicians are still reluctant to initiate insulin therapy.
-
▸
Developments in insulin delivery during the past 20 years have focused on increasing patient convenience and improved glycemic control.
-
▸
The newer insulin delivery modes include insulin pens, insulin injection ports, continuous subcutaneous insulin infusion pumps, transdermal patches, and inhalable devices.
Barriers to Conventional Insulin Injection Therapy
Psychological Insulin Resistance
Psychological insulin resistance, defined as reluctance to initiate insulin injection therapy, is common among healthcare professionals and patients with diabetes mellitus.8,11,13,14 Despite ample evidence that many patients with type 2 diabetes do not achieve glycemic control with oral therapy alone, some physicians are still reluctant to initiate insulin therapy.12,14 Koro and colleagues found that despite frequent failure to achieve glycemic targets, the use of insulin declined from the 24% reported in the National Health and Nutrition Examination Survey (NHANES) III (1988–1994) to 16% in the initial release of NHANES IV (1999–2000), whereas the use of oral glucose-lowering monotherapy increased.15
This may in part reflect the availability of more oral medications for diabetes, but it may also be the result of the perceived complexity and inconvenience of the therapeutic regimen, the belief that it is not effective in type 2 diabetes, and fears of hypoglycemic episodes and weight gain. In addition, clinicians may perceive that initiation of insulin therapy will require more practice resources than are readily available.14
The relationship between psychological barriers to medication adherence and glycemic control can have important therapeutic implications. In a systematic literature review covering 1985 to 2007, Brod and colleagues evaluated 116 peer-reviewed articles to assess the impact of psychological insulin resistance on diabetes management.16 The investigators concluded that this phenomenon is affected by the following components16:
Patients' beliefs and knowledge about diabetes and insulin
Negative self-perceptions and attitudinal barriers
Fear of side effects and complications of insulin use
Lifestyle adaptations
Restrictions required by insulin use
Social stigma.
These factors may lead to delayed treatment initiation and compromised glucose control.
Reduced Medication Adherence
Decreased adherence because of injection-related anxiety can influence glycemic control and quality of life in patients with insulin-treated diabetes.11,17–20 Adherence to a daily regimen of multiple injections can be difficult to maintain, interfering with lifestyle, compromising optimal glycemic control, and potentially resulting in CV complications.17,20 In one study of elderly patients (aged ≥65 years) with type 2 diabetes who were treated in a managed care setting, an inverse correlation was observed between blood glucose–lowering medication adherence and healthcare service utilization (eg, emergency department visits, outpatient visits, hospitalizations).21 In this longitudinal cohort study, an increased medication possession ratio (MPR) for diabetes medications was the strongest predictor of decreased total annual healthcare costs: between 8.6% and 28.9% decrease in annual costs for every 10% increase in the MPR (P <.001).21
Alternative Modes of Insulin Delivery
Insulin may have greater patient acceptance and reduced psychological impact when administered via an alternative (ie, non-vial/syringe) delivery mode.22 Newer routes of insulin delivery have been introduced over the years that may be more convenient and less traumatic than standard multiple daily injection therapy. There is sufficient evidence supporting patient preferences for modes of insulin delivery that result in ease of use, reduced fear/anxiety about insulin injections, and reduced fear of hypoglycemia.22 The evidence suggests that novel delivery systems improve medication adherence compared with conventional injection delivery and can lead to enhanced glycemic control, patient satisfaction, and improved health-related quality of life.17,23,24
The alternative modes of insulin delivery are summarized in the Table. Various preparations of insulin and insulin analogs are available for these systems. Administration schedules usually combine types of insulin in a regimen specific to the individual needs of each patient in an attempt to mimic physiologic secretion of insulin.
Table.
