Syed MR Gillani, Baldev M Singh
Wolverhampton Diabetes Centre, New Cross Hospital, Wolverhampton, UK.
Address for correspondence: Dr Syed MR Gillani
Wolverhampton Diabetes Centre, New Cross Hospital, Wednesfield Road, Wolverhampton, WV10 0QP, UK.
Tel: +44 (0)1902 695313
E-mail: syed.gillani@nhs.net
Br J Diabetes Vasc Dis 2014;14:98-101
http://dx.doi.org/10.15277/bjdvd.2014.022
Aims: Optimisation of glycaemic control in type 1 diabetes often results in unwanted weight gain. glucagon-like peptide-1 (GLP-1) agonist use is associated with weight reduction in type 2 diabetes but its use in type 1 diabetes is little studied.
Methods: We developed a protocol for GLP-1 use in people with type 1 diabetes and obesity in which liraglutide was initiated and up-titrated whilst insulin doses were simultaneously titrated according to glycaemic parameters.
Results: Of 15 patients offered treatment, 8 proceeded. Baseline parameters were (n=8, mean + SD): (age 50 ± 6 years, BMI 40.4 ± 5.5 kg/m2, weight 123.0 ± 23.9 kg, HbA1c 8.5 ± 1.7%, total daily insulin dose 131 ± 112 units/day. By intention to treat analysis (n=8, 12 months), at 3, 6 and 12 months compared to baseline, weight loss was 6.8 ± 4.1 kg, 10.0 ± 5.6 kg and 8.9 ± 8.4 kg (p=0.026). The reductions in insulin dosage were significant over 6 months (n=8, p=0.045) or when analysing only those who completed 12 months of liraglutide therapy (n=6, p=0.044).
Conclusions: GLP-1 agonist use in patients with type 1 diabetes may be advantageous where weight reduction becomes both a constraint and a therapeutic objective.
Key words: GLP-1, insulin, liraglutide, obese, type 1 diabetes, weight
The management of type 1 diabetes is complex with multiple challenges. Optimisation of glycaemic control plays a key role in the prevention of both macro- and micro vascular complications1 but often results in unwanted weight gain2 and adverse clinical outcomes.3 Even small reductions in weight significantly improve outcomes of obesity related chronic diseases.4 Currently life style modifications are main stay treatment of obesity in type 1 diabetes. Whilst pharmacotherapy can augment the effect of life style modifications,5 its role is limited such that bariatric surgery
is often the only effective treatment for morbid obesity.6 One of its subsidiary mechanisms may be increased production of GLP-17 since GLP-1 regulates appetite and satiety. That may be one reason, amongst many, why GLP-1 agonist use is associated with significant weight reduction in type 2 diabetes8 and the non-diabetic obese population.9,10 GLP-1 agonist use in type 1 diabetes is little studied either for the modification of glycaemic control or for weight. Preliminary evidence suggests liraglutide use in type 1 diabetes benefits glycaemic control, glucose variability, reduced dosage of insulin and body weight.11-13 Based on this, we have developed and audited a local protocol for the use of liraglutide in obese patients with type 1 diabetes.
We developed a protocol for GLP-1 use in people with type 1 diabetes, obesity (BMI >35kg /m2), progressive weight gain with or without constraint to insulin titration for better glycaemic control. The diagnosis of type 1 diabetes was according to standard clinical and biochemical parameters (acute onset, ketosis at presentation, insulin therapy from diagnosis and mandatory on-going insulin need, C-peptide levels). Acceptance of patients onto the protocol required dual consultant specialist approval. After providing them with relevant information at consultation and in writing using a standardised information sheet, informed written agreement was obtained from all patients about the dual unlicensed use of liraglutide in type 1 diabetes and for the management of obesity. Liraglutide was initiated and up-titrated from 0.6 to 1.8mg over a 4–6 week period, whilst insulin doses were titrated according to glycaemic parameters. Patients had open access to support and follow up, and were minimally reviewed monthly. The key objectives were safe glycaemic control, weight loss of >5% at 6 months and GLP-1 agonist tolerability. Patients were reviewed for withdrawal at 3 months and withdrawn at 6 months if these were not attained. This protocol was agreed with local clinical governance committees, but since this was a service development and the presented data are an audit of the protocol, formal ethical committee approval was deemed not to be required. Statistical analysis was in SPSS version 21. The non-parametric Freidman test for repeated, related measures was applied to test differences in parameters over time with p<0.05 taken as significant. Data are presented as the mean ± SD with the range.
Over 1 year, of 15 patients offered treatment, 7 declined and 8 proceeded (age 50 ± 6 years, 4 females). One patient with BMI 30kg/m2 was included due to rapid weight rise during insulin intensification such that the patient did not want to proceed without co-management of weight gain.
Summary results are presented in Table 1 and individual outcomes are shown in Figure 1.
