1. Therapeutic options after basal bolus fails in type 2 diabetes?
Speaker name and affiliation
UKHMG00717(1) October 2015
Prescribing information is available on the last slide.
© 2013 Eli Lilly and Company

2. Importance of maintaining glycaemic control

3. Intensive glucose control in type 2 diabetes: The “legacy” effect
Holman R et al (2008) N Engl J Med 359:1577–89

4. Combination therapy: A conservative target-based approach
Diet
Time since diagnosis
OAD
monotherapy
combination
+ insulin
up-titration
Target HbA1c
Glycaemic burden
HbA1c (%) 6 7
7.5 8
8.5
OAD=oral antidiabetic. Adapted from Campbell I (2000) Br J Cardiol 7: 625–31

5. Combination therapy: An early, intensive, target-based approach
Diet 10
Monotherapy 9
Combination therapy/ Insulin
Glycaemic burden
HbA1c (%) 8
Target HbA1c 7 6
Time since diagnosis
Adapted from Campbell I (2000) Br J Cardiol 7: 625–31

6. Plasma glucose concentration (mmol/L)
Why we need to address both mealtime and basal hyperglycaemia in type 2 diabetes
Plasma glucose concentration (mmol/L)
10.0
5.0
06:00
12:00
Time of day (hours)
18:00
00:00
7.5
12.5
2.5
15.0
Diagram shows 24-hour plasma glycaemic pattern typical of healthy people (lower border of grey area) and those with mild non-insulin dependent diabetes mellitus (upper border). Red area shows part of the glycaemic abnormality of diabetes accounted for by excessive postprandial hyperglycaemia, whereas grey area shows part due to elevated basal glycaemia.
Adapted from Riddle MC (1990) Diabetes Care 13: 676–86

7. There are several ways of addressing PPG and FPG with insulin
Basal–bolus insulin therapy
Premixed insulin therapy (with various ratios of longer- and shorter- acting insulin components)
FPG=fasting plasma glucose; PPG=postprandial glucose.

8. What options exist for those with suboptimal control on Basal Bolus Regimen?

9. Options for patients sub-optimally controlled on Basal Bolus
Options for people with suboptimal control on Basal Bolus
Continue with therapy
Adjust bolus or basal insulin doses
Education/Lifestyle review
Move to a premixed preparation
Move to low premix insulin preparation
Move to a premixed preparation with greater prandial coverage?

10. Basal and bolus regimen vs Low premix insulin
Evidence from randomised trials and considerations

11. Premixed insulin compared with basal–bolus: The GINGER study
A 52-week, open-label, randomised, multinational, multicentre trial that included 310 subjects with type 2 diabetes on premixed insulin (human or analogue – either 25/75 or 30/70), with or without metformin.
Participants randomised to a basal–bolus regimen (with glargine and glulisine) or twice-daily premixed insulin (either human 30/70, or aspart 30/70).
Presenter notes:
The abstract of the paper appears below.
Aim: To compare the efficacy and safety of an intensified insulin regimen, using insulin glargine (glargine) once daily and pre-meal insulin glulisine (glulisine) (basal–bolus), with a conventional therapy, using premixed insulin (premix) twice daily.
Methods: This 52-week, open-label, randomized, multinational, multicentre trial included 310 subjects with type 2 diabetes (T2D) on premix, with or without metformin, who were randomized to a basal-bolus regimen with glargine and glulisine (n = 153; mean ± s.d. age 60.2 ± 7.5 years; HbA1c 8.6 ± 0.8%; weight 87.0 ± 15.1 kg; T2D duration 12.8 ± 5.8 years) or twice-daily premix (n = 157; age 60.9 ± 7.8 years; HbA1c 8.5 ± 0.9%; weight 84.3 ±15.0 kg; T2D duration 12.5 ± 6.8 years). The primary endpoint was change in HbA1c from baseline to endpoint.
Results: Mean decrease in baseline-to-endpoint HbA1c for basal-bolus vs. premix was −1.31 vs. −0.80% (difference: −0.476%; 95% Cl: −0.714, −0.238; p=0.0001, ANCOVA). More subjects reached HbA1c ≤7.0% in the basal–bolus group than in the premix group [68 (46.6%) vs. 43 (27.9%); p=0.0004], while they also experienced significantly lower mean ± s.d. daytime (−2.7 ± 2.3 vs. −2.3 ± 2.5 mmol/l; p=0.0033) and postprandial (−3.1 ± 2.6 vs. −2.5 ± 2.8 mmol/l; p < ) blood glucose. Endpoint daily insulin doses were 98.0 ± 48.7 vs ± 44.3 IU (p = ); mean weight gain was +3.6 ± 4.0 vs ± 4.5 kg (p=0.0073). Mean number of overall hypoglycaemic events with basal–bolus and premix was and events/patient year, respectively (difference: −3.90; 95% CI: −10.40, 2.60; p=0.2385).
Conclusions: An intensified basal-bolus regimen using glargine/glulisine results in a significantly superior glycaemic control vs. premix therapy in a population with long-standing insulin-treated T2D, with no increase in the rates of hypoglycaemia.
GINGER=Glulisine in Combination with Insulin Glargine in an Intensified Insulin Regimen.
Fritsche A et al (2010) Diabetes Obes Metab 12: 115–23

