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Inhaled Insulin Improves Glycemic Control When Substituted for or Added to Oral Combination Therapy in Type 2 Diabetes: A Randomized, Controlled Trial

Julio Rosenstock, MD; Bernard Zinman, MD; Liam J. Murphy, MD; Stephen C. Clement, MD; Paul Moore, MD; C. Keith Bowering, MD; Rosa Hendler, MD; Shu-Ping Lan, MPH; and William T. Cefalu, MD
[+] Article and Author Information

From Dallas Diabetes and Endocrine Center at Medical City, Dallas, Texas; University of Toronto and Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada; University of Manitoba, Winnipeg, Manitoba, Canada; Georgetown University, Washington, DC; Austin Diagnostic Clinic, Austin, Texas; University of Alberta and Royal Alexandra Hospital, Edmonton, Alberta, Canada; Yale University School of Medicine, New Haven, and Pfizer Global Research and Development, Groton, Connecticut; and Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana.


Note: A preliminary report of this study was submitted to the American Diabetes Association 62nd Annual Meeting and Scientific Sessions, San Francisco, California, 14–18 June 2002.

Acknowledgments: The authors thank the investigators (Appendix 2) and coordinators who participated in this study and the General Clinical Research Center, MO1 RR 00125, Yale University.

Grant Support: By a research grant from Pfizer Inc. and the sanofi-aventis Group. The study was conducted by investigators and their institutions contracted by and under the direction of the sponsors (Pfizer Global Research and Development and the sanofi-aventis Group). The investigators were responsible for recruiting patients, adhering to the study procedures described in the protocol, keeping records of study drug, capturing and recording data, and accurately completing and signing the case report forms supplied by the sponsors.

Potential Financial Conflicts of Interest: Employment: S.-P. Lan (Pfizer Inc.); Consultancies: J. Rosenstock (Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin), B. Zinman (Eli Lilly Inc., sanofi-aventis, Pfizer Inc.), C.K. Bowering (Eli Lilly Inc., GlaxoSmithKline, Novo Nordisk, AstraZeneca); W.T. Cefalu (sanofi-aventis, Pfizer Inc.); Honoraria: J. Rosenstock (Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin), B. Zinman (Eli Lilly Inc., sanofi-aventis, Pfizer Inc.), L.J. Murphy (Eli Lilly Inc., Pfizer Inc., GlaxoSmithKline, sanofi-aventis); C.K. Bowering (Eli Lilly Inc., GlaxoSmithKline, Novo Nordisk, AstraZeneca, Pfizer Inc., sanofi-aventis), W.T. Cefalu (sanofi-aventis, Pfizer Inc.); Stock ownership or options (other than mutual funds): S.-P. Lan (Pfizer Inc.); Grants received: J. Rosenstock (Merck, Pfizer Inc., sanofi-aventis, Novo Nordisk, Eli Lilly Inc., GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Sankyo, MannKind), B. Zinman (Pfizer Inc.), S.C. Clement (Pfizer Inc.), C.K. Bowering (GlaxoSmithKline, AstraZeneca, Pfizer Inc., sanofi-aventis), R. Hendler (Pfizer Inc.), W.T. Cefalu (Pfizer Inc.).

Requests for Single Reprints: Julio Rosenstock, MD, Dallas Diabetes and Endocrine Center, 7777 Forest Lane, Suite C618, Medical City Dallas, Dallas, TX 75230; e-mail, juliorosenstock@dallasdiabetes.com.

Current Author Addresses: Dr. Rosenstock: Dallas Diabetes and Endocrine Center, 7777 Forest Lane, Suite C618, Medical City Dallas, Dallas, TX 75230.

Dr. Zinman: Department of Medicine, Mount Sinai Hospital, L 5-024, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.

Dr. Murphy: Department of Internal Medicine, University of Manitoba, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R8, Canada.

Dr. Clement: Department of Endocrinology, Georgetown University Hospital, Building D, Room 232, 4000 Reservoir Road NW, Washington, DC 20007.

Dr. Moore: Austin Diagnostic Clinic, 12221 MoPac Expressway North, 2nd Floor, South Entrance, Austin, TX 78758-2483.

Dr. Bowering: Multidisciplinary Diabetic Foot Clinic, Royal Alexandra Hospital, 10240 Kingsway Avenue, Edmonton, Alberta T5H 3V9, Canada.

Dr. Hendler: Department of Internal Medicine, Yale University School of Medicine, Fitkin 1, 333 Cedar Street, PO Box 208020, New Haven, CT 06520-8020.

