Chapter 9: Insulin
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11/27/2017 at 12:51:38 PM GMT
Posts: 40
Chapter 9: Insulin

Dear ISPAD member/friend,

The 2014 ISPAD Clinical Practice Consensus Guidelines were much appreciated. We are happy to announce that preparations for the 2018 Guidelines are now well underway and that a new draft chapter is now ready for your comments and input. We look forward to hearing your thoughts and ideas on the Insulin treatment chapter here below!

Kind regards,

David Maahs

ISPAD Secretary General

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Last edited Tuesday, February 20, 2018
12/17/2017 at 10:16:53 PM GMT
Posts: 6
Dear David,

Many thanks for the opportunity to comment upon the insulin guidelines chapter.

General comment:
I was surprised to see that of the 18 summary points, nine had an evidence rating of ‘E’. It is a sad reflection on the clinical research base that something so core to clinical management as insulin use does not have a more solid evidence base. In such a context, one has to be sceptical then of any recommendations that are made dogmatically. Also, given that many of the conclusions are arrived at by agreement of the author group one has to look at the representative nature of this group and how critical the thinking has been on the issues canvassed. There is only one author who is not from a western tertiary diabetes care centre. In the Conflict of Interest Disclosures 6/9 authors have significant relationships with companies that have a direct interests in insulins or insulin delivery vehicles. I have similar CoI’s, so no moral high ground coming from me, but I nevertheless wonder if this is the appropriate group to be making dogmatic statements around insulin use mostly on the basis of ‘expert consensus’. I also wonder if a group of professional literature analysts without ties to device or pharma would arrive at the same conclusions.

I think it would be helpful for the readership to be given some sense of the clinical significance of the stated impacts of some insulins/insulin regimens (eg on page 7 it states “The Cochrane review from 2016 stated that in patients with type 1 diabetes, the weighted mean difference in HbA1C was -0.1% in favour of insulin analog (- 0.2% when using CSII)”; and on page 21 the recent DPV JAMA paper is canvassed showing a lower HbA1C of 0.18% associated with CSII). To put this into context- the health economists regard an change in HbA1C of < 0.5% as insignificant (Cummins et al Health Technol Assess 2010;141-181) and the Hawthorne effect upon HbA1C from being in any diabetes trial is 0.24% (Gale). So one could easily argue that the cited figures of an improved HbA1c of 0.1-0.2% are clinically underwhelming.

Specific comments:
Page 4- “As CSII has proven to be safe at all ages…” I would draw the authors’ attention to the following references-
Wheeler et al Diabet Technol Therap 2014 16:204-7- 45% rate of pump adverse events with 8% rate of hospital attendance
Guenego et al Diabet Technol Therap 2016 18:820-4- 68% pump malfunction rate
Cope et al, J Diabetes Sci Technol 2012; 6: 1053-9- MAUDE data showing 43% rate of hospitalization in kids when pumps fail (ie not a trivial issue)
Hommel et al Acta Diabetol 2014; 51:845-51- SWITCH study 44-50% rate of adverse events whilst on CSII. Roughly 1 in 20 hospitalised
Hanas et al, Pediatr Diabetes 2009; 10:33-7 – risk of DKA doubled amongst pump users
Brorrson et al, Pediatr Diabetes 2015; 16:546-53- risk of DKA increased 5.6 fold if using CSII
Cox et al Diabetes Care 2009; 32:2177-80 – drivers using CSII 35% more likely to experience a hypoglycaemia-related driving mishap

Page 5- “Although the importance of these new analogue insulins for the reduction of hypoglycaemia observed in registries (15) cannot be distinguished from advances in devices or education, all possible efforts should be made to have these new treatment options available to patients with T1D”. This statement is scientifically oxymoronic- it is saying that we have no evidence that specifically says that analogue insulins prevent hypoglycaemia, yet we should spare no effort in advocating for the use of analogue insulins to improve hypoglycaemia. Edwin Gale summarised the lack of benefits seen with the use of analogue insulins in his well-known editorial ‘Nice insulins, pity about the evidence’ (Diabetologia 2007). I would draw the authors’ attention to the following additional references (although these references are old, they are in the most part more recent than those [refs #33-37] cited by the authors):
Cherubini et al Diabetes Care 2006; 29: 2311-12- no improvement seen with short acting analogues in HbA1c
Dixon et al, Pediatr Diab 2005; 6:150-154- no improvement seen in HbA1c in long-acting analogues
Paivarinta et al, Pediatr Diab 2008; 9:83-90- no improvement seen in HbA1c in long-acting analogues

Page 22- Discussion of sensor augmented pump therapy. There is a recent paper (Abraham et al Diabetes Care 2017 e-pub- CoI statement: I am a co-author) that is probably worth considering as a citation. It is a 6 month RCT of SAP vs CSII + CGM using the Medtronic 640G system. To date I think this is the largest and longest published RCT of SAP in adolescents.