12. Main results of the GINGER study
At study end:
Number of overall hypoglycaemic events per year were higher in the premix group, but the difference was not significant (P=0.2385).
Weight gain was significantly greater in the basal–bolus group (+3.6 vs kg; P=0.0073).
(-9 mmol/mol)
(-14 mmol/mol)
(P=0.0001)
GINGER=Glulisine in Combination with Insulin Glargine in an Intensified Insulin Regimen.
Fritsche A et al (2010) Diabetes Obes Metab 12: 115–23

13. In “Real World” Practice, Is Basal–Bolus Always The Gold Standard?
High injection frequency can lead to poor adherence, causing inadequate glycaemic control in insulin treated type 2 patients.1
Noncompliance in insulin treated type 2 patients is associated with increased all-cause mortality.2
Many people with type 2 diabetes on basal–bolus therapy have suboptimal glycaemic control. In one large study*, almost two thirds of people failed to achieve HbA1c ≤7% (≤53 mmol/mol).3
Poor adherence to the diabetic regimen is widely acknowledged as a potential cause of poor metabolic control. In this Scottish study by Donnelly et al between 1995 and 2001 adherence to insulin was a significant predictor of HbA1c, in other words better adherence to insulin was associated with lower HbA1c. In addition, there was an inverse linear relationship between adherence and number of injections.
Currie and colleagues found that noncompliance (noncompliance was defined as missing more than one scheduled visit or having at least one
provider code for not taking medications as prescribed) was independently associated with increased all-cause mortality in insulin treated type 2 patients.
*This was a multinational, 52-week, open-label, parallel-group, non-inferiority, treat-to-target trial, designed to compare the efficacy and safety profiles of detemir and glargine as the basal insulin component of a basal–bolus regimen in people with type 2 diabetes. Insulin aspart was used as the bolus insulin. The intention-to-treat population included 319 participants.
Donnelly LA et al (2007) Q J Med 100: 345–50
Currie CJ et al (2012) Diabetes Care 35(6):
Hollander P et al (2008) Clin Ther 30: 1976–87

14. A question for you to consider:
How many of your patients with type 2 diabetes on a basal–bolus regimen adjust their insulin based on the amount of carbohydrate they eat?
Donnelly LA et al (2007) Q J Med 100: 345–50
Hollander P et al (2008) Clin Ther 30: 1976–87

15. Summary
There is some evidence that basal–bolus regimens provide glycaemic benefit compared with twice-daily premixed insulin.
However, there are some practical factors that make basal–bolus regimens unfeasible for some people with type 2 diabetes.

16. Options for patients sub-optimally controlled on Basal Bolus
Options for people with suboptimal control on Basal Bolus
Continue with therapy
Adjust bolus or basal insulin doses
Education/Lifestyle review
Move to a premixed preparation
Move to low premix insulin preparation
Move to a premixed preparation with greater prandial coverage?

