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Home , Insulin (medication), Insulin glargine

EDITORIAL

Insulin Glargine (HOE901) First responsibilities: understanding the data and ensuring safety

n this issue, Heinemann et al. (1) and Rat- decline in activity through the duration of other journals. They leave the reader with ner et al. (2) provide the results of stud- the 30-h study. The authors conclude that a sense of promise, but without the firm Iies of glargine (formerly known as provides a flatter metabolic conviction that insulin glargine is clearly HOE901), the most recent addition to the profile than NPH insulin. Theoretically, this superior to other long-acting forms of growing family of insulin analogs and for- could prove to be advantageous in accom- insulin. The pharmacodynamic study sug- mulations. The authors report insulin modating the basal insulin requirements of gests that the peakless profile of action glargine’s pharmacodynamic characteristics patients with . should provide an advantage that can be (1) and data concerning its safety and effi- Ratner et al. (2) report initial results for used to produce clinically meaningful cacy when administered to subjects with the U.S. Study Group of Insulin Glargine in improvements in glycemic control. The who were treated with reg- Type 1 Diabetes. In their article, they ’s demonstration of a reduction ular insulin (2). Insulin glargine is produced describe the results of a large randomized in and in fasting plasma glu- by recombinant DNA technology with 2 prospective 28-week trial of insulin cose levels appears to provide an opportu- modifications of the native human insulin glargine versus NPH insulin. Patients with nity to advance further lowering to structure: substitution of the amino acid type 1 diabetes who were previously achieve a reduction in GHb. However, in glycine for the native asparagine at position treated with regular and NPH insulin par- this study, no change in GHb was evident. A21 of the A-chain of human insulin and ticipated in the study. Prior reports of clin- This characteristic does not lessen glargine’s the addition of 2 arginine molecules to the ical efficacy with insulin glargine have potential significance. Reducing hypogly-

NH2-terminal end of the B-chain of human involved short-term studies and few are cemia is a worthy end in itself. Several insulin. The resulting insulin glargine available except as abstracts or in review recent reports have attested to the impor- demonstrates an isoelectric point at pH 6.7, articles (3). This protocol could not be tance of reducing the frequency and sever- which is in contrast to the native molecule’s masked, because glargine is a clear solution ity of hypoglycemic reactions. isoelectric pH of 5.4. As a result, glargine is and NPH insulin is a milky suspension. In Currently, the available data concern- soluble at acidic pH and less soluble at the study, subjects who were randomized ing insulin glargine create a situation simi- physiological pH. Insulin glargine is sup- to insulin glargine administered it as a sin- lar to the circumstances in 1996, when plied as a clear colorless solution at acidic gle bedtime injection. Subjects random- lispro insulin was first marketed in the U.S. pH balances. Upon , ized to NPH insulin remained on the NPH In the case of lispro insulin, good pharma- the acid in the vehicle is neutralized and schedule that they were using before ran- codynamic data and promising studies sug- glargine precipitates, thereby delaying its domization (once daily at bedtime or twice gested that hypoglycemia reduction was absorption and prolonging its duration of daily before breakfast and at bedtime). possible. Studies demonstrating improve- action. At the time this editorial was written, Dose titration of both insulin glargine and ments in GHb have only recently been the Food and Drug Administration (FDA) NPH insulin was performed on the basis of published (4,5). In particular, the research was conducting its review of insulin capillary results. of Lalli et al. (5) demonstrates the difficulty glargine. The goal was to achieve a fasting blood glu- of translating the theoretical benefits of new Heinemann et al. (1) document the cose level between 4.4 and 6.7 mmol/l therapy into clinically significant benefits. results of single-dose double-blind (80–120 mg/dl), as limited by symptomatic The reported regimen used combinations crossover euglycemic clamp studies in hypoglycemia. The protocol examined of lispro and NPH in various ratios at each healthy male volunteers and compare the glycemic control and hypoglycemia as end meal. Certainly, the initial patients of the time-action profiles of subcutaneously points. Insulin glargine was well tolerated study group were not treated with the reg- injected glargine, NPH insulin, and without evidence of antibody formation imen that they eventually studied. Adapta- placebo. Prior pharmacodynamic studies and with only minimal injection site reac- tions were required due to the context of using insulin glargine have evaluated for- tions. Insignificant reductions from base- the society in which the patients lived mulations with higher and lower zinc con- line in glycohemoglobin (GHb) were (Italy) and because of the content of the centrations than the current formulation demonstrated in both groups. Insulin patient education program that was avail- (zinc 30 µg/ml), and they have only been glargine demonstrated a significantly able to them. The researchers’ understand- reported in abstract form or in review arti- greater reduction in fasting plasma glucose ing of the of lispro and cles. The work of Heinemann et al. demon- levels. After the initial titration phase their extensive clinical experience resulted strates that glargine provides an essentially (2 months), there also was a significant in the development of a technique that peakless profile of action with its onset of reduction in hypoglycemia, including noc- worked well for their patients. Their results action at 2–4 h and with a duration 24 h. turnal and severe hypoglycemic episodes. are nothing short of spectacular, and they By comparison, NPH human insulin was These two articles are among many are clearly the product of painstaking clin- again documented to provide a substantial studies conducted with insulin glargine ical observation complemented by excel- peak in action at 4 h with a subsequent that will be published in Diabetes Care and lent clinical research. Clinicians have

