Evidence review

Advice

Clinical effectiveness
Safety
Evidence strengths and limitations

Evidence review

This evidence review is based on the following phase III studies in adults with type 2 diabetes that have been published in full:

BEGIN Basal-Bolus Type 2 of insulin degludec compared with insulin glargine in people who had previously used basal insulin (Garber et al. 2012; see table 1). This study was originally reviewed in ESNM4 Type 2 diabetes: insulin degludec, which this ESNM has superseded.
BEGIN Once Long of insulin degludec compared with insulin glargine in people who were insulin naive (Zinman et al. 2012; see table 2).
BEGIN Early of insulin degludec compared with sitagliptin in people who were insulin naive (Philis-Tsimikas et al. 2013; see table 3).

Two other phase III studies that have been published in full, BEGIN Flex (Meneghini et al. 2013) and BEGIN Low Volume (Gough et al. 2013), are discussed briefly for context in the clinical effectiveness section.

BEGIN Basal-Bolus Type 2 ( Garber et al. 2012 )

Design: open-label, non-inferiority, 52-week randomised controlled trial (RCT). Allocation concealed.
Population: 1006 adults (mean age just under 60 years across 123 sites in 12 countries) with type 2 diabetes (BMI 40 kg/m² or less) and HbA_1c 53–86 mmol/mol (7.0–10.0%) after using any insulin regimen (with or without oral antidiabetic drugs) for 3 months or longer. All oral antidiabetic drugs were stopped at randomisation apart from metformin or pioglitazone. About 60% continued metformin alone or in combination and 7% or less continued pioglitazone alone or in combination. Mean HbA_1c was around 67 mmol/mol (8.3%) and mean BMI was around 32 kg/m².
Intervention and comparison: subcutaneous insulin degludec (100 units/ml) once daily in the evening compared with subcutaneous insulin glargine (100 units/ml, once daily, at the same time each day), both in combination with subcutaneous mealtime insulin aspart, in a treat-to-target approach. Basal and bolus insulin were titrated to aim for self-measured plasma glucose levels of between 3.9 mmol/l and less than 5.0 mmol/l before breakfast for basal insulin, and pre-prandially and at bedtime for bolus insulin. It was recommended that bolus insulin was titrated after the basal insulin had been titrated.
Outcome: the primary outcome was non-inferiority of insulin degludec to insulin glargine, assessed as a reduction in HbA_1c from baseline after 52 weeks, with the intention-to-treat analysis. Secondary outcomes included change from baseline in fasting plasma glucose.

Table 1 Summary of BEGIN Basal-Bolus Type 2: Garber et al. (2012)

	Insulin degludec	Insulin glargine	Analysis
Randomised	n=755	n=251
Efficacy Full analysis set^a (ITT group)	n=744	n=248
Primary outcome: mean change in HbA_1c from baseline to week 52	−1.10% points from baseline of 8.3% (67 mmol/mol)	−1.18% points from baseline of 8.4% (68 mmol/mol)	Estimated treatment difference in the ITT group 0.08% points (95% CI −0.05 to 0.21; for 1-sided test of non-inferiority^b evaluated at the 2.5% level) Estimated treatment difference in the per-protocol^c analysis 0.05% points (95% CI −0.08 to 0.18)
Selected secondary outcomes:
Mean change in FPG from baseline to week 52	−2.3 mmol/l	−2.0 mmol/l	Estimated treatment difference −0.29 mmol/l (95% CI −0.65 to 0.06; p=0.1075)
Safety Safety analysis set^d	n=753	n=251
Participants with severe hypoglycaemia (needing assistance)	5% (34/753) 0.06 per PYE	4% (11/251) 0.05 per PYE	Insufficient episodes for statistical assessment of estimated rate ratio
Participants with overall confirmed^e hypoglycaemia	81% (609/753) 11.09 per PYE	82% (206/251) 13.63 per PYE	Estimated rate ratio 0.82 (95% CI 0.69 to 0.99; p=0.0359)
Participants with nocturnal confirmed^e hypoglycaemia	40% (298/753) 1.39 per PYE	47% (119/251) 1.84 per PYE	Estimated rate ratio 0.75 (95% CI 0.58 to 0.99; p=0.0399)
Participants with diurnal confirmed^ehypoglycaemia	78% (586/753) 9.28 per PYE	79% (198/251) 11.39 per PYE	Estimated rate ratio 0.82 (95% CI 0.684 to 0.995; p=0.044) based on post-hoc analysis^f
Participants reporting serious adverse events	15% (112/753) 21 events per 100 PYE	16% (40/251) 20 events per 100 PYE	There was no statistically significant difference
Mean weight gain	3.6 kg (SD 4.9)	4.0 kg (SD 4.6)	Statistical significance not reported
Injection-site reactions	4% (27/753)	3% (7/251)	Statistical significance not reported
Abbreviations: CI, confidence interval; FPG, fasting plasma glucose; ITT, intention-to-treat; n, number of patients; PYE, patient-years of exposure; SD, standard deviation. ^a All participants who were randomly assigned to treatment, excluding 14 patients from 1 closed trial site. ^b Non-inferiority was confirmed if the upper limit of the 95% confidence interval of the treatment difference was less than or equal to 0.4% points (4.4 mmol/mol), as recommended by regulatory guidelines. ^c All participants who had at least 12 weeks' exposure to treatment, who did not have any major protocol violations, and who had valid assessments of HbA_1c at baseline and at or after 12 weeks of treatment (insulin degludec, n=694; insulin glargine, n=233). ^d All participants who received at least 1 dose of study drug. ^e Confirmed hypoglycaemia was defined as those episodes in which the plasma glucose value was lower than 3.1 mmol/l (irrespective of symptoms) or severe episodes needing assistance.