17. Moving to a premixed insulin with a greater prandial coverage
Rationale for considering “mid-mix” insulins

18. Relative contribution (%)
As people with diabetes get closer to HbA1c targets, the need to manage PPG increases
100 50
Relative contribution (%)
>10.2
10.2–9.3
9.2–8.5
8.4–7.3
<7.3
HbA1c (%) quintiles
70%
30%
Fasting plasma glucose
Postprandial glucose
Presenter notes:
The link between fasting plasma glucose and postprandial hyperglycaemia
This study analysed the diurnal glycaemic profiles of 290 patients with type 2 diabetes investigated at different levels of HbA1c. The patients were treated with diet or oral hypoglycaemic agents (not acarbose). Plasma glucose (PG) concentrations were determined at fasting and during postprandial and post absorptive periods. The areas under the curve above fasting PG concentrations and >6.1 mmol/l (110 mg/dl) were calculated for further evaluation of the relative contributions of postprandial and fasting PG increments to the overall diurnal hyperglycaemia. The value of 6.1 mmol/l (110 mg/dl) was chosen because this threshold has been defined as the upper limit of normal PG at fasting or preprandial times by the American Diabetes Association. The data were compared over quintiles of HbA1c. The main contributor to overall hyperglycaemia in patients with poorly controlled type 2 diabetes was found to be fasting hyperglycaemia. Fasting hyperglycaemia was the dominant factor in patients who were furthest from HbA1c target.
Adapted from Monnier L et al (2003) Diabetes Care 26: 881–5

19. In people without diabetes, basal secretion represents approximately 50% of total daily insulin
Normal
Obese
100
200
300
400
500
Percent basal insulin secretion
06:00
10:00
14:00
18:00
22:00
02:00
Time (hours)
When the basal insulin secretion rate was extrapolated over a 24-h period and expressed as a percentage of the total 24-h insulin secretion, basal secretion represented 50.1±3.1% of the total 24-h insulin secretion in normal subjects and 45.2±2.2% in obese patients.
600
Presenter notes:
The pattern of endogenous insulin secretion over a 24-h period, which included three mixed meals, was evaluated in 15 obese subjects and 14 age and sex matched normal volunteers. Insulin secretory rates were calculated from plasma C-peptide levels using individually derived C-peptide kinetic parameters and a validated open two compartment model of peripheral C-peptide kinetics. Insulin secretion rates were consistently elevated in the obese subjects under basal conditions (11.6±1.2 vs. 5.4±0.5 nmol/h) and in the 4 hrs after breakfast (139±15 vs. 63±5 nmol/4 h, P< 0.001), lunch (152±16 vs. 67±5 nmol/4 h, P < 0.001), and dinner (145±18 vs. 65±6 nmol/4 h, P < 0.001). In the normal subjects, basal insulin secretion represented 50±2.1% of total 24-h insulin production, insulin secretion returned to baseline between meals, and equal quantities of insulin were secreted in the 4 hrs after breakfast, lunch, and dinner, despite the fact that subjects consumed half the number of calories at breakfast compared to lunch and dinner. Overall glucose responses were also similar after the three meals. In contrast, the pattern of insulin secretion in obese subjects was largely normal, albeit set at a higher level. However, the insulin secretion rate after meals did not return to baseline, and the secretion rate immediately before lunch (350.5±81.9 pmol/min) and dinner (373.6±64.8 pmol/min) was considerably higher than the secretion rate immediately before breakfast(175.5±18.5 pmol/min). In these overweight subjects, the glucose response after lunch was lower than after dinner. Analysis of individual 24-hrs insulin secretory profiles in the normal subjects revealed that insulin secretion was pulsatile. On average 11.1±0.5 pulses were produced in each 24-h period. The most prevalent temporal distribution of postmeal secretory pulses was two pulses after breakfast and three pulses after both lunch and dinner. Insulin secretion was also pulsatile during the period without meal stimuli: 3.9±0.3 pulses occurred during the period of overnight sampling and in the 3-hr period before ingestion of the breakfast meal. In the obese subjects, the number and timing of secretory pulses was similar to those of normal volunteers, although the amplitude of the pulses was significantly greater. In both groups of subjects,> 80% of insulin pulses were concomitant with a pulse in glucose concentration in the postmeal period. The concomitancy rate was significantly lower in the interval without the meal stimuli, averaging 47% in both groups.
Thus in obesity, although hypersecretion of insulin can be documented, the temporal pattern of secretion is largely unaltered, which suggests that the functioning beta cell mass is enhanced, but normal regulatory mechanisms influencing secretion are still operative.
Polonsky KS et al (1988) J Clin Invest 81: 442–8