Ms. Lan: Pfizer Inc., MS 6025-A4269, 50 Pequot Avenue, New London, CT 06320.

Dr. Cefalu: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808.

Author Contributions: Conception and design: J. Rosenstock, B. Zinman.

Analysis and interpretation of the data: J. Rosenstock, B. Zinman, S.-P. Lan.

Drafting of the article: J. Rosenstock, W.T. Cefalu.

Critical revision of the article for important intellectual content: J. Rosenstock, B. Zinman, L.J. Murphy, P. Moore, C.K. Bowering, R. Hendler, S.-P. Lan, W.T. Cefalu.

Final approval of the article: J. Rosenstock, B. Zinman, L.J. Murphy, S.C. Clement, P. Moore, C.K. Bowering, R. Hendler, W.T. Cefalu.

Provision of study materials or patients: J. Rosenstock, B. Zinman, L.J. Murphy, S.C. Clement, P. Moore, C.K. Bowering, R. Hendler, W.T. Cefalu.

Statistical expertise: S.-P. Lan.

Obtaining of funding: J. Rosenstock, B. Zinman.

Administrative, technical, or logistic support: J. Rosenstock, B. Zinman.

Collection and assembly of data: J. Rosenstock, S.C. Clement, B. Zinman.


Ann Intern Med. 2005;143(8):549-558. doi:10.7326/0003-4819-143-8-200510180-00005
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A large clinical trial program assessed the efficacy and safety of inhaled insulin in patients with type 1 or type 2 diabetes. In patients with type 1 diabetes, inhaled insulin showed similar decreases in mean hemoglobin A1c level compared with subcutaneous insulin in studies of 6 months' duration (22, 30). In patients with type 2 diabetes, treatment for 6 months with inhaled insulin or subcutaneous insulin also resulted in similar improvements in glycemic control (23). The results of a 2-year study demonstrated the efficacy and long-term pulmonary safety of inhaled insulin in combination with an oral agent regimen in patients with type 2 diabetes (31). Finally, we offered continued, open-label inhaled insulin therapy to patients who completed the randomized, controlled clinical trials. Four-year data from these extension studies show that inhaled insulin can be used to maintain long-term glycemic control in patients with type 1 or type 2 diabetes (32).

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Figures

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Figure 1.
The inhaled insulin delivery system.

The pulmonary inhaler consists of a reusable dry powder inhaler and unit-dose blisters containing insulin powder for inhalation. The system is designed to deliver the aerosolized powder to the small airways and alveoli to enable systemic insulin absorption. The pulmonary inhaler is solely mechanical, using no batteries or electronics, and requires only modest effort by the patient to operate. The chamber is transparent to allow the patient to see the insulin cloud after powder aerosolization. The inhaler measures approximately 16.5 cm in length when in the closed position and approximately 27.5 cm when in use (fully extended). The weight is approximately 6 oz (170 g). On the basis of experience from the clinical trial program, replacement of the insulin release unit is required every 2 weeks.

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Figure 2.
Flow of patients through the study.1c

AE = adverse event; ITT = intention-to-treat. *One patient was randomly assigned to receive inhaled insulin monotherapy but received inhaled insulin plus 2 oral agents. †Discontinuation from the study did not by itself exclude a patient from analysis. ‡Patients were excluded from the full analysis set for lack of baseline or postbaseline hemoglobin A1c values.

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Figure 3.
Hemoglobin A1c values during 3 months of treatment (top) and patients reaching target hemoglobin A1c level at study end (bottom).

Top. Mean (SD) hemoglobin A1c values during 3 months of treatment with inhaled insulin (INH) plus 2 oral agents (OAs), INH monotherapy, or 2 OAs. *INH plus 2 OAs vs. 2 OAs adjusted difference at week 12 (last observation carried forward [LOCF]), −1.67 percentage points (95% CI, −1.90 to −1.44 percentage points). †INH vs. 2 OAs adjusted difference at week 12 (LOCF), −1.18 percentage points (CI, −1.41 to −0.95 percentage point). Numbers of patients analyzed at each time point by treatment group are shown below the graph. Bottom. Percentages of patients reaching target hemoglobin A values at study end with INH plus 2 OAs, INH monotherapy, or 2 OAs. ‡INH plus 2 OAs vs. 2 OAs adjusted odds ratio was 40.5 (CI, 17.0 to 96.9) for hemoglobin A1c level < 8% and 44.7 (CI, 6.0 to 335.2) for hemoglobin A1c level < 7%. §INH vs. 2 OAs adjusted odds ratio was 7.5 (CI, 3.6 to 15.5) for hemoglobin A1c level < 8% and 19.0 (CI, 2.5 to 145.8) for hemoglobin A1c level < 7%.