Alternative Modes of Insulin Delivery
Device | Advantages | Disadvantages |
---|---|---|
Insulin pen (replaceable cartridge and prefilled) | Discreet Injection may be more comfortable and less time consuming than vial/syringe Refrigeration not required Easy to use Accurate dosing Disposable |
Initially can be more expensive than vial/syringe Cannot mix insulin types Some insulin is wasted Possibility of air bubbles |
Insulin injection port | Reduces need for multiple daily skin punctures May remain in place for 72 hrs before application of a new port Discreet |
Possibility of crimping of device's soft cannula, resulting in limited medication delivery Possible skin irritation or failure of injection port adhesive patch |
Insulin infusion pump (continuous subcutaneous insulin infusion) | Uses only rapid-acting insulin (most consistent profile) Accurate dosing Allows flexible lifestyle Closest to mimicking body's physiologic secretion of insulin |
Possibility of crimping of infusion set soft cannula, resulting in limited medication delivery Possible skin irritation or failure of infusion set adhesive patch Pump and supplies expensive Undetected interruptions in insulin delivery may occur Requires high patient motivation, involvement, and commitment to use |
Transdermal insulin patch | Reduces need for conventional needles | Technology is new and costly Potential damage to the skin must be more completely evaluated |
Inhalable insulin | Need for fewer/no injections | Larger doses of insulin required Lack of patient/physician acceptance Pulmonary route not suitable for smokers or patients with asthma or other pulmonary problems Long-term impact on lung structure/function not clear Nasal route yields poor transport across nasal mucosa |
Insulin Pens
The insulin pen device uses an insulin cartridge rather than a vial, as well as disposable needles. Pens are the predominant insulin delivery system in most of the world, except in the United States.25
The 2 types of insulin pens available are replaceable and prefilled cartridge. A replaceable cartridge pen reuses the pen portion. When the insulin is used up, the cartridge is replaced with a new cartridge. A prefilled pen is entirely disposable: when the insulin is gone, the pen is discarded.
The insulin pen was an important milestone in the delivery of insulin, because it is convenient, portable, and discreet. These characteristics are more accommodating to a patient's lifestyle and may therefore improve quality of life. A randomized, open-label, crossover study was conducted at 50 physician offices in the United States.22 Patients completed several questionnaires, including the Insulin Device Preference Questionnaire. Among the entire cohort (N = 162), 72% of the patients indicated an overall preference for a disposable form of dosing (similar to an insulin pen) compared with 22% of those who preferred the vial/syringe (P <.001).22
Other advantages for pen users include convenience, ease of use, comfort associated with use in public and social settings, as well as decreased fear of self-injection.22 When multiple daily injections are required to reach recommended glycemic targets, pens may facilitate acceptance of such regimens, even when the increased frequency of injection is perceived to be a disadvantage.
Some insulin is wasted when pens are used: 1 to 2 units of insulin are lost when the pen is primed before each injection, and usually some insulin remains in the pen or cartridge (but not enough to inject) after use. Insulin pens do not permit mixing of insulin types; therefore, if the insulin mixture needed is not available as a premix, 2 injections must be given, 1 injection for each type of insulin.
In addition, pens are mechanically more complex and more costly than syringes and vials,13 with an annual cost (of insulin and supplies) between $2500 and $4500. However, these costs may be offset by decreased hospitalizations. A recent study indicated that annual hypoglycemia-associated costs were reduced by $788 per patient (from $1415 to $627; P <.01), predominantly as a result of decreased hospitalization costs (from $857 to $288; P <.01). Annual diabetes-attributable costs were reduced by $600 per patient (from $8827 to $8227; P <.01).17
Insulin Injection Ports
An insulin injection port is a novel, low-profile device that can reduce the impact of daily injections in adults and in children.26 This new technology offers a portal for delivering multiple doses of medication directly into the subcutaneous tissue without the need for multiple skin punctures.
The injection port is applied via a short insertion needle whereby a soft flexible cannula is guided into the subcutaneous space. Once applied, the insertion needle is removed, and only the soft, flexible cannula remains under the skin. A resealable medication port is directly atop the cannula and is kept in place on the skin's surface with an adhesive pad. Through a standard insulin syringe or an insulin pen, the patient receives a dose of insulin given by injection through the port. Because the device can typically be worn for 72 hours, it can substantially reduce the number of daily skin punctures, because insulin is injected through the port rather than the skin. Potential application sites include the abdomen and thighs. Once instructed by a healthcare provider, patients can then self-apply the injection port.
Use of the injection port can result in relief of preinjection anxiety, injection problems, and the procedural pain of repeated injections.27,28 Reported side effects include erythema and possible skin irritation.26 Measures of glycosylated albumin were within equivalence analysis limits compared with standard injections (P = .99).26
The use of injection ports is not restricted to insulin. They can be used for other prescribed medications that require multiple daily subcutaneous injections. Indeed, the newer incretin mimetics, which mimic the effect of glucagonlike peptide-1, are injectable products that could be delivered in the same fashion.