20. Doses adjusted to achieve target preprandial and bedtime BG levels.
Patients with type 2 diabetes on intensive insulin therapy regimens use 50% basal and 50% bolus insulin
Basal dose
Bolus doses
% Total daily insulin dose
Multiple daily injection (n=50)
Continuous subcutaneous insulin infusion (n=48)
After titrating doses throughout the study each group independently had a regimen that consisted of approximately 50% basal and 50% preprandial insulin.
100 50
Presenter notes:
The abstract of the paper appears below.
OBJECTIVE— To compare the efficacy and safety of continuous subcutaneous insulin infusion (CSII) and multiple daily injection (MDI) in older adults with insulin-treated type 2 diabetes and to assess treatment satisfaction and quality of life.
RESEARCH DESIGN AND METHODS— Adults (n=107) ≥60 years of age (mean age 66 years) with insulin-treated type 2 diabetes (mean duration 16 years, BMI 32 kg/m2, and HbA1C [A1C] 8.2%) were randomized to CSII (using insulin lispro) or MDI (using insulin lispro and insulin glargine) in a two-center, 12-month, prospective, randomized, controlled clinical trial. Efficacy was assessed with A1C, safety by frequency of hypoglycaemia, and treatment satisfaction and quality of life with the Diabetes Quality of Life Clinical Trial Questionnaire and the 36-item short-form health survey, version 2.
RESULTS— Forty-eight CSII subjects (91%) and 50 MDI subjects (93%) completed the study. Mean A1C fell by 1.7 ±1.0% in the CSII group to 6.6% and by 1.6 ±1.2% in the MDI group to 6.4%. The difference in A1C between treatment groups was not statistically significant (P=0.20). Eighty-one percent of CSII subjects and 90% of MDI subjects experienced at least one episode of minor (self-treated) hypoglycaemia (P =0.17), and three CSII and six MDI subjects experienced severe hypoglycaemia (P=0.49). Rates of severe hypoglycaemia were similarly low in the two groups (CSII 0.08 and MDI 0.23 events per person-year, P=0.61). Weight gain did not differ between groups (P=0.70). Treatment satisfaction improved significantly with both CSII and MDI (P <0.0001), and the difference between groups was not statistically significant (P=0.58).
CONCLUSIONS— In older subjects with insulin-treated type 2 diabetes, both CSII and MDI achieved excellent glycaemic control with good safety and patient satisfaction.
Doses adjusted to achieve target preprandial and bedtime BG levels.
BG=blood glucose.
Herman WH et al (2005) Diabetes Care 28: 1568–73

21. Currently available human and analogue premixed insulins
Composition
Human insulins
Biphasic human insulin (Humulin® M3)
30% soluble insulin
70% isophane insulin
Biphasic human insulin (Insuman® Comb 15)
15% soluble insulin
85% isophane insulin
Biphasic human insulin (Insuman® Comb 25)
25% soluble insulin
75% isophane insulin
Biphasic human insulin (Insuman® Comb 50)
50% soluble insulin
50% isophane insulin
Analogue insulins
Biphasic insulin lispro (Humalog® Mix25)
25% lispro
75% lispro protamine
Biphasic insulin lispro (Humalog® Mix50)
50% lispro
50% lispro protamine
Biphasic insulin aspart (NovoMix® 30)
30% aspart
70% aspart protamine
Presenter notes:
Highlight that Humalog Mix50 is a “mid-mix” insulin and why this is (i.e. 50% rapid acting insulin 50% basal insulin).
Higher proportion of rapid-acting insulin component provides greater activity in the postprandial period.