The baseline parameters were: BMI 40.4 ± 5.5 kg/m2, (range 30-47.7 kg/m2), weight 123.1 ± 23.9 kg (70.9-153.2 kg), HbA1c 8.5 ± 1.7% (7.1-12.5%), total daily insulin dose 131 ± 112 units /day (30-352 units/day), creatinine 76 ± 21 µmol/L (53-110), ACR 1.5 ± 2.4 mg/mmol (0.3-7.5) , cholesterol 4.4 ± 0.8 mmol/L (3.2-5.5), C-peptide was negative (<94 pmol/l (analysed by the Mercodia C-peptide ELISA assay)) in 6 patients and low in 2 (281, 131 pmol/l), retinopathy status (none=1, background=2, pre proliferative and above=5), foot risk (low risk=5, intermediate risk=3) and only one patient had macrovascular complications.
On an intention to treat basis at 3, 6 and 12 months, weight loss was 6.8 ± 4.1 kg, 10.0 ± 5.6 kg and 9.0 ± 8.5 kg (range -21 to +6.8 kg) (p=0.026). Percentage weight loss at year end was 8 ± 6% (range +4 to -16%). Daily insulin dose fell by 52 ± 69 units, 50 ± 69 units and 43 ± 60 units (median 16, range -168 to +6 units) (p=0.107, ns). Insulin dosage in units/kg was 1.0 ± 0.9, 0.7 ± 0.4, 0.7 ± 0.4 and 0.7 ± 0.6 (p=0.136, ns). HbA1c changes were not significant (p=0.962, ns).
Two patients were unable to tolerate liraglutide and withdrew at 6 months. They are indicated in Figure 1. In one there was no response in any parameter (HbA1c, weight or insulin dose), also mandating withdrawal. In the other, weight and insulin dosage rose following cessation of GLP-1 therapy. Excluding these two cases (n=6), insulin dose reduction over 1 year was significant (p =0.044) at 12 months (-44 ± 66 units per day) but with no significant difference when assessed by units/kg (p=0.158, ns). Percentage weight loss at year end was 11 ± 3% (range -7 to -16%, p=0.003).
Alternatively, analysis to the 6 month time point (n=8) showed significant falls in weight (p=0.021) and a significant reduction in insulin either by total daily dose (p=0.045) or in daily units/kg (p=0.044) whilst HbA1c remained static.
There were no significant hypoglycaemic events nor any episodes of acute metabolic destabilisation.
Under this tightly observed protocol, in motivated patients with type 1 diabetes, under close clinical supervision (and by whatever mechanisms of action14-17), significant weight reduction occurred without metabolic destabilisation. Clinically and statistically significant reductions in insulin dosages were achieved which appeared to be a consequence of the weight loss, possibly indicative of an improvement in insulin resistance as determined by the crude measure of the changes in units/kg. Perhaps disappointingly, attainment of glycaemia, did not improve. This at least allowed the true potential for weight loss to emerge independent of changes that might have resulted from sharp improvements or deteriorations in glycaemic control. The magnitude of weight loss in this group appeared to exceed that expected in type 2 diabetes,18 possibly because of the interplay of GLP-1 effects together with the reduced pro-obesity effect of falling insulin dosage. It is possible that weight loss might not have been so good if we had simultaneously achieved a significant HbA1c reduction, and it is known that intensification of insulin therapy to attain good control is associated with weight gain.2 Interestingly, we observed a similar amplification effect when adding GLP-1 agonist therapy to those already on insulin therapy in type 2 diabetes.19
The individual variation of responses was of clinical importance. One patient had poor tolerability. Otherwise it can be seen that an effective response was clearly evident very early in the use of GLP-1 agonist therapy and, equally, non-responsiveness in a single patient was similarly obvious by 3 months.
Ethical issues around unlicensed uses of liraglutide in type 1 diabetes must focus on safety. Our preliminary experience is reassuring, but it is small scale and provides no more than a cautious “proof of concept” amongst the few other small-scale trials that have been published.11-13, 20,21 There are no currently available data to suggest harm over and above the standard cautions and side effects understood and observed in mainstream clinical practice. Large, prospectively randomised studies have started to explore the role of liraglutide as additional treatment in type 1 diabetes.22,23 Until they report, we would urge colleagues not to embark on this therapy without due regard to all local clinical governance processes, tight systems of clinical supervision, clear mechanism for independent peer review and a fully informed and consented patients, who have appropriate (and assessed and documented) levels of self-care proficiency.
We conclude that, under the appropriate conditions, and with appropriate patient selection, GLP-1 agonist therapy in type 1 diabetes may be advantageous where weight reduction becomes both a constraint and a therapeutic objective.
Conflict of interest None.
Funding None.