Continuous Subcutaneous Insulin Infusion Pumps
The continuous subcutaneous insulin infusion (CSII) pump, using a battery-powered pump, was introduced to treat type 1 diabetes more than 20 years ago. Rapid-acting insulins are appropriate for use in pumps. The CSII provides an approximation of normal plasma insulin profiles and increased flexibility regarding timing of meals and snacks compared with conventional insulin injection regimens.
Insulin pump therapy has been shown to result in improved metabolic control and reduced frequency of severe hypoglycemia.29 Pumps reduce the need for injections and are more adaptable to lifestyle modifications, such as delaying meals, variable sleep schedules, or variations in exercise patterns. Studies comparing CSII and multiple daily injections in patients with type 1 diabetes have shown outcomes (ie, improved glycemic control) that were comparable with or favored the former.29–33
However, pumps are not necessarily discreet to use, and pump infusion sets may result in site infections, abscess formation, and scarring.34 They also require a high level of patient motivation and commitment. Furthermore, they are expensive, costing more than $5000 in initial costs (pump and supplies) and about $2500 to $4500 in subsequent annual costs. Proponents assert that insulin pump therapy produces long-term reductions in complications, which offset these costs.35 Cost-benefit may be realized primarily in patients with frequent episodes of hypoglycemia.
Transdermal Patches
The insulin molecule is far too large to penetrate the skin passively. Therefore, active transdermal delivery systems have been developed that involve a chemical or mechanical disruption of the skin barrier. By using an applied force, such as ultrasound or an electrical current, active transdermal systems can deliver large-molecule formulations through the skin and into the bloodstream.36 However, this technology is costly and still under development; before replacing conventional needles, the safety and efficacy of these patches in delivering insulin without damage to the skin must be more completely evaluated.
Inhalable Insulin Devices
The first inhaled version of insulin became available in September 2006 in the United States. However, this system failed to gain the acceptance of patients and physicians. Despite this product's failure, one company continues the development of inhalable insulin devices, and the United States may see a return of inhalable insulin to the market in the near future.
The bioavailability of inhaled insulin is less than 20%; therefore, dosage requirements and cost per treatment are increased in comparison with insulin administered by subcutaneous injection. In addition, the long-term effects of intra-alveolar insulin deposition and immunogenic safety of inhaled insulin have not been fully elucidated.37
Delivery of inhaled insulin to the upper nasal airways suffers from poor transport across the nasal membranes. Delivery via this route requires very large doses of insulin or the use of a chemical to enhance insulin transport.38 Chemicals used to enhance insulin transport often cause nasal irritation and a runny nose. Underlying lung disease could disrupt the absorption of the intended insulin dose.
Implications
The increasing prevalence of diabetes worldwide is cause for concern, in terms of associated morbidity and increasing health costs. Insulin therapy is an integral part of the treatment of diabetes. The long-term benefits of insulin therapy to control blood glucose levels have been demonstrated in multiple clinical trials in patients with type 1 and type 2 diabetes mellitus.4–6,39,40 These studies demonstrated a correlation between tight glycemic control and a reduction in the progression of chronic complications associated with diabetes mellitus.
The insulin delivery mode is vital for its acceptance and adherence to therapy for achieving glycemic targets. Conventional multi-injection insulin delivery has been associated with perceived barriers on the part of patients and physicians. Substantial developments have occurred in insulin delivery during the past 20 years, focusing on increasing patient convenience and achieving better glycemic control to overcome barriers associated with conventional insulin injections.
Conclusion
Newer delivery devices may add a substantial upfront cost; however, the use of these devices to improve adherence could have significant implications on overall disease burden costs for patients and payers alike. These devices can also help to improve quality of life for patients with diabetes by reducing the number of daily skin punctures or providing enhanced convenience, and can help patients lead a life as normal as possible. In the long-term, cost-benefit analyses incorporating patient preferences would help gauge the cost-savings resulting from the use of these newer delivery devices.
Acknowledgments
This manuscript was supported by a grant from Patton Medical Devices, LP. The authors would like to thank Laurie Kozbelt for her editorial assistance with this manuscript.