Page 25- BD regimens are only recommended in “cases of very bad compliance, honey moon period or very limited access to diabetes care”. There are many centres who regularly use BD regimens with reasonable outcomes (our centre being one- we average 2.7 visits per patient to clinic per year, we have a 20% of our patients on BD regimens with a clinic median HbA1C of 7.9% which is lower than many Australian, US, UK and many European centres). Flemish and Hvidoere group data shows that this experience is not unique to our clinic (Doggen et al Eur J Pediatr 2012; 171: 1679-85; Holl et al, Eur J Pediatr 2003; 162:22-29; De Beaufort et al Diabetes Care 2007; 30:2245-50; De Beaufort et al Pediatr Diabetes 2013; 14:422-428). Many centres in developing countries (such as we have heard from Sudan) do not have the option of CSII or MDI yet also get results on BD regimens that are equivalent to or better than centres in developed countries that exclusively use CSII or MDI regimens. Thus, this unqualified relegation of BD regimens to a ‘hope of the hopeless’ status is I think unwarranted in terms of outcomes and discouraging particularly for centres in developing countries. It can also be distracting for centres in developed countries- for example in order to improve our outcomes, our priority arguably should be to increase the number of clinic visits per year rather than use limited resources to change everyone over to MDI or CSII therapy.

I hope these comments are helpful and are taken in the spirit of constructive criticism.



12/17/2017 at 11:03:03 PM GMT
Posts: 40
Dear Fergus,

Thank you very much for these comments and indeed they are appreciated in the spirit of making the guidelines the best possible to help us inform care. We certainly need greater evidence to support our practice as you note and helping to generate this is a mission of ISPAD.

I look forward to additional comments and discussion.


1/6/2018 at 7:55:53 PM GMT
Posts: 9
Chapter 9: Insulin

This chapter is comprehensive and authoritative. Contains the latest, up to date information on insulins and insulin delivery methods; i.e., "the state-of-the-art". There is an overwhelming predominance of information relevant to the practice of pediatric diabetes in high income countries.

In order for the guidelines to be useful and relevant to practice in middle and low income countries where penetration of technology is more limited and analogs may not be available or are unaffordable for many, it seems to me that this chapter should contain a more complete discussion of how best to use "simpler" insulin regimens (e.g, twice daily using regular and NPH).

Other specific comments:


P.15 In addition to 300 unit cartridges, there are also 3mL vials available for various insulins (Humalog, Regular, NPH, Humulin 70/30)

P.17 30 unit or 0.3 mL syringes with ½ unit markings also available

P.21 The sentence: “short disconnection of the pump … blood glucose increment of 1 mg/dL i.e., 1.5 mmol/l per30 minutes …” appears to have a typo 1.5 mmol/l is 27 mg/dL.

? meant to state 1 mg/dL per minute or 30 mg/dL per 30 minutes

P.28  “Pumps have the possibility of delivering the bolus dose in different ways in order to reduce the postprandial blood glucose excursions (212)”

I think I know what this means but wonder if the “different ways” should be explained here for the benefit of readers who may not be experts in pump therapy:  dual wave, extended bolus, etc.?

1/20/2018 at 11:25:06 AM GMT
Posts: 5
Another important study, quite small but frightening if the result represents the reality for those who need Pharma insulin for their survival:

Alan W. Carter and Lutz Heinemann. Insulin Concentration in Vials Randomly Purchased in Pharmacies in the United States: Considerable Loss in the Cold Supply Chain. Journal of Diabetes Science and Technology DOI: 10.1177/1932296817747292.

1/25/2018 at 10:56:02 AM GMT
Posts: 40
The forum discussion on Chapter 9: Insulin is now closed.

While ISPAD does very much appreciate your feedback, kindly note that any comments posted here after 25/01/2018 will only be taken into account for the 2022 Guidelines!

Thank you very much for your understanding.

Last edited Thursday, January 25, 2018
1/26/2018 at 5:00:41 PM GMT
Posts: 8
Dear all,

Than you for the nice Guideline. In comment to fergus I would like to add, that the aim of the JAMA paper comparing CSII and MDI was to Show that we see fewer adverse Events like DKA and sever hypoglycemia in the real world Setting outside a RCT. I agree that the difference in HbA1c is not very high however taking into account that most patients/families on CSII additionally have a better quality of live (Müller-Godeffroy E, Treichel S, Wagner VM; German Working Group for Paediatric Pump Therapy.Diabet Med. 2009 May;26(5):493-501. doi: 10.1111/j.1464-5491.2009.02707.x.) I would suggest there is still some evidence favoring CSII.
Howevere the treatement decission is allways an indiviual decission taking into accoutn all familiar and Patient related arguments.

I know I am to late but I wanted to comment on the discussion

BW Thomas Kapellen

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