BEGIN Once Long ( Zinman et al. 2012 )

Design: open-label, non-inferiority, 52-week RCT with a 52-week extension (not yet fully published). Allocation concealed.
Population: 1030 insulin-naive adults (mean age 59 years across 166 sites in 12 countries) with type 2 diabetes (BMI 40 kg/m² or less) and HbA_1c 53–86 mmol/mol (7.0–10.0%) after taking oral antidiabetic drugs (metformin monotherapy or metformin in any combination with a sulfonylurea, a glinide, a gliptin or acarbose for 3 months or longer). Participants were excluded if they received a glitazone, exenatide or liraglutide within 3 months of screening. At randomisation, participants discontinued all oral antidiabetic drugs apart from metformin and a gliptin. Mean HbA_1c was 66 mmol/mol (8.2%) and mean BMI was around 31 kg/m².
Intervention and comparison: subcutaneous insulin degludec (100 units/ml) once daily with the main evening meal compared with subcutaneous insulin glargine (100 units/ml, once daily, at the same time each day), in a treat-to-target approach. Basal insulin was titrated to aim for self-measured plasma glucose concentrations of between 3.9 mmol/l and 4.9 mmol/l before breakfast.
Outcome: the primary outcome was non-inferiority of insulin degludec to insulin glargine, assessed as a reduction in HbA_1c from baseline after 52 weeks, with the intention-to-treat analysis. Secondary outcomes included change from baseline in fasting plasma glucose and frequency of 'responders' for HbA_1c less than 7.0% (53 mmol/mol).

Table 2 Summary of BEGIN Once Long: Zinman et al. (2012)

	Insulin degludec	Insulin glargine	Analysis
Randomised	n=773	n=257
Efficacy Full analysis set^a (ITT group)	n=773	n=257
Primary outcome: mean change in HbA_1c from baseline to week 52	−1.06% points from a baseline of 8.2% (66 mmol/mol)	−1.19% points from a baseline of 8.2% (66 mmol/mol)	Estimated treatment difference in the ITT group 0.09% points (95% CI −0.04 to 0.22) confirms non-inferiority^b Estimated treatment difference in the per-protocol^c analysis 0.13% points (95% CI −0.01 to 0.26)
Selected secondary outcomes:
Mean change in FPG from baseline to week 52	−3.8 mmol/l	−3.3 mmol/l	Estimated treatment difference −0.43 mmol/l (95% CI −0.74 to 0.13; p=0.005)
Participants achieving HbA_1c concentrations <7.0% (53 mmol/mol) at week 52	52% (400/773)	54% (139/257)	p=0.40 No statistically significant difference
Safety (safety analysis set^d)	n=766	n=257
Participants with severe hypoglycaemia (needing assistance)	0.3% (2/766) 0.003 per PYE	1.9% (5/257) 0.023 per PYE	Estimated rate ratio 0.14 (95% CI 0.03 to 0.70; p=0.017)
Participants with overall confirmed^e hypoglycaemia	46.5% (356/766) 1.52 per PYE	46.3% (119/257) 1.85 per PYE	Estimated rate ratio 0.82 (95% CI 0.64 to 1.04; p=0.106) No statistically significant difference
Participants with nocturnal confirmed^e hypoglycaemia	13.8% (106/766) 0.25 per PYE	15.2% (39/257) 0.39 per PYE	Estimated rate ratio 0.64 (95% CI 0.42 to 0.98; p=0.038)
Participants reporting serious adverse events	8.1% (62/766)	10.1% (26/257)	Statistical significance not reported
Mean weight gain	2.4 kg	2.1 kg	p=0.28 No statistically significant difference
Injection-site reactions	0.10 per PYE	0.13 per PYE	Statistical significance not reported
Abbreviations: CI, confidence interval; FPG, fasting plasma glucose; ITT, intention-to-treat; n, number of patients; PYE, patient-years of exposure. ^a All participants who were randomly assigned to treatment. ^b Non-inferiority was confirmed if the upper limit of the 95% confidence interval of the treatment difference was less than or equal to 0.4% points (4.4 mmol/mol), as recommended by regulatory guidelines. ^c All participants who had at least 12 weeks' exposure to treatment, who did not have any major protocol violations, and who had valid assessments of HbA_1c at baseline and at or after 12 weeks of treatment (insulin degludec, n=665; insulin glargine, n=221). ^d All participants who were exposed to treatment. ^e Confirmed hypoglycaemia was defined as those episodes in which the plasma glucose value was lower than 3.1 mmol/l (irrespective of symptoms) or severe episodes needing assistance.