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Figure 4.
Adjusted mean change in fasting plasma glucose concentration (top) and 2-hour postprandial glucose concentration (bottom) from baseline to study end after 12 weeks of treatment.

Top. Adjusted mean change in fasting plasma glucose concentration with inhaled insulin (INH) plus 2 oral agents (OAs), INH monotherapy, or 2 OAs. *Adjusted difference at week 12, −2.9 mmol/L (−53 mg/dL) (95% CI, −3.7 mmol/L [−66 mg/dL] to −2.3 mmol/L [−41 mg/dL]). †Adjusted difference at week 12, −1.3 mmol/L (−24 mg/dL) (CI, −2.0 mmol/L [−36 mg/dL] to −0.6 mmol/L [−11 mg/dL]). Bottom. Adjusted mean change in 2-hour postprandial glucose concentration from baseline to study end after 12 weeks of treatment with INH plus 2 OAs, INH monotherapy, or 2 OAs. Adjusted difference at week 12, −4.2 mmol/L (−76 mg/dL) (CI, −5.2 mmol/L [−93 mg/dL] to −3.2 mmol/L [−58 mg/dL]). †Adjusted difference at week 12, −3.4 mmol/L (−62 mg/dL) (CI, −4.4 mmol/L [−79 mg/dL] to −2.5 mmol/L [−45 mg/dL]).

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Letters

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Comments

Submit a Comment
Curiousity about Timing of Inhaled Insulin Publication
Posted on November 3, 2005
Lorraine Tosiello
Overlook Hospital, Summit NJ
Conflict of Interest: None Declared

November 2, 2005

To the Editors:

Like many general internists we have had our interest piqued about inhaled insulin for several years, with data eking out slowly, largely thru endocrinologic publications and meetings. So, we were delighted to see the issue addressed recently in "our journal"(1).

However, after reading the article, we were disappointed by the design of the study and wonder about the editors' decision to publish it at this time.

Our concerns about the methodology include the following issues. First, there is a lack of blinding, which could introduce conscious and unconscious biases and could have been avoided by having a placebo inhaler for the group remaining on their oral agents. Second, the "control group" was clearly failing their regimen. A more rigorous arm of the study would have been to compare the clinical standard of care (ie: comparison to an added dose of intermediate acting insulin at bedtime.) Finally, the duration of the study is so short that it neither assuages our worries about metabolic worsening due to longterm insulin therapy nor our concern about pulmonary outcomes.

The study as designed shows that in patients failing their oral regimen for Type 2 diabetes, the addition or substitution of insulin (in the innovative inhaled form) effects impressive short term glucose control. Most clinicians have been aware of the efficacy of insulin in this setting, but opt for insulin as a last resort specifically because of the metabolic issues of hyperinsulinemia and weight gain.

We couldn't help but note that the study was conducted 7 years ago (troglitazone could be part of the dual regimen) and also that the publication date of October 18, 2005 coincided with the FDA deliberations regarding approval for inhaled insulin. Could the anticipated media interest surrounding the FDA decision have influenced the editors' enthusiasm for publishing the article at this time?

Sincerely,

Lorraine Tosiello, MD, FACP Priya Ravi, MD Department of Internal Medicine Overlook Hospital, Summit, NJ

(1). Rosenstock J, Zinman B, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes. Ann Int Med. 2005;143:549-558.

Conflict of Interest:

None declared

Inhaled insulin and glycemic control
Posted on November 8, 2005
Yujiro Kida
Department of Anatomy II, Tsurumi University, School of Dental Medicine
Conflict of Interest: None Declared

Rosenstock et al. reported that inhaled insulin improved overall glycemic control and hemoglobin A1c (HbA1c) level in patients with type 2 diabetes when added to or substituted for dual oral agent therapy with an insulin secretagogue and sensitizer (1). As Comi RJ pointed out in editorial (2), it is very surprising that HbA1c level decreased from 9.3% to 7.9% in the patients using inhaled insulin alone without prescribing intermediate- or long- acting insulin. Although premeal inhaled insulin regimen replace intrinsic prandial insulin, intrinsic basal insulin secretion would not be restored by the regimen of Rosenstock and coworkers, because inhaled insulin act for 4 to 6 hours. Although the authors did not mention, it would often happen nocturnal hyperglycemia by their regimen.