22. Moving to a premixed insulin with a greater prandial coverage
Evidence from clinical trials

23. Switching from twice-daily premixed insulin 30/70 or 25/75 to premixed insulin 50/50
Before switching to biphasic insulin lispro 50/50*
12.5 10
7.5 5
2.5
–2.5
Change in blood glucose from FBG (mmol/L)
FBG AB BL AL BS AS Bedtime
*** **
n=13
After switching to biphasic insulin lispro 50/50
Switching to twice-daily Mix 50/50 insulin injections controlled post-prandial blood glucose levels and stabilised diurnal blood glucose variations in patients with type 2 diabetes mellitus who had poor glucose control on insulin 30/70 or 25/75.
Presenter notes:
This study assessed the clinical effects of switching from twice-daily rapid-acting insulin 70/30 or 75/25 to twice-daily rapid acting insulin lispro mixture 50/50 (Mix 50/50) in order to stabilize the diurnal variation of blood glucose levels in patients who showed poor control of blood glucose levels on their original medication. The patients were hospitalized for the switch. The initial dose (units of insulin) of Mix 50/50 that patients were switched to was the same as that of the insulin preparations that they were receiving previously. Mix 50/50 significantly suppressed blood glucose elevation from the time before breakfast to the period between breakfast and lunch and also from the time before supper to the period between supper and bedtime, thereby stabilizing the diurnal variation of blood glucose levels. None of the patients experienced any episodes of hypoglycaemia. In conclusion, switching to twice-daily Mix 50/50 insulin injections controlled post-prandial blood glucose levels and stabilized diurnal blood glucose variations in patients with type 2 diabetes mellitus who had poor glucose control on insulin 70/30 or 75/25.
*Participants were receiving biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine), biphasic human insulin 30/70 (30% rapid-acting insulin, 70% NPH), or biphasic insulin lispro 25/75 (25% lispro, 75% lispro protamine). **<0.05; ***P<0.01.
AB=after breakfast; AL=after lunch; AS=after supper; BL=before lunch; BS=before supper; FBG=fasting blood glucose; NPH=neutral protamine Hagedorn.
Tanaka M, Ishii H (2010) J Int Med Res 38: 674–80

24. Biphasic insulin lispro 50/50 (TID) vs premixed human insulin 30/70 (BID)
Study design
Primary measure: mean blood glucose (BG) change.
Secondary measures: HbA1c, 7-point BG profile, and hypoglycaemia.
6-month, single-centre, prospective, randomised, open-label, 2-period crossover.
40 candidates (35 completed the study) on conventional insulin therapy received biphasic insulin lispro 50/50 (TID) or human insulin 30/70 (30% regular/70% NPH, BID) for 12 weeks, and then switched to the opposite sequence.
BID=twice-daily; NPH=neutral protamine Hagedorn; TID=three-times-daily.
Schernthaner G et al (2004) Horm Metab Res 36: 188–93

25. Biphasic insulin lispro 50/50 (TID) resulted in greater reduction in HbA1c compared with premixed human insulin 30/70 (BID)
P<0.001 9
P=0.034
P=0.021 8
n=35 7
8.4
Both treatments reduced HbA1c from baseline, lispro 50/50 significantly more than human 30/70. 6
8.1 5
Mean HbA1c (%)
7.6 4 3 2 1
Baseline
Human
30/70
Lispro
50/50
BID=twice-daily; TID=three-times-daily
Schernthaner G et al (2004) Horm Metab Res 36:188–93

26. Compared with human 30/70 (BID), lispro 50/50 (TID):
Biphasic insulin lispro 50/50 (TID) vs premixed human insulin 30/70 (BID): summary
Compared with human 30/70 (BID), lispro 50/50 (TID):
Produced a greater decrease in mean blood glucose.
Produced a greater reduction in HbA1c.
Was associated with smaller postprandial blood glucose excursions.
Improved overall glycaemic control, and no significant difference in hypoglycaemia risk between treatment groups.
BID=twice-daily; TID=three-times-daily.
Schernthaner G et al (2004) Horm Metab Res 36:188–93