BEGIN Early ( Philis-Tsimikas et al. 2013 )

Design: open-label, superiority, 26-week RCT. Allocation concealed.
Population: 458 insulin-naive adults (mean age 56 years across 78 sites in 7 countries) with type 2 diabetes (BMI 40 kg/m² or less) and HbA_1c 58–98 mmol/mol (7.5–11.0%) after using 1 or 2 oral antidiabetic drugs, including metformin, sulfonylureas, glinides or pioglitazone in any combination, with an unchanged dose, for at least 3 months. Mean HbA_1c was around 74 mmol/mol (8.9%) and mean BMI was around 30 kg/m².
Intervention and comparison: subcutaneous insulin degludec (100 units/ml) once daily at any time of day (minimum of 8 hours and maximum of 40 hours between injections) compared with sitagliptin 100 mg tablet (once daily), as add-on to stable treatment with 1 or 2 oral antidiabetic drugs. Insulin degludec was given in a treat-to-target approach, aiming for self-measured plasma glucose concentrations of less than 5.0 mmol/l before breakfast.
Outcome: the primary outcome was change from baseline in HbA_1c after 26 weeks of treatment, in the intention-to-treat population. Secondary outcomes included change from baseline in fasting plasma glucose and frequency of 'responders' for HbA_1c less than 7.0% (53 mmol/mol) at the end of the trial, and at the end of the trial without confirmed hypoglycaemic episodes.

Table 3 Summary of BEGIN Early: Philis-Tsimikas et al. (2013)

	Insulin degludec	Sitagliptin	Analysis
Randomised	n=229	n=229
Efficacy Full analysis set^a (ITT group)	n=225	n=222
Primary outcome: mean change in HbA_1c from baseline to week 26	−1.52% points from baseline of 8.8% (73 mmol/mol)	−1.09% points from baseline of 9.0% (75 mmol/mol)	Estimated treatment difference −0.43% (95% CI −0.61 to −0.24; p<0.0001)
Selected secondary outcomes:
Mean change in FPG from baseline to week 26	−3.41 mmol/l	−1.24 mmol/l	Estimated treatment difference −2.17 mmol/l (95% CI −2.59 to −1.74; p<0.0001)
Participants achieving HbA_1c concentrations <7.0% (53 mmol/mol) at week 26	41% (patient numbers not reported)	28% (patient numbers not reported)	Estimated OR 1.60 (95% CI 1.04 to 2.47; p=0.034)
Participants achieving HbA_1c concentrations <7.0% [53 mmol/mol] without hypoglycaemia at week 26	25% (patient numbers not reported)	23% (patient numbers not reported)	Estimated OR 0.92 (95% CI 0.55 to 1.53) No statistically significant difference
Safety (safety analysis set^b)	n=226	n=228
Participants with severe hypoglycaemia (needing assistance)	0.4% (1/226) 0.01 per PYE	0% (0/228) 0.00 per PYE	Insufficient episodes for statistical assessment of estimated rate ratio
Participants with overall confirmed^c hypoglycaemia	42.5% (96/226) 3.07 per PYE	12.7% (29/228) 1.26 per PYE	Estimated rate ratio 3.81 (95% CI 2.40 to 6.05; p<0.0001)
Participants with nocturnal confirmed^c hypoglycaemia	12.8% (29/226) 0.52 per PYE	5.7% (13/228) 0.30 per PYE	Estimated rate ratio 1.93 (95% CI 0.90 to 4.10; p=0.09) No statistically significant difference
Participants reporting adverse events	62.4% (141/226)	63.2% (144/228)	No statistical testing reported
Participants reporting serious adverse events	6.2% (14/226) 17 events per 100 PYE	4.4% (10/228) 10 events per 100 PYE	No statistical testing reported
Participants reporting adverse events leading to discontinuation	3.9% (9/229)	0.9% (2/229)	No statistical testing reported
Mean weight change	+2.28 kg	−0.35 kg	Estimated treatment difference 2.75 kg (95% CI 1.97 to 3.54; p<0.0001)
Injection-site reactions	4.4% (10/226)	Not applicable
Abbreviations: CI, confidence interval; FPG, fasting plasma glucose; ITT, intention-to-treat; n, number of patients; OR, odds ratio; PYE, patient-years of exposure. ^a All participants who were randomly assigned to treatment, excluding patients from 1 closed trial site. ^b All participants exposed to treatment. ^c Confirmed hypoglycaemia was defined as those episodes in which the plasma glucose value was lower than 3.1 mmol/l (irrespective of symptoms) or severe episodes needing assistance.