1. The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–86. http://dx.doi.org/10.1056/NEJM199309303291401
2. Russell-Jones D, Khan R. Insulin-associated weight gain in diabetes--causes, effects and coping strategies. Diab Obes Metab 2007;9:799-812. http://dx.doi.org/10.1111/j.1463-1326.2006.00686.x
3. Purnell J, Zinman B, Brunzell J. The effect of excess weight gain with intensive diabetes mellitus treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus. Circulation 2013;127:157-9. http://dx.doi.org/10.1161/CIRCULATIONAHA.111.077487
4. Brinkworth GD, Wycherley TP, Noakes M, et al. Reductions in blood pressure following energy restriction for weight loss do not rebound after re-establishment of energy balance in overweight and obese subjects. Clin Exp Hypertens 2008;30:385-96. http://dx.doi.org/10.1080/10641960802275734
5. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005;353:2111-20. http://dx.doi.org/10.1056/NEJMoa050156
6. Czupryniak L, Strzelczyk J, Cypryk K, et al. Gastric bypass surgery in severely obese type 1 diabetic patients. Diab Care 2004;27:2561-2. http://dx.doi.org/10.2337/diacare.27.10.2561
7. Näslund E, Kral JG. Impact of Gastric bypass surgery on gut hormones and glucose homeostasis in type 2 diabetes. Diab Care 2006;55:92-7. http://dx.doi.org/10.2337/db06-S012
8. Horton E, Silberman C, Davis K, et al. Weight loss, glycaemic control, and changes in cardiovascular biomarkers in patients with type 2 diabetes receiving incretin therapies or insulin in a large cohort database. Diab Care 2010;33:1759-65. http://dx.doi.org/10.2337/dc09-2062
9. Lisa MN, Robert FK. Emerging role of GLP-1 receptor agonists in the treatment of obesity. Diab Met Synd Obes: Targets and Therapy 2010;3 263-73.
10. Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analogue, Liraglutide. Int J Obes 2012;36:843-54. http://dx.doi.org/10.1038/ijo.2011.158
11. Varanasi A, Bellini N, Rawal D, et al. Liraglutide as additional treatment for type 1 diabetes. Eur J Endocrinol 2011;165:77-84. http://dx.doi.org/10.1530/EJE-11-0330
12. Kielgast U, Krarup T, Holst JJ, et al. Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function. Diab Care 2011;34:1463-8. http://dx.doi.org/10.2337/dc11-0096
13. Kuhadiya N, Malik R, Bellini N, et al. Long-term follow-up of patients with type 1 diabetes on liraglutide and the effect of liraglutide as additional treatment in obese patients with type 1 diabetes. Endocr Review 2012;33; (03 meeting abstracts): OR 17-1, http://edrv.endojournals.org/cgi/content/meeting_abstract/33/03_MeetingAbstracts/OR17-1, Last accessed 28/4/13.
14. Lovshin JA, Drucker DJ. Incretin-based therapies for type 2 diabetes mellitus. Nature Rev: Endocrinol 2009;5:262-9. http://dx.doi.org/10.1038/nrendo.2009.48
15. Flint A, Raben A, Astrup A, et al. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515-20. http://dx.doi.org/10.1172/JCI990
16. Egan JM, Meneilly GS, Habener JF, et al. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. JCEM 87:3768-73.
17. Wettergen A, Scholdager B, Mortensen PE, et al. Truncated GLP-1 (proglucagon 87-107amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci 1993;38:665-73. http://dx.doi.org/10.1007/BF01316798
18. Madsbad S. Liraglutide Effect and Action in Diabetes (LEADTM) trial. Expert Rev Endocrinol Metab 2009;4:119-29. http://dx.doi.org/10.1586/17446651.4.2.119
19. Nayak UA, Govindan J, Baskar V, et al. Exenatide therapy in insulin treated type 2 diabetes and obesity. QJM 2010;103:687-94. http://dx.doi.org/10.1093/qjmed/hcq112
20. Creutzfeldt WO, Kleine N, Willms B, et al. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diab Care 1996;19:580-6. http://dx.doi.org/10.2337/diacare.19.6.580
21. Gutniak M, Orskov C, Hoist JJ, et al. Antidiabetogenic effect of glucagon-like peptide-l (7-36)amide in normal subjects and patients with diabetes. N Engl J Med 1992;326:1316-22. http://dx.doi.org/10.1056/NEJM199205143262003
22. “Liraglutide as Additional Treatment in Patients With Type 1 Diabetes Mellitus”, Clinical Trials US National Institute of Health, http://clinicaltrials.gov/show/NCT01299012, Last accessed 08/05/13
23. “The efficacy and safety of liraglutide as adjunct therapy to insulin in the treatment of type 1 diabetes”, ClinicalTrials.gov registration: NCT01836523, http://www.novonordisk-trials.com/website/search/trial-registry-details.aspx?id=37790&p=1&search=t, Last accessed 08/05/13.