27. Comparing twice daily insulin aspart 30/70 with thrice daily 50/50 or 70/30
Biphasic insulin aspart 30/70*
50/50 (30/70)**
70/30 (30/70)***
Reduction in mean HbA1c (%) at 36 weeks of treatment, intent-to-treat population. Glycaemic control improved with thrice-daily biphasic insulin aspart 50/50 without higher incidence of hypoglycaemia compared with twice-daily insulin aspart 30/70.
8.9
8.9
8.8
−0.5
Reduction in HbA1c (%) −1
Aim: To evaluate clinical efficacy and safety of biphasic insulin aspart (BIAsp) 30 twice daily (b.i.d.) vs. BIAsp 50 or BIAsp 70 (high mix regimens) thrice daily (t.i.d.) all in combination with metformin in a 36-week clinical trial in subjects with type 2 diabetes.
Methods: Efficacy measurements included haemoglobin A1c (HbA1c) and eight-point plasma glucose (PG); safety included adverse events (AEs) and hypoglycaemic episodes. The three treatment groups (approximately 200 subjects in each group) were well matched regarding sex ratio, ethnicity, age and body mass index.
Results: After 12 weeks, 43% and 54% in the BIAsp 50 and 70 groups, respectively, switched their dinner insulin to BIAsp 30. Both high-mix regimens were non-inferior to BIAsp 30 b.i.d., as measured by change in HbA1c, and the BIAsp 50 regimen was superior. The odds for meeting the American Diabetes Association and The American Association of Clinıcal Endocrinologists HbA1c targets of <7% and <6.5%, respectively, were significantly higher with the BIAsp 50 regimen than with BIAsp 30. A significantly lower PG level was achieved from lunch until 02:00 hours with both high-mix regimens compared with BIAsp 30 b.i.d. AEs were mild or moderate with all three regimens. Frequency of hypoglycaemic episodes was comparable for the BIAsp 50 and the BIAsp 30 b.i.d. regimens but was significantly higher with BIAsp 70 t.i.d.
Conclusions: Glycaemic control improved with BIAsp 50 t.i.d. without higher incidence of hypoglycaemia compared with BIAsp 30 b.i.d.; with BIAsp 70 t.i.d. lower PG levels were observed from lunch to hours, but more hypoglycaemic episodes occured compared with BIAsp 30 b.i.d.
7.3
−1.5
7.2
7.0 NS
−0.30% (P=0.0004) −2
*Participants received twice-daily biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine) throughout the study (ITT=200); **Participants received thrice-daily biphasic insulin aspart 50/50 (50% aspart, 50% aspart protamine) throughout the study (ITT=114), or switched their dinner insulin to biphasic insulin aspart 30/70 at 12 weeks (ITT=87); ***Participants received thrice-daily biphasic insulin aspart 70/30 (70% aspart, 30% aspart protamine) throughout the study (ITT=91), or switched their dinner insulin to biphasic insulin aspart 30/70 at 12 weeks (ITT=107). All regimens were in combination of metformin. NS=not significant; ITT=intent-to-treat.
Cucinotta D et al (2009) Diabetes Obes Metab 11: 700–8