Clinical effectiveness

Insulin degludec compared with insulin glargine

Two open-label RCTs compared insulin degludec with insulin glargine. One in people who had previously used basal insulin (Garber et al. 2012) and the other in people who were insulin naive (Zinman et al. 2012). Both RCTs found insulin degludec was non-inferior to insulin glargine in terms of glycaemic control. Both basal insulins reduced HbA_1c levels from baseline to week 52 to a similar degree (as would be expected with a treat-to-target trial design). In addition, non-inferiority was confirmed in both the intention-to-treat analyses and the per-protocol analyses.

In BEGIN Basal-Bolus Type 2 (Garber et al. 2012), the reduction in fasting plasma glucose was similar between the insulins. However, in BEGIN Once Long (Zinman et al. 2012), the reduction in fasting plasma glucose levels was statistically significantly greater with insulin degludec compared with insulin glargine (estimated treatment difference −0.43 mmol/l; 95% confidence interval [CI] −0.74 to 0.13, p=0.005).

Both RCTs reported effects on health-related quality of life using the SF-36 health survey version 2. In BEGIN Basal-Bolus Type 2 (Garber et al. 2012), there was a statistically significant difference of 1.4 points (95% CI 0.1 to 2.7, p=0.0320) for the domain of 'bodily pain' in favour of insulin degludec. In BEGIN Once Long (Zinman et al. 2012), there were statistically significant differences favouring insulin degludec for the domains of 'overall physical' (1.0 points; 95% CI 0.1 to 2.0, p=0.033) and 'physical functioning' (1.4 points; 95% CI 0.3 to 2.4, p=0.016). However, the clinical significance of these changes is unclear. There were no other statistically significant differences reported between insulin degludec and insulin glargine in other domains of health-related quality of life in these RCTs, such as general health or mental health.

Insulin degludec compared with sitagliptin

In BEGIN Early (Philis-Tsimikas et al. 2013), insulin degludec was superior to sitagliptin in terms of glycaemic control in people who were insulin naive. After 26 weeks of treatment, HbA_1c levels were reduced by 1.52% with insulin degludec compared with a reduction of 1.09% with sitagliptin (estimated treatment difference −0.43% (95% CI −0.61 to −0.24; p<0.0001). The reduction in fasting plasma glucose levels from baseline was also statistically significantly greater with insulin degludec compared with sitagliptin (estimated treatment difference −2.17 mmol/l; 95% CI −2.59 to −1.74; p<0.0001).

More participants achieved an HbA_1c level of less than 7.0% points (53 mmol/mol) at the end of the trial with insulin degludec compared with sitagliptin (41% compared with 28%, odds ratio [OR] 1.60; 95% CI 1.04 to 2.47; p=0.034). However, the proportion of participants achieving this HbA_1c target without experiencing confirmed hypoglycaemic episodes was not statistically significantly different (25% with insulin degludec and 23% with sitagliptin, OR 0.92; 95% CI 0.55 to 1.53).

This RCT reported effects on health-related quality of life using the SF-36 health survey version 2; effects appeared to be similar between insulin degludec and sitagliptin.

Insulin degludec flexible dosing

In BEGIN Early (Philis-Tsimikas et al. 2013), insulin degludec could be given once daily at any time of day, with a minimum of 8 hours and maximum of 40 hours between injections. During the trial, 42% of participants chose to change the time of their injection on at least 1 occasion.