576 DIABETES CARE, VOLUME 23, NUMBER 5, MAY 2000 Editorial worked very hard to develop techniques to insulin (instead of ) for the coincide with the launch of insulin use the insulin formulations that have been therapy of type 1 diabetes is rapidly glargine. By contrast, it is an outrage that available for decades. It will inevitably take increasing in specialty clinics and offices, the data for a number of other products time to learn how to actually exploit the the use of glargine (in all probability) will marketed for various indications in the theoretical advantages of insulin glargine. be rapidly adopted in those practices. It is therapy of diabetes are available only under At the University of North Carolina, an even within the realm of possibilities that Freedom of Information Act queries to the insulin glargine study site, we tried to iden- the “poor man’s pump” (multiple daily FDA. It is even more infuriating when tify subjects who had done poorly on mul- injection regimens using insulin pens) may claims are implied by data presented in tiple daily injection regimens, despite prove to be as effective, less expensive, and promotional material, although there are maximal interventions. This was driven by more convenient than continuous subcu- neither available raw data nor plans to con- our unwillingness to change the insulin taneous insulin infusion with the use of duct the appropriate trials to fully investi- regimens of our patients who were doing insulin glargine. Data that suggest the ben- gate those claims. well. The subjects we sought would have efit of glargine therapy in Second, as a community of diabetes been excellent candidates for also exist in abstract form. Full publication professionals, we need to help the pharma- therapy. However, they had either refused of those results in combination with clini- ceutical industry understand the limita- pump therapy or faced financial barriers cal experience may reveal the potential of tions of their data, whether published or that prevented them from using an insulin insulin glargine as an insulin supplement in promotional. We need to suggest trials pump. Other patients enrolled in the study, patients with moderate insulin deficiency and/or gather clinical data in a systematic motivated by personal interest or a desire to and as a basal insulin replacement in fashion to highlight the need for further mitigate health care expenses. Because the patients with more complete insulin insuf- study or to generate hypotheses. As an study was not masked, both subjects and ficiency. Many other potential uses of example, the reviewers of this manuscript investigators were fully aware of what for- insulin glargine will also require specific have raised the issue of how the use of mulation of insulin each individual was study before they can be widely consid- insulin glargine would compare with the taking. As Ratner et al. (2) suggest, this may ered, such as its use in and as a use of human . Given that have subconsciously limited our enthusi- form of immunomodulatory therapy in the there are both strong proponents and asm to aggressively manipulate the dose of prevention of autoimmune diabetes. opponents of ultralente use, this topic an unfamiliar product in subjects who were The limitations of the insulin glargine appears to be deserving of exploration in, at often quite well controlled. (The average data that have been developed through reg- least, limited trials. Also, we should GHb concentration of the participants was ulatory approval processes and that remain remember that tremendous interindivid- 7.7%, but many were significantly higher, incompletely available in the peer review ual differences among drug responses exist. because only subjects with GHb concen- literature have wider implications for new We should be careful to recognize that no trations 12% were excluded.) In our drug development, marketing, and pre- approaches work optimally in all patients, small sample, the most dramatic responses scribing. Diabetes professionals are often regardless of the clinical trial data available. to insulin glargine were in patients who called on to help in the design and execu- The usefulness of an approach that consid- could not achieve glycemic control targets tion of drug trials and in the dissemination ers each patient interaction as an “n = 1” without unacceptable levels of hypogly- of the data in promotional and continuing clinical trial cannot be underestimated. cemia, despite multiple attempts with var- medical education presentations. It is Finally, as a community generally eager ious regimens involving essentially all increasingly critical for us to exhort our col- to adopt the use of newly released products possible combinations of available insulin leagues in the pharmaceutical industry to for the therapy of diabetes, we need to be formulations. Not only did their glycemic both conduct appropriate trials and to pub- judicious in exploring the usefulness of all control improve during glargine therapy, lish the findings of those trials. The useful- new technology. Careful individualized but it also worsened with the withdrawal of ness of every new product in each and education should be part and parcel of insulin glargine at the conclusion of the every clinical situation for which it is mar- each prescription for new products. We study. In the other subjects who were ran- keted must be thoroughly scrutinized cannot underestimate how patients with domized to glargine, it was less clear through trials and data analysis. My com- diabetes, over the course of months and whether their enthusiasm was based on mentary is not specifically directed to the years, become finely attuned to their treat- real improvements or on the belief that the insulin glargine developers or to the mem- ment regimens with purposeful and sub- newer product represented an advance- bers of the FDA who are involved in the conscious behaviors that vary from ment in medicine. drug approval process. The studies that are individual to individual. In addition, Based on the theoretical benefits, the published in this issue and other studies patients should be encouraged to contact available data concerning insulin glargine, that have been presented as abstracts are their health care teams quickly if problems and my limited experience, I predict that logical and practical. However, they repre- arise with new therapy. Not only can we patients with type 1 diabetes who have dif- sent only an initial step in documenting provide assistance, but we may also learn ficulty with glycemic control will be helped the safety and efficacy in treating the full from the experiences and observations of by insulin glargine. I suspect that the pas- panoply of patients with diabetes. In fact, our patients. As a medical community sage of time and the accumulation of clini- the developers of glargine should be equipped to understand and investigate cal experience will enable us to take full applauded for the availability of several adverse events, we need to report them advantage of the pharmacodynamics of this full research reports in peer-review litera- promptly to both the pharmaceutical product, alone and in combination with ture. These and other articles under edito- industry and to the FDA through the Med- lispro insulin. Just as the use of lispro rial review will likely be published to Watch program (on-line reporting avail-