28. How does this approach compare with basal–bolus therapy?
Evidence from clinical trials

29. Thrice-daily biphasic insulin lispro 50/50 was non-inferior to basal–bolus therapy
In people with type 2 diabetes uncontrolled on insulin glargine or lispro mix 25/75 (25% lispro, 75% lispro protamine): a non-inferiority intensification substudy of the DURABLE trial.
Biphasic insulin lispro 50/50 (n=174)
Basal–bolus therapy* (n=171)
Baseline 9 8 7 6 5 4 3 2 1
Time (months)
P=0.660
P=0.566
P=0.990
HbA1c remained stable in both treatment groups.
Presenter notes:
The abstract of the paper appears below.
Background: Insulin glargine and insulin lispro mix 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection [LM75/25]) represent two common starter insulin regimen classes: basal and premixed. After initiation of starter insulin therapy, if patients with type 2 diabetes mellitus (DM) are unable to achieve a glycosylated hemoglobin (HbA1c) level <7.0%, insulin intensification may be indicated. The DURABLE (Assessing Durability of Basal Versus Lispro Mix 75/25 Insulin Efficacy) trial was designed to compare initiating insulin therapy with analogue basal insulin versus premixed analogue insulin in patients unable to achieve good glyceamic control while taking multiple oral antihyperglyceamic drugs (OADs).
Objective: To provide objective information about insulin intensification, the DURABLE trial also included a substudy evaluating a systematic approach to advancing insulin therapy in those patients who did not achieve glycaemic control with their initial insulin regimen. This substudy, the results of which are reported here, tested the hypothesis that advancing insulin therapy with premixed insulin is noninferior to basal–bolus therapy (BBT) in patients with type 2 DM unable to achieve an HbA1c level ≤7.0% after 6 months of starting insulin therapy.
Methods: In the main DURABLE study, 2091 patients (age range, 30–80 years) with type 2 DM and HbA1c values >7.0% receiving ≥2 OADs were randomized to receive insulin glargine (n = 1046) or LM75/25 (n = 1045), both in combination with prestudy OADs. After 6 months, patients with HbA1c levels >7.0% could enter this intensification substudy; OADs except sulfonylureas were continued. Patients originally receiving insulin glargine were enrolled in intensification arm A and were randomized to receive BBT (insulin glargine once daily plus mealtime insulin lispro TID) or LM75/25 BID. Patients originally receiving LM75/25 were enrolled in intensification arm B and randomized to receive BBT or mealtime 50% insulin lispro protamine suspension and 50% insulin lispro injection (LM50/50) TID. Insulin doses were adjusted based on preprandial plasma glucose levels. The primary end point was noninferiority of premixed therapy versus BBT with respect to end-point HbA1c. Secondary end points included change in HbA1c and weight, percentage of patients reaching HbA1c target levels, total daily insulin dose, and rates of hypoglycemia. The safety profile was also assessed.
Results: Of the 475 patients in the insulin glargine + OAD arm of the main study who had HbA1c levels >7.0% at 6 months, 399 (84%) entered intensification arm A. The mean age was 57 years, 53% of the patients were male, and mean (SD) HbA1c was 8.0% (1.0%) at baseline. Of those patients, 199 were randomly assigned to receive BBT and 200 were assigned to receive LM75/25. Of the 411 patients in the LM75/25 + OAD arm of the main study who had an HbA1c level >7.0% at 6 months, 345 (84%) entered intensification arm B. The mean age was 55 years, 51% of the patients were male, and mean (SD) HbA1c was 8.0% (0.9%) at baseline. Of those patients, 171 were randomly assigned to receive BBT and 174 were assigned to receive LM50/50. At end point, noninferiority of LM75/25 or LM50/50 to BBT was supported, with a 95% CI of –0.10 to 0.37 and –0.25 to 0.25, respectively. At 6 months, HbA1c did not differ significantly from baseline in any group. Regardless of treatment group, <20% of patients achieved an HbA1c level <7.0%. There were no significant differences between groups in total daily insulin dose, weight gain, incidence or rate of hypoglycemia, or incidence of serious adverse events.
Conclusions: No group had significant improvement from baseline in HbA1c. Our study results suggest that premixed therapy, dosed 2 times per day (LM75/25) or 3 times per day (LM50/50), was noninferior to BBT (4 injections/d) in this population of adult patients with type 2 DM previously uncontrolled with OADs plus basal insulin or twice-daily premixed insulin.
HbA1c (%)
*Glargine plus mealtime insulin lispro.
DURABLE=assessing durability of basal versus lispro mix 25/75 insulin efficacy.
Miser WF et al (2010) Clin Ther 32: 896–908

30. Twice-daily biphