21 st Expert Committee on Selection and Use of Essential Medicines Peer Review Report [long acting insulin analogues glargine and detemir] (1) Does the application adequately address the issue of the public health need for the medicine? Diabetes is a highly prevalent chronic disease. Its prevalence has nearly doubled worldwide since 1980 and it currently accounts for 14.5% all-cause mortality in people aged 20 to 79 years. The number of patients living with diabetes continues to increase at a steady, it is estimated that 642 million people will be living with diabetes by 2040. All patients with type 1 diabetes require insulin as well as more than 10% patients with type 2 diabetes. Insulin is an expensive medication and half of the patients that need it aren t able to afford it, being this, a global problem. (2) Have all important studies/evidence of which you are aware been included in the application? Please provide brief comments on any relevant studies that have not been included: (3) Does the application provide adequate evidence of efficacy/effectiveness of the medicine for the proposed use? (a) Briefly summarise the reported benefits (e.g. clinical versus surrogate) and comment, where possible, on the actual magnitude of benefit associated with use of the medicine: This application uses a well-conducted systematic review and network meta-analysis to evaluate the efficacy of long acting insulin analogues. The limitations of this review are mostly related to the limitations of the body of evidence. This review found slight benefit of long acting insulin analogues for glycaemic control compared to intermediate acting insulin analogues. It evaluated Hb A1C for glycemic control. This outcome was evaluated in 26 RCT (6776 patients). Glargine Qd, Determir Qd and Determir Qd/BID resulted in a statistically significant reduction of HbA1C compared to NPH once daily. These results were not significant in network meta-analysis including predictive interval.
HbA1C Comparison Direct comparison Indirect Comparison 95% predictive interval Glargine Qd vs NPH Qd Determir Qd vs NPH Qd NPH Qd/BID NPH Qd 0.50%, 0.87% to 0.13% 0.16%, 0.30% to 0.03% 0.04%, 0.12% to 0.03% 0.39%, 0.59% to 0.19% 0.26%, 0.48% to 0.03% 0.05%, 0.28% to 0.18% 0.9% to 0.12% 0.78% to 0.26% 0.58% to 0.47% NA 0.36, 0.65 to 0.08 0.92 to 0.20 Results were consistent in poorly controlled and well-controlled HbA1C (HbA1C values below and equal/ over 8%). Unfortunately the effect size was small and it is unclear if it will translate in a significant effect on patient important outcomes. Other outcomes evaluated for efficacy in this review included micro and macrovascular complications, all cause mortality and episodes of severe hyperglycaemia. Development of DKA was not evaluated. Since these outcomes were only reported in a small number of trials no indirect comparisons were developed. Macrovascular complications: o TIA was reported in one study. After 16 weeks of follow up no difference was observed between the use of Determir BID and NPH BID (RR 2.93, 0.12 to 71.33). o Death due to myocardial infarction was reported in one study. After 32 weeks of follow up no difference was observed between the use of Determir Q and NPH Qd (RR 4.47, 0.24 to 82.58) Microvascular complication: o Retinopathy was reported in 3 studies, each of them evaluated a different comparison. statistically significant differences were observed for glargine BID vs. NPH BID after 16 weeks of follow-up (RR 1.28, 0.48 to 3.40), detemir BID vs. NPH BID after 24 weeks of follow-up (RR 0.89, 0.43 to 1.86), or detemir BID vs. NPH BID after 26 weeks of follow-up (RR 1.62, 0.66 to 3.93). Nephropathy and neuropathy were not evaluated All cause mortality: Evaluated by 2 RTCs. After a median of 24 follow up of 24 weeks, no a statistically significant difference was observed between detemir BID and NPH BID for all cause mortality (OR 0.97, 0.10 to 9.44; I =0%). The accurate evaluation of these outcomes (micro and macrovascular complications) requires extensive follow up, it is expected not to see a significant effect in such a short period as the follow up reported by these studies. A cohort study might be a more suitable study design for the evaluation of these outcomes since it allows for a longer follow up. Severe hyperglycemia: This outcome was reported in one study. clear definition was given. After 26 weeks of follow up, no statistically significant difference existed between detemir BID and NPH BID (RR 5.74, 0.23 to 140.48).
