The Use of Insulin Preparations—an Evaluation of the DPV Registry

Amongst the most important developments in diabetic care over the past decades was the introduction of delayed-release insulin, human insulin produced by gene engineering, as well as (ultra-)rapid (1996, 2017) and long-acting analog insulins of the first and second generation (2000, 2015) (1). The further development of rapid-acting insulins is aimed at matching the physiological action profile of endogenous insulin to lower postprandial blood glucose spikes and subsequent episodes of hypoglycemia. Long-acting insulins are designed to reduce the number of daily injections and so improve quality of life. The aim of the present analysis is to show which insulins have been used by patients with type 1 diabetes (T1D) and which insulins have been used by those with type 2 diabetes (T2D), using data from the German DPV registry (diabetes patient registry) gathered since it was established 27 years ago.

Methods

All patients with T1D (children: N = 88 564; adults: N = 79 448) and all adults with T2D (N = 444 450) from Germany whose data are recorded in the DPV database were included (2). The proportion of zinc insulins, neutral protamine Hagedorn (NPH) insulin, and first and second generation long-acting analog insulins, as well as the proportion of regular insulin, rapid-acting analog insulins, and ultrarapid insulin analogs were determined for the years 1995 thru 2021. In addition, odds ratios (OR) were calculated for the use of rapid-acting/long-acting analog insulins in the patients’ most recent year of treatment in relation to age, sex, place of residence (old versus new German states), body mass index (BMI), HbA1c level, and type of therapy (pump versus injection). All evaluations were carried out for three subgroups:

• T1D—children (age <18 years)
• T1D—adults
• T2D—adults (≥18 years).

This was done using logistic regression models, adjusted for

• Age groups (T1D—children: <6, 6 to <12, 12 to <18 years; T1D—adults: 18 to <30, 30 to <50, ≥50 years; T2D—adults: < 50, 50 to <70, ≥70 years)
• Sex
• Diabetes duration groups (T1D—children: <2, 2 to <5, ≥5 years; T1D—adults: <5, 5 to <10, 10 to <20, ≥20 years; T2D—adults: <5, 5 to <10, ≥10 years).

Results

From 1996 onward, the proportion of rapid-acting insulin analogs clearly increased in all groups. In those with T1D, the proportion of regular insulin shrank to 4% by 2021 (Figure a). This increase came earlier and was steeper in adults with T1D, with 10% of patients using ultra-rapid analogs in 2021 (6.5% in pediatrics). Adults with T2D are still slightly more likely to use regular insulin (25% in 2021), whereas ultra-rapid insulin analogs accounted for only 2% in 2021 (Figure b). As for long-acting insulins, NPH insulin was used almost exclusively from 1995 to 1999, together with a 7–25% proportion of zinc insulins in T1D. The proportion of NPH insulin decreased continuously in all groups, together with a simultaneous increase in long-acting analog insulins. Since 2015, second generation long-acting insulin analogs have been increasingly prescribed to adults with T1D (42% in 2021), whereas a significant rise has only been seen in children since 2019 (21% in 2021, Figure a). In 2021, adults with T2D still used NPH insulin (16% in 2021) (Figure b) more often than adults with T1D (5% in 2021). Insulin analogs were used more often in the new German states. Longer diabetes duration, a higher HbA1c level, and the use of an insulin pump (rapid-acting analogs) were the most important predictors for the use of insulin analogs in all groups. Gender differences were minimal. BMI played a minor role in children, while obesity in adults was associated with a lower use of rapid-acting insulin analogs (T1D) and a higher use of long-acting insulin analogs (T2D).

Figure

Relative proportion of various rapid-acting and long-acting insulins from 1995 to 2021 according to diabetes type

Discussion

Although insulin analogs were initially controversial due to an absence of long-term data and their higher price, they have meanwhile achieved widespread acceptance over human insulin. Their lower risk for (nocturnal) hypoglycemia and more reproducible effect have been shown to be advantages of analog insulins in the treatment of T1D (3). Reducing the time between injection and eating and the possibility of administering the insulin dose during, or even after, a meal in certain situations could contribute towards a better quality of life. Using DPV data covering the last 27 years, we were able to confirm the trend towards increased use of analog insulins. Insulin analogs account for by far the largest share of all insulins used by T1D patients. This is also due to the high proportion of insulin pump therapy for children (>90% in children of preschool age) (4). The slightly delayed rise in the use of new insulin analogs in children is most likely due to the later market approval for this group of patients and an overall caution regarding newly developed drugs.