Biography
Luther B. Travis
Disclosure Statement
Dr Akhrass is a Consultant to Patton Medical Devices and is on the Speaker's Bureau of Amylin, AstraZeneca, Daiichi Sankyo, Forest, Lilly, and Takeda. Dr Boswell is a Consultant to Patton Medical Devices. Ms Skinner is a Consultant to Patton Medical Devices and is on the Advisory Board of Boehringer Ingelheim. Dr Travis is Co-chair of the Scientific Advisory Committee of and a Consultant to Patton Medical Devices.
Contributor Information
Firas Akhrass, Endocrinologist, Diabetes and Glandular Disease Clinic, San Antonio, TX.
Nancy Skinner, President, Riverside Healthcare Consulting, Whitwell, TN.
Kimberly Boswell, Assistant Director, Xcenda, Palm Harbor, FL.
Luther B. Travis, Emeritus Professor of Pediatrics, UTMB, Galveston, TX.
References
- 1.National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics, 2007. www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm#7. Accessed July 2, 2008.
- 2.Carver C. Insulin treatment and the problem of weight gain in type 2 diabetes. Diabetes Educ. 2006; 32: 910–917. [DOI] [PubMed] [Google Scholar]
- 3.Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000; 36: 646–661. [DOI] [PubMed] [Google Scholar]
- 4.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993; 329: 977–986. [DOI] [PubMed] [Google Scholar]
- 5.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352: 837–853 Erratum in: Lancet. 1999; 354: 602. [PubMed] [Google Scholar]
- 6.Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321: 405–412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.American Diabetes Association. Executive summary: standards of medical care in diabetes—2008. Diabetes Care. 2008; 31 (suppl 1): S5–S11. [DOI] [PubMed] [Google Scholar]
- 8.Stotland NL. Overcoming psychological barriers in insulin therapy. Insulin. 2006; 1: 38–45. [Google Scholar]
- 9.Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004; 2: 12–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Brod M, Skovlund SE, Wittrup-Jensen KU. Measuring the impact of diabetes through patient report of treatment satisfaction, productivity and symptom experience. Qual Life Res. 2006; 15: 481–491. [DOI] [PubMed] [Google Scholar]
- 11.Funnell MM. Overcoming barriers to the initiation of insulin therapy. Clin Diabetes. 2007; 25: 36–38. [Google Scholar]
- 12.Siddiqui NI, Rahman S, Nessa A. Development of insulin delivery systems. Mymensingh Med J. 2008; 17: 102–110. [PubMed] [Google Scholar]
- 13.Korytkowski M, Niskanen L, Asakura T. FlexPen: addressing issues of confidence and convenience in insulin delivery. Clin Ther. 2005; 27 (suppl B): S89–S100. [DOI] [PubMed] [Google Scholar]
- 14.Davis SN, Renda SM. Psychological insulin resistance: overcoming barriers to starting insulin therapy. Diabetes Educator. 2006; 32 (suppl 4): 146S–152S. [DOI] [PubMed] [Google Scholar]
- 15.Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care. 2004; 27: 17–20. [DOI] [PubMed] [Google Scholar]
- 16.Brod M, Kongsø JH, Lessard S, Christensen TL. Psychological insulin resistance: patient beliefs and implications for diabetes management. Qual Life Res. 2009; 18: 23–32. [DOI] [PubMed] [Google Scholar]
- 17.Lee W, Balu S, Cobden D, et al. Medication adherence and the associated health-economic impact among patients with type 2 diabetes mellitus converting to insulin pen therapy: an analysis of third-party managed care claims data. Clin Ther. 2006; 28: 1712–1725. [DOI] [PubMed] [Google Scholar]
- 18.Donnelly LA, Morris AD, Evans JM; DARTS/MEMO Collaboration. Adherence to insulin and its association with glycaemic control in patients with type 2 diabetes. QJM. 2007; 100: 345–350. [DOI] [PubMed] [Google Scholar]
- 19.Hauber AB, Johnson FR, Sauriol L, Lescrauwaet B. Risking health to avoid injections: preferences of Canadians with type 2 diabetes. Diabetes Care. 2005; 28: 2243–2245. [DOI] [PubMed] [Google Scholar]