UKPDS showed that beta-cell failure is progressive; 50%of normal beta-cell function at diagnosis with a steady decline following diagnosis (3). Concomitantly, 53% of patients with type 2 diabetes initially treated with sulfonylureas required insulin therapy by 6 years, and almost 80% required insulin by 9 years (4). In the study by Rosenstock and colleagues, mean duration of diabetes in eligible patients was 9 to 10 years (1). Therefore, it is problem ethically that Rosenstock et al. set the group receiving only dual oral agent in spite of poor glycemic control, even if the study duration was 12 weeks.

Conflict of Interest:

None declared

Editor's Reply
Posted on November 9, 2005
Harold Sox
American College of Physicians
Conflict of Interest: None Declared

As a matter of editorial policy, we avoid doing anything that people would interpret as collusion with a commercial company to draw attention to their product. In this case, we knew that the FDA had not yet approved inhaled insulin, but we had no idea when it would announce its decision. We could not and did not engineer the publication date to coincide with the FDA announcement.

Conflict of Interest:

None declared

Is the era of insulin injections for diabetes patients drawing to a close?
Posted on November 11, 2005
Dr Shamsul A Bhuiyan
No Affiliation
Conflict of Interest: None Declared

Probably not, at least not yet. Even so, some researchers exploring alternative delivery systems believe that inhaled insulin is now on the fast track and could emerge as a viable, noninvasive avenue for administering insulin.

We found this study (by Julio Rosenstock et al) encouraging. Rosenstock et al. reported that inhaled insulin improved overall glycemic control and hemoglobin A1C (HbA1c) level in patients with type 2 diabetes when added to or substituted for dual oral agent therapy with an insulin secretagogue and sensitizer. There was little unclear point about this study, At the bottom author Julio Rosenstock et al mentioned that, a preliminary report of this study was submitted to the American Diabetes Association 62nd Annual Meeting and Scientific Sessions, San Francisco, California, 14"“18 June 2002. This means that this article is published after 3 years. This is confusing! We are disappointed by the design of the study and wonder about the editors' decision to publish it at this time. Study method would be more appropriate if it was double blinded and one group of patient taking placebo inhaler, while other group taking insulin inhaler. Duration of study is really short, which is not encouraging to see long- term control of glycemic effect. Only use of inhaler insulin would give more accurate conclusion.

For more than 80 years, patients with type 1 and type 2 diabetes have relied on subcutaneous injections as the route for exogenous insulin administration. But inhaled intrapulmonary delivery of insulin appears to be a promising option and perhaps a way to maintain glycemic control without the need for injections before meals. Although inhaled insulin is not a new idea"”it was first suggested in the 1920s"”encouraging findings from recent studies, including phase 3 trials, captured considerable attention at the American Diabetes Association's (ADA's) 65th Scientific Sessions(1). Another study (2) was done 1993 at Johns Hopkins University School of Hygiene and Public Health where they found that approximately 1.0 U of aerosolized insulin per kilogram of body weight, delivered by oral inhalation and deposited predominantly within the lungs, is well tolerated and can effectively normalize plasma glucose levels in patients with NIDDM. In conclusion I would like to say that Rosenstock et al study will encourage more other researchers about the inhaled insulin use in diabetes patients.

Reference: 1. Richard Trubo Interest in Inhaled Insulin Grows JAMA, September 14, 2005; 294: 1195 - 1196.

2. B. L. Laube; A. Georgopoulos; G. K. Adams 3rd Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients JAMA, Apr 1993; 269: 2106 - 2109.

Conflict of Interest:

None declared

Letter to editor
Posted on November 11, 2005
Balavenkatesh Kanna
Weill Medical College of Cornell University, Lincoln Hosiptal NY
Conflict of Interest: None Declared

In reference to the interesting study by Rosenstock et al (1), we have the following comments. The study included type 2 diabetes patients with a wide range of body mass index (BMI). In patients with type 2 diabetes, obesity is associated with poor treatment response to insulin. (2) As higher BMI may be a potential confounder of the study's primary outcome namely change in baseline Hemoglobin A1C (HbA1C), a stratified analysis based on pre-defined BMI strata would provide valuable information regarding the effect of inhaled insulin among patients within different BMI strata. In addition, analysis of the confounding effects of dietary restriction and exercise regimen on diabetic control is also necessary. As in any open label study, performance and observation biases of the un- blinded patients receiving the new inhaled insulin treatment as well as the treatment administering investigators may have a significant impact on outcome measurements. (3) Lastly, mean outcome HbA1C levels are affected by outliers that can increase error rates and cause alteration of estimates in statistical testing. (4) Therefore, readers will be interested to view the distribution of the pre and post treatment HbA1C levels of the study groups.