The efficacy and safety of variable once-daily dosing intervals of insulin degludec (100 units/ml) has been evaluated in the open-label, treat-to-target RCT, BEGIN Flex (Meneghini et al. 2013). In this trial, once-daily insulin degludec in a prespecified flexible dosing schedule, creating 8 to 40 hour intervals between injections, was compared with once-daily insulin degludec (100 units/ml) at the main evening meal, or once-daily insulin glargine (100 units/ml) at the same time each day. Participants had type 2 diabetes and were either insulin naive and taking oral antidiabetic drugs, or previously on basal insulin with or without oral antidiabetic drugs. After 26 weeks, variable once-daily dosing of insulin degludec was non-inferior to insulin glargine for glycaemic control, with no statistically significant difference in overall or nocturnal hypoglycaemia (see table 4). Severe hypoglycaemia was rare (2 episodes in each treatment group).

Table 4 Key results from BEGIN Flex: Meneghini et al. (2013)

	Insulin degludec variable once-daily dosing (n=229)	Insulin degludec once daily (n=228)	Insulin glargine once daily (n=230)	Analysis
Primary outcome: mean change in HbA_1c from baseline to week 26	−1.28% points from a baseline of 8.5% (69 mmol/mol)	−1.07% points from a baseline of 8.4% (68 mmol/mol)	−1.26% points from a baseline of 8.4% (68 mmol/mol)	Estimated treatment difference between insulin degludec flexible dosing and insulin glargine 0.04% points (95% CI −0.12 to 0.20) confirms non-inferiority^a
Participants with overall confirmed^b hypoglycaemia	51% (117/230) 3.6 per PYE	44% (99/226) 3.6 per PYE	49% (113/229) 3.5 per PYE	Estimated rate ratio between insulin degludec flexible dosing and insulin glargine 1.03 (95% CI 0.75 to 1.40; not statistically significant)
Participants with nocturnal confirmed^b hypoglycaemia	13% (31/230) 0.6 per PYE	11% (24/226) 0.6 per PYE	21% (49/229) 0.8 per PYE	Estimated rate ratio between insulin degludec flexible dosing and insulin glargine 0.77 (95% CI 0.44 to 1.35; not statistically significant)
Abbreviations: CI, confidence interval; n, number of patients; PYE, patient-years of exposure. ^a Non-inferiority was confirmed if the upper limit of the 95% confidence interval of the treatment difference was less than or equal to 0.4% points (4.4 mmol/mol), as recommended by regulatory guidelines. ^b Confirmed hypoglycaemia was defined as those episodes in which the plasma glucose value was lower than 3.1 mmol/l (irrespective of symptoms) or severe episodes needing assistance.

Insulin degludec: higher strength

Insulin degludec is available in the European Union-wide standard strength for insulin of 100 units/ml and also in a higher strength 200 units/ml formulation. The Medicines and Healthcare Products Regulatory Agency (MHRA) has issued advice to minimise the risk of medication errors associated with a 200 units/ml formulation (see the section on Safety for more information; Drug Safety Update April 2013).

The efficacy and safety of the 200 units/ml formulation has been evaluated in the open-label, treat-to-target RCT, BEGIN Low Volume (Gough et al. 2013). In this trial, subcutaneous once-daily insulin degludec 200 units/ml with the main evening meal was compared with subcutaneous once-daily insulin glargine 100 units/ml at the same time each day in people with type 2 diabetes who were insulin naive and taking oral antidiabetic drugs, but qualified for intensification of treatment. After 26 weeks, higher strength insulin degludec was non-inferior to insulin glargine for glycaemic control, with no statistically significant difference in overall or nocturnal hypoglycaemia (see table 5). There were no reports of severe hypoglycaemia in either group.

Table 5 Key results of BEGIN Low Volume: Gough et al. (2013)