Although the proportion of insulin analogs in adults with T2D also rose steadily, the proportion of regular insulin did not fall significantly until after 2008 and still accounts for one quarter of rapid-acting insulins. NPH insulin is also still used by 16% of T2D patients. This may be due to premixed insulin combinations as part of a conventional insulin therapy (CT), some of which contain regular insulin. Other possible reasons include the lack of evidence on the benefits of rapid-acting analog insulins over regular insulin therapy for T2D, as reported in a recent Cochrane review (5), and at times higher costs for insulin analogs, depending on the type of diabetes. Population-based registries with the ability to collect representative data on more than 600 000 patients spanning several decades will continue to be important for illustrating the reality of medical care and monitoring further developments in insulin therapy.

Alexander J. Eckert, Peter Bramlage, Thomas Danne, Andrea Näke, Michael Hummel, Karl Otfried Schwab, Steffen Mühldorfer, Gebhard Buchal, Antonia Müller, Reinhard W. Holl

Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University (Eckert, Holl) [e-mail]

German Center for Diabetes Research (DZD), Munich-Neuherberg (Eckert, Holl)

Institute for Pharmacology and Preventive Medicine, Cloppenburg (Bramlage)

Children’s and Adolescent’s Hospital AUF DER BULT, Hannover (Danne)

Department of Endocrinology and Diabetology, Clinic and Polyclinic for Pediatric and Adolescent Medicine, Dresden University Hospital, Dresden (Näke)

Rosenheim Diabetes Center, Rosenheim (Hummel)

Center for Child and Adolescent Medicine, Pediatric Endocrinology, Diabetology, Lipidology and Clinical Research, University Hospital Freiburg, Freiburg (Schwab)

Department of Gastroenterology, Bayreuth Medical Center, Bayreuth (Mühldorfer)

Red Cross Children‘s Hospital Siegen, (Buchal)

Department for Diabetes and Metabolic Diseases, Karlsburg Hospital Dr. Guth GmbH & Co KG, Karlsburg (Müller)

Acknowledgments

We would like to thank Ramona Ranz and Andreas Hungele (Data Scientists at ZIBMT, Institute of Epidemiology and Medical Biometry, University of Ulm) for gathering and supplying the data.

Funding

This study was funded by the German Center for Diabetic Research (DZD, 82DZD14A02). Additional financial support was provided by the Robert Koch Institute (RKI) and the German Diabetes Society (DDG) as well as Diabetes Agenda 2000. The Diabetes Agenda 2020 receives financial support from Sanofi, Bayer, and AstraZeneca.

Conflict of interest statement

Prof. Bramlage has received consulting fees and/or research funding from Roche, Sanofi, Abbott, Bayer, Boehringer, and AstraZeneca.

Prof. Danne has received lecture and consulting fees and/or research funding as well as travel and conference fee reimbursement from Abbott, AstraZeneca, Bayer, Boehringer, DexCom, Insulet Corp., Eli Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Ypsomed. He is a partner of DreaMed Ltd.

Prof. Michael Hummel has received fees for lectures and/or consulting services from Astra Zeneca, Bayer, Berlin Chemie, Boehringer, Dexcom, Novo Nordisk, MSD, Lilly, Sanofi-Aventis.

Prof. Schwab has been involved in consulting activities, has presented paid lectures, has had travel and congress expenses reimbursed, and has had research projects paid for by Akcea, Alexion, Ipsen, Merck, Novartis, NovoNordisk, Pfizer, Sanofi-Aventis, and Sandoz.

The other authors confirm that no conflict of interest exists.

Manuscript received on 31 January 2021, revised version accepted on 09 June 2022.

Translated from the original German by Dr. Grahame Larkin

Cite this as:
Eckert AJ, Bramlage P, Danne T, Näke A, Hummel M, Schwab KO, Mühldorfer S, Buchal G, Müller A, Holl RW: The use of insulin preparations—an evaluation of the DPV registry. Dtsch Arztebl Int 2022; 119: 649–50. DOI: 10.3238/arztebl.m2022.0253

References

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2. Universität Ulm: Diabetes-Patienten-Verlaufsdokumentation (DPV) Homepage. https://buster.zibmt.uni-ulm.de/projekte/DPV/ (last accessed on 18 January 2022).

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