Conflict of Interest:

None declared

Rosenstock et al response to letters
Posted on February 7, 2006
Julio Rosenstock
Dallas Diabetes and Endocrine Center
Conflict of Interest: None Declared

TO THE EDITOR

We would like to thank Annals readers for their interest in our paper (1) and take this opportunity to address some of the points raised in their letters.

We agree that a limitation of the study was the open-label design. However, a double-blind study was not feasible for three principal reasons: (i) it was not possible to manufacture a suitable placebo for inhaled human insulin (INH), (ii) it seemed inappropriate to blind treatment when individualized flexible dose titration is needed, and (iii) given the immediate effects of INH on blood glucose, unblinding INH or placebo by patients or physicians would have been very easy.

Ours was a proof-of-concept study, designed in 1998, according to good clinical practices at the time, and based on a previous study of similar design. (2) We do not believe there were any ethical issues for patients randomized to the control group as microvascular complications are associated with long-term hyperglycemia, and there is no evidence that a relatively short period of inadequate glucose control will have a deleterious effect. The reality is that many patients with type 2 diabetes continue on oral agents rather than initiate insulin therapy despite poor glycemic control. (3) A 3-month duration was selected as a compromise between sufficient time to show an effect,(2) and minimizing exposure to hyperglycemia in the control group. Further, all subjects had the option to receive INH by enrolling in an open-label extension upon study completion.

In response to concerns regarding the timing of the publication, we would like to reaffirm the Editor's Reply of 9 November 2005 and definitively state that the publication of this paper was not engineered to coincide with the FDA Advisory Committee report on Exubera. It is essential that data such as these are subject to rigorous scientific scrutiny in a peer review journal. Indeed, the paper was subject to two rounds of review by Annals over several months, which also required the submission of additional analyses and thus it would be impossible to predict if publication would coincide with the FDA Advisory Committee report.

As highlighted in the associated Editorial,(4) we were also pleasantly surprised at the robust response to INH despite what might appear to be a "non-traditional" approach. Further, the effects observed with INH extended beyond the predicted pharmacokinetics with substantial improvements in fasting plasma glucose, which probably contributes to the robust effects on HbA1c reductions.

Where INH could really have an impact will be if healthcare professionals and patients start to use insulin much earlier and more aggressively in adults with type 2 diabetes. The availability of INH as a treatment option has already been shown to significantly increase the proportion of patients who would theoretically choose insulin overall when failing to achieve glycemic control on diet and/or oral antidiabetic agents.(5) We agree with the viewpoint expressed in the associated Editorial,(3) in the end it will be patient acceptance and preference that will determine the future use of Exubera.

1. Rosenstock J, Zinman B, Murphy LJ, Clement SC, Moore P, Bowering CK, Hendler R, Lan SP, Cefalu WT. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med 2005;143:549- 558.

2. Weiss et al Weiss SR, Cheng SL, Kourides IA, Gelfand RA, Landschulz WH, for the Inhaled Insulin Phase II Study Group: Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial. Arch Intern Med 2003; 163:2277-2282.

3. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004;27:1535-1540.

4. Comi RJ. Treatment of type 2 diabetes mellitus: a weighty enigma. Ann Intern Med 2005;143:609-610.

5. Freemantle N, Blonde L, Duhot D, Hompesch M, Eggertsen R, Hobbs R, Martinez L, Ross S, Bolinder B, Striddle E. Availability of inhaled insulin promotes greater perceived acceptance of insulin therapy in patients with type 2 diabetes. Diabetes Care 2005;28:427-428.

Conflict of Interest:

Consultancies: Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin); Honoraria: Pfizer Inc., sanofi-aventis, Novo Nordisk, GlaxoSmithKline, Takeda, Centocor, Johnson & Johnson, Amylin; Grants received: Merck, Pfizer Inc., sanofi-aventis, Novo Nordisk, Eli Lilly Inc., GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Sankyo, MannKind.

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Summary for Patients

Inhaled Insulin with or Instead of Oral Medications for Type 2 Diabetes

The summary below is from the full report titled “Inhaled Insulin Improves Glycemic Control When Substituted for or Added to Oral Combination Therapy in Type 2 Diabetes. A Randomized, Controlled Trial.” It is in the 18 October 2005 issue of Annals of Internal Medicine (volume 143, pages 549-558). The authors are J. Rosenstock, B. Zinman, L.J. Murphy, S.C. Clement, P. Moore, C.K. Bowering, R. Hendler, S.-P. Lan, and W.T. Cefalu.

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