DIABETES CARE, VOLUME 23, NUMBER 5, MAY 2000 577 Editorial able at http://www.fda.gov/medwatch/, by availability of a true basal insulin is cer- action profile of the long-acting insulin ana- phone at 800-FDA-1088, and by fax at tainly a long-awaited advance. Careful log insulin glargine (HOE901) in compar- 800-FDA-0178). It is only through this attention to experience in clinical use on ison with those of NPH insulin and process that we can ensure the safety of our part, combined with the initiation of placebo. Diabetes Care 23:644–649, 2000 every new product and device. These prin- additional studies and the promise of their 2. Ratner RE, Hirsch IB, Neifing JL, Garg SK, ciples are certainly relevant to insulin published results, will define how well we Mecca TE, Wilson CA, for the U.S. Study glargine. Particularly among patients with can use this new technology to benefit Group of Insulin Glargine in Type 1 Dia- betes: Less hypoglycemia with insulin type 1 diabetes treated in specialty practice, our patients. glargine in intensive insulin therapy for there will appropriately be significant inter- type 1 diabetes. Diabetes Care 23:639–643, est in using this product. Care must be JOHN BUSE, MD, PHD 2000 taken to educate the patient to not mix 3. Pieber TR, Eugène-Jolchine I, Derobert E, glargine with other formulations of insulin From the Diabetes Care Center, University of North the European Study Group of HOE 901 in (because the glargine will precipitate Carolina, Durham, North Carolina. Address correspondence to John Buse, MD, PhD, Type 1 Diabetes: Efficacy and safety of HOE instantly) and to review both sick-day rules University of North Carolina, Diabetes Care Center, 901 versus NPH insulin in patients with and the management of hypo- and hyper- 5316 Highgate Dr., Suite 125, Durham, NC 27713. type 1 diabetes. Diabetes Care 23:157–162, glycemia. It would be prudent to encourage E-mail: [email protected]. 2000 more frequent monitoring, particularly at J.B. is a consultant for and has received honoraria and 4. Zinman B, Tildesley H, Chiasson J, Tsui E, bedtime and midsleep, for at least a week research support from Aventis Pharm and and Co. Strack T: in CSII: results of a after switching formulations. Obviously, double-blind crossover study. Diabetes the provision of specific guidelines for con- 46:440–443, 1997 tacting the health care team if problems 5. Lalli C, Ciofetta M, Del Sindaco P, Torlone Acknowledgments — Thanks to Jennifer E, Pampanelli S, Compagnucci P, Carte- should ensue will be important in mini- Camia Grant and Lyn Reynolds for extremely chini MG, Bartocci L, Brunetti P, Bolli GB: mizing adverse events. helpful editorial suggestions. Long-term intensive treatment of type 1 These are exciting times in diabetes diabetes with the short-acting insulin ana- treatment and research. Many of the phar- References log lispro in variable combination with macological obstacles to ideal patient care 1. Heinemann L, Linkeschova R, Rave K, NPH insulin at mealtime. Diabetes Care are gradually being surmounted. The Hompesch B, Sedlak M, Heise T: Time- 22:468–477, 1999

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