- 20.Pladevall M, Williams LK, Potts LA, et al. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes. Diabetes Care. 2004; 27: 2800–2805. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Balkrishnan R, Rajagopalan R, Camacho FT, et al. Predictors of medication adherence and associated health care costs in an older population with type 2 diabetes mellitus: a longitudinal cohort study. Clin Ther. 2003; 25: 2958–2971. [DOI] [PubMed] [Google Scholar]
- 22.Stockl K, Ory C, Vanderplas A, et al. An evaluation of patient preference for an alternative insulin delivery system compared to standard vial and syringe. Curr Med Res Opin. 2007; 23: 133–146. [DOI] [PubMed] [Google Scholar]
- 23.Gerber RA, Cappelleri JC, Kourides IA, Gelfand RA. Treatment satisfaction with inhaled insulin in patients with type 1 diabetes: a randomized controlled trial. Diabetes Care. 2001; 24: 1556–1559. [DOI] [PubMed] [Google Scholar]
- 24.Freemantle N, Blonde L, Duhot D, et al. Availability of inhaled insulin promotes greater perceived acceptance of insulin therapy in patients with type 2 diabetes. Diabetes Care. 2005; 28: 427–428. [DOI] [PubMed] [Google Scholar]
- 25.RNCOS. Drug delivery. Insulin delivery systems market analysis (2007–2010). Summary. www.rncos.com/Report/IM509.htm. Accessed May 1, 2009.
- 26.Blevins T, Schwartz SL, Bode B, et al. A study assessing an injection port for administration of insulin. Diabetes Spectrum. 2008; 21: 197–202. [Google Scholar]
- 27.Zamudio V. Role of devices in diabetes management. US Endocrine Disease. 2007; 1: 32–33. [Google Scholar]
- 28.Rayman G, Wise PH. An indwelling subcutaneous FEP cannula for intermittent insulin injection: patient experience and effect on diabetic control. Diabet Med. 1988; 5: 592–595. [DOI] [PubMed] [Google Scholar]
- 29.Weissberg-Benchell J, Antisdel Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care. 2003; 26: 1079–1087. [DOI] [PubMed] [Google Scholar]
- 30.Wood JR, Moreland EC, Volkening LK, et al. Durability of insulin pump use in pediatric patients with type 1 diabetes. Diabetes Care. 2006; 29: 2355–2360. [DOI] [PubMed] [Google Scholar]
- 31.Doyle EA, Weinzimer SA, Steffen AT, et al. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes Care. 2004; 27: 1554–1558. [DOI] [PubMed] [Google Scholar]
- 32.DeVries JH, Snoek FJ, Kostense PJ, et al. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Diabetes Care. 2002; 25: 2074–2080. [DOI] [PubMed] [Google Scholar]
- 33.Tsui E, Barnie A, Ross S, et al. Intensive insulin therapy with insulin lispro: a randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection. Diabetes Care. 2001; 24: 1722–1727. [DOI] [PubMed] [Google Scholar]
- 34.Richardson T, Kerr D. Skin-related complications of insulin therapy: epidemiology and emerging management strategies. Am J Clin Dermatol. 2003; 4: 661–667. [DOI] [PubMed] [Google Scholar]
- 35.Ulahannan T, Myint NN, Lonnen KF. Making the case for insulin pump therapy. Pract Diabetes Int. 2007; 24: 252–256. [Google Scholar]
- 36.Park EJ, Dodds J, Smith NB. Dose comparison of ultrasonic transdermal insulin delivery to subcutaneous insulin injection. Int J Nanomedicine. 2008; 3: 335–341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Mandal TK. Inhaled insulin for diabetes mellitus. Am J Health Syst Pharm. 2005; 62: 1359–1364. [DOI] [PubMed] [Google Scholar]
- 38.Cernea S, Raz I. Noninjectable methods of insulin administration. Drugs Today (Barc). 2006; 42: 405–424. [DOI] [PubMed] [Google Scholar]
- 39.Qaseem A, Vijan S, Snow V, et al. Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Glycemic control and type 2 diabetes mellitus: the optimal hemoglobin A1c targets. A guidance statement from the American College of Physicians. Ann Intern Med. 2007; 147: 417–422. [DOI] [PubMed] [Google Scholar]
- 40.Nathan DM, Cleary PA, Backlund JY, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353: 2643–2653. [DOI] [PMC free article] [PubMed] [Google Scholar]