	Insulin degludec 200 units/ml (n=228)	Insulin glargine 100 units/ml (n=229)	Analysis
Primary outcome: mean change in HbA_1c from baseline to week 26	1.3% points from a baseline of 8.3% (67 mmol/mol)	1.3% points from a baseline of 8.2% (67 mmol/mol)	Estimated treatment difference 0.04% points (95% CI −0.11 to 0.19) confirms non-inferiority^a
Secondary outcome: mean change in FPG from baseline to week 26	−3.7 mmol/l	−3.4 mmol/l	Estimated treatment difference −0.42 mmol/l (95% CI −0.78 to −0.06)
Participants with overall confirmed^b hypoglycaemia	28.5% (65/228) 1.22 per PYE	30.7% (70/228) 1.42 per PYE	Estimated rate ratio 0.86 (95% CI 0.58 to 1.28) No statistically significant difference
Participants with nocturnal confirmed^b hypoglycaemia	6.1% (14/228) 0.18 per PYE	8.8% (20/228) 0.28 per PYE	Estimated rate ratio 0.64 (95% CI 0.30 to 1.37) No statistically significant difference
Abbreviations: CI, confidence interval; FPG, fasting plasma glucose; n, number of patients; PYE, patient-years of exposure. ^a Non-inferiority was confirmed if the upper limit of the 95% confidence interval of the treatment difference was less than or equal to 0.4% points (4.4 mmol/mol), as recommended by regulatory guidelines. ^b Confirmed hypoglycaemia was defined as those episodes in which the self-measured blood glucose value was lower than 3.1 mmol/l (irrespective of symptoms) or severe episodes needing assistance.

Safety

Insulin degludec compared with insulin glargine

In both RCTs (Garber et al. 2012 and Zinman et al. 2012), the proportion of participants reporting adverse events and the proportion who withdrew because of adverse events were similar with insulin degludec or insulin glargine. The rates of serious adverse events were also similar between the 2 groups in both trials (see tables 1 and 2).

With regard to hypoglycaemia, in BEGIN Basal-Bolus Type 2 (Garber et al. 2012), the rates of confirmed episodes of overall hypoglycaemia, nocturnal hypoglycaemia and (in a post-hoc analysis) hypoglycaemic episodes occurring during the day (diurnal hypoglycaemia) were statistically significantly lower with insulin degludec compared with insulin glargine at week 52. The rates of hypoglycaemia were as follows:

81% of participants reported confirmed overall hypoglycaemia in the insulin degludec group compared with 82% in the insulin glargine group (a reduction of about 2.5 episodes per patient per year of exposure, p=0.0359).
40% of participants reported confirmed nocturnal hypoglycaemia in the insulin degludec group compared with 47% in the insulin glargine group (a reduction of about 0.5 episodes per patient per year of exposure, p=0.0399).
78% of participants reported confirmed diurnal hypoglycaemia in the insulin degludec group compared with 79% in the insulin glargine group (a reduction of about 2.1 episodes per patient per year of exposure, p=0.044).

The rates of severe hypoglycaemia were similar between the 2 groups, and owing to low numbers of severe hypoglycaemic events, it was not possible to assess for statistically significant differences.

In BEGIN Once Long (Zinman et al. 2012), there was no statistically significant difference between insulin degludec and insulin glargine in confirmed episodes of overall hypoglycaemia at week 52. Confirmed episodes of nocturnal hypoglycaemia were statistically significantly lower with insulin degludec compared with insulin glargine, as were episodes of severe hypoglycaemia. However, very low numbers of severe hypoglycaemic episodes were reported in each group (2 out of 766 participants in the degludec group and 5 out of 257 participants in the glargine group), and this result should be viewed with caution. The rates of hypoglycaemia were as follows:

46.5% of participants reported confirmed overall hypoglycaemia in the insulin degludec group compared with 46.3% in the insulin glargine group (p=0.106).
13.8% of participants reported confirmed nocturnal hypoglycaemia in the insulin degludec group compared with 15.2% in the insulin glargine group (a reduction of about 0.14 episodes per patient per year of exposure, p=0.038).
0.3% of participants reported severe hypoglycaemia in the insulin degludec group compared with 1.9% in the insulin glargine group (a reduction of about 0.02 episodes per patient per year of exposure, p=0.017).

Insulin degludec compared with sitagliptin

In BEGIN Early (Philis-Tsimikas et al. 2013), the proportion of participants reporting adverse events and serious adverse events was similar with insulin degludec and sitagliptin. However, more participants withdrew because of adverse events with insulin degludec (3.9% in the insulin degludec group compared with 0.9% in the sitagliptin group; statistical significance not reported).

The rate of confirmed episodes of overall hypoglycaemia was statistically significantly higher with insulin degludec compared with sitagliptin (3.07 episodes per patient per year of exposure with insulin degludec compared with 1.26 episodes per patient per year of exposure with sitagliptin, difference 1.81, p<0.0001). For confirmed nocturnal hypoglycaemia, the increased rate with insulin degludec was not statistically significant (0.52 episodes per patient per year of exposure with insulin degludec compared with 0.30 episodes per patient per year of exposure with sitagliptin, p=0.09).

Insulin degludec increased body weight from baseline (+2.28 kg) compared with no increase with sitagliptin (−0.35 kg; p<0.0001).

Medicines and Healthcare Products Regulatory Agency (MHRA) advice

Insulin degludec is the first insulin approved in Europe at a higher strength than the European Union-wide standard of 100 units/ml. The MHRA has issued the following advice to minimise the risk of medication errors associated with a 200 units/ml formulation (Drug Safety Update April 2013).

Prescribing:

When prescribing insulin degludec, ensure that the strength is included on the prescription.
Do not convert (recalculate) doses when transferring patients from one strength of insulin degludec to another – the pen device shows the number of units of insulin to be injected irrespective of strength.

Dispensing:

Pharmacists should ensure that the correct strength of insulin degludec is dispensed; if in doubt, contact the prescriber.
Pharmacists should ask patients to visually identify the strength of insulin degludec dispensed, and should ensure patients are able to read the dose counter of the pen device. Ask patients with poor vision to always seek assistance from a person who has good vision and is appropriately trained in use of the device

Administration:

Patients and healthcare staff must never use a syringe to withdraw insulin from a prefilled pen or from a cartridge.

Transfer from other medicines:

Close glucose monitoring is recommended during the transfer and in the following weeks. Doses and timing of concurrent rapid-acting or short-acting insulin products or other concomitant antidiabetic treatment may need to be adjusted.
For most patients, changing the basal insulin to Tresiba can be done unit-to-unit based on the previous basal insulin dose with subsequent individual dose adjustments.

Information to give to patients:

Patients should be aware that there are two different strengths of insulin degludec, and should be informed that the pen device will calculate the dose of insulin that they need irrespective of strength, so they simply need to check the dose-counter window of the pen device which displays the dose in units, and make sure this matches the dose they wish to administer. Patients must never count audible clicks to determine the dose of Tresiba to be administered.
Patients should be provided with a patient booklet and Insulin Passport (or safety card), and should be trained on the correct use of Tresiba before the product is prescribed or dispensed.
Warn patients that they should only use Tresiba as they have been trained because using it any other way may result in a dangerous overdose.
Patients must be instructed to always check the manufacturer's packaging and dispensing label before every injection to ensure they have the correct insulin.

Clinical management and storage:

Healthcare providers should risk assess electronic and paper systems used to prescribe, dispense and administer Tresiba. Carefully check the product strength selected in electronic systems.
Risk assess the clinical storage arrangements for Tresiba to help ensure selection of the correct strength.

Additional safety information

The European Medicines Agency's (EMA's) European public assessment report on Tresiba provides further safety information on insulin degludec. It concluded that: 'Overall, the results of the clinical studies demonstrate that the use of insulin degludec in patients with type 1 and type 2 diabetes as monotherapy or in combination with oral antidiabetic agents is safe and in line with the safety profile of other insulin analogues.'

Several 'adverse events of special interest' were considered in the assessment report. These included:

Injection site reactions which were reported at a similar rate with both strengths of insulin degludec and comparators. None of the injection site reactions was serious.
Neoplastic events which were reported as low and balanced between insulin degludec and comparator groups.
Cardiovascular safety which was assessed based on a meta-analysis of independently confirmed and blindly adjudicated major adverse cardiovascular events. The assessment report concluded that 'the current data does not reveal an increased cardiovascular risk for insulin degludec treated patients', and no pharmacovigilance activities are proposed. However, the US Food and Drug Administration has requested additional cardiovascular data from a dedicated cardiovascular outcomes trial before the review of the new drug application for insulin degludec can be completed in the USA.

Evidence strengths and limitations

The study design and analysis of results was appropriate to demonstrate non-inferiority of insulin degludec to insulin glargine in terms of glycaemic control in people who had previously used basal insulin in BEGIN Basal-Bolus Type 2 (Garber et al. 2012) and in people who were insulin naive in BEGIN Once Long (Zinman et al. 2012).

The primary end point in these RCTs was the surrogate outcome of change in HbA_1c levels. As expected, there are no data on the effect of insulin degludec on patient-oriented, long-term complications of type 2 diabetes (such as cardiovascular or microvascular events) from RCTs designed to assess these clinical outcomes. Studies conducted over many years will be needed to generate such data; for example, such data only became available in 2012 for insulin glargine, many years after it came to market (The ORIGIN Trial Investigators 2012).

NPH (isophane) insulin is the preferred basal insulin recommended in the NICE clinical guideline on the management of type 2 diabetes. Although other long-acting insulin analogues, such as insulin glargine and insulin detemir, have been compared with NPH (isophane) insulin, there are no published studies comparing insulin degludec with NPH (isophane) insulin.