(b) Is there evidence of efficacy in diverse settings and/or populations? Please provide brief details:, the studies included in this review were developed in different countries and multiple hospitals. Results are limited to adults and most of the countries were the studies were developed and part of the developed world. (4) Has the application adequately considered the safety and adverse effects of the medicine? Are there any adverse effects of concern, or that may require special monitoring? This systematic review evaluated multiple safety outcomes/ adverse events. Weight gain: This outcome was evaluated by 13 RCTs including 3396 patients. Paients receiving Determir Qd and Glargine Qd were associated with less weight gain compared to NPH Qd. Similar results were seen in network meta-analysis predictive interval. Determir Qd/BID showed significant less weigh when compared to NPH Qd/BID. Results of network meta-analysis were not consistent in this case. A limitation for the evaluation of this outcome is that the mean follow up was 26 weeks which is a short period of time considering that patients with type 1 diabetes will need insulin for life. Comparison Direct comparison Weight gain - kg Indirect Comparison 95% predictive interval Glargine Qd vs NPH Qd NA 5.14, 6.07 to 4.21 6.69 to 3.59 Determir Qd vs NPH Qd 0.8, 1.65 to 0.04 0.60, 1.13 to 0.08 1.79 to 0.58 NPH Qd/BID 0.96, 1.52 to 0.39 0.87, 1.44 to 0.30 2.09 to 0.35 Severe hypoglycaemia: This outcome was evaluated by 16 RCTs including 3396 patients. The use of detemir Qd/BID had statistically significant lower chance of developing severe hypoglycaemia compared to NPH Qd/BID. This was consistent in direct results of direct comparison and indirect comparison but not in network meta-analysis including predictive value. other comparison showed reduction of hypoglycaemia episodes. Comparison Severe hypoglycemia Direct comparison Indirect Comparison 95% predictive interval Glargine Qd vs NPH Qd NA 1.30, 0.27 to 6.21 0.18 to 9.72
Determir Qd vs NPH Qd 0.58, 0.40 to 0.83 0.59, 0.32 to 1.09 0.20 to 1.75 NPH Qd/BID 0.68, 0.52 to 0.89 0.62, 0.42 to 0.91 0.25 to 1.58 Incident of cancer: statistically significant difference was observed between glargine Qd and NPH BID for pancreatic cancer (relative risk 0.33, 0.01 to 8.12) after 16 weeks of followup. After 26 weeks of follow-up, no statistically significant difference was observed between detemir BID and NPH BID for uterine cancer (relative risk 1.46, 0.06 to 35.63). (5) Please comment on the overall benefit to risk ratio of the medicine (e.g., favourable, uncertain etc). Favourable
ADDITIONAL CONSIDERATIONS: (6) Are there special requirements or training needed for the safe, effective and/or appropriate use of the medicine? Training is needed for the appropriate administration, monitoring and handling of insulin. This applies to patients and health personnel. Patients and their caregiver should be able to manage complication and mistakes. This includes management of hypo/hyperglycemia and possible DKA, management of intercurrent illnesses, glucose monitoring, between others. (7) Are there any issues regarding the registration of the medicine by regulatory authorities? (e.g., recent registration, new indications, off-label use) Long acting insulin analogues (glargine and determir) are licensed globally with the indication of treatment of diabetes mellitus in adults, adolescents and children 2 years of age. Basaglar has been recently approved. By EMA in 2014 and FDA in 2015 Copies of glargine have been approved and brought onto the market in several countries. (8) Is the medicine recommended for use in a current WHO GRC-approved Guideline (i.e., post 2008)? (9) Please comment briefly on issues regarding cost and affordability of this medicine. Insulin is an expensive drug. Other than buying the medication additional equipment is required for its administration and monitoring which adds to the cost. Due to this half of the patients that need it aren t able to afford it. Published cost-effectiveness analyses have shown contradictory information in terms of cost and some of them may be biased since they have been funded by the pharmaceutical industry. Overall long acting insulin seems to be more expensive but more effective than NPH. (10) Any additional comments? Episodes of DKA was not considered as an outcome in this review. (11) Please frame the decisions and recommendations that the Expert Committee could make.
Long acting insulin (determir and glargine) is currently an important part of the management of children and adults with type 1 diabetes. These insulins have shown to be slightly superior to intermediate acting analogues for glycaemic control. Additionally they have proven to be safer in terms of severe hypoglycaemic events and weight gain. Taken this into account they provide a treatment option that may lead to less injections/ monitor checks to patients with a high burden. Cost- effectiveness analyses have shown controversial evidence but there seems to be a tendency to show that they are more costly but also more effective. This highlights the importance of making them more accessible for the general population. All these factors contribute to the decision of including these medications in the WHO EML. (12) References (if required)