The publication of BEGIN Early (Philis-Tsimikas et al. 2013) is helpful in allowing us to compare the strategies of adding a basal insulin (insulin degludec) or adding another oral antidiabetic drug (sitagliptin) to the treatment regimen for people who are insulin naive and whose glycaemia is inadequately controlled with 1 or 2 oral antidiabetic drugs. Insulin degludec was superior to sitagliptin in terms of glycaemic control, but resulted in more episodes of overall confirmed hypoglycaemia. However, as insulin was titrated weekly in a treat-to-target approach, and the mean insulin dose increased throughout the trial, these results may be expected.

Like many studies of insulins, all 3 RCTs had an open-label design because the different delivery devices of insulin degludec and insulin glargine, and the fact that sitagliptin is given orally, prevented blinding. This could have affected how clinicians and patients used and viewed the different treatments. In turn, this could have affected the outcomes of the study, particularly subjective outcomes, such as symptomatic hypoglycaemia and quality of life (Tahrani et al. 2012). In addition, it is important to note that when patients did not complete the study, the method of last observation carried forward was used to fill in the missing data. In this approach, regardless of when a patient left the trial (for example, after week 1, week 6 or week 23), the last available result for that patient was carried forward and analysed as though it were the result at the study end.

As the EMA notes in its guideline on missing data in confirmatory clinical trials, it is unrealistic to expect that all participants in any clinical trial will receive treatment with full compliance to the treatment schedule and with a complete follow-up as per protocol: some participants will drop out of the trial before the scheduled conclusion, and among those who stay in, some will have data not recorded for some reason. The guideline states that it is unacceptable simply to ignore such missing data, but there is no universally applicable method that adjusts the analysis to take these missing values into account, and different approaches may lead to different conclusions.

In the clinical trials discussed in this evidence summary, drop-out rates ranged from 18% to 24% among participants randomised to insulin degludec, 16% to 23% among those randomised to insulin glargine and were 24% in those randomised to sitagliptin. The EMA's guideline on missing data in confirmatory clinical trials notes that people who do not complete a clinical trial may be more likely to have extreme values than those who do (for example, treatment failure might lead to drop-out, whereas extremely good response might lead to loss of follow-up). Therefore, the loss of these 'non-completers' could lead to an underestimate of variability and hence artificially narrow the confidence interval for the treatment effect. In a superiority trial this could lead to a false conclusion of a statistically significant result. Similarly, in a non-inferiority trial this could lead to a false conclusion of non-inferiority. Only under certain restrictive assumptions does the method of last observation carried forward produce an unbiased estimate of the treatment effect. Moreover, it is not always the case that a last observation carried forward approach would tend to produce conservative estimates (that is, estimates unlikely to be biased in favour of the experimental treatment). Because the choice of primary analysis will be based on assumptions that cannot be verified, the EMA advises that it will almost always be necessary to investigate the robustness of trial results through appropriate sensitivity analyses that make different assumptions.

The safety end points of overall, nocturnal and (only on post-hoc analysis) daytime hypoglycaemia were statistically significantly reduced with insulin degludec compared with insulin glargine in BEGIN Basal-Bolus Type 2 (Garber et al. 2012). In BEGIN Once Long (Zinman et al. 2012), there was no statistically significant difference between insulin degludec and insulin glargine in overall hypoglycaemia, but nocturnal and severe hypoglycaemia were statistically significantly reduced with insulin degludec compared with insulin glargine. However, these differences were small in absolute terms. There were reductions of about 2.5 episodes of overall hypoglycaemia, 0.5 episodes of nocturnal hypoglycaemia, and 2.1 episodes of daytime hypoglycaemia per patient per year of treatment in BEGIN Basal-Bolus Type 2; and reductions of 0.14 episodes of nocturnal hypoglycaemia in BEGIN Once Long. These results relate to self-treated, rather than severe, hypoglycaemic episodes.

The rates of severe hypoglycaemia were low in both trials, and because of this it was not possible to assess for statistically significant differences between groups in BEGIN Basal-Bolus Type 2. In BEGIN Once Long, a statistically significant reduction of 0.02 episodes of severe hypoglycaemia was reported with insulin degludec. However, this is based on very low numbers of just 2 episodes with insulin degludec and 5 episodes with insulin glargine.

As highlighted earlier, there are no data showing how basal insulin degludec compares with basal NPH (isophane) insulin in terms of hypoglycaemic events, which would help local decision makers to be able to determine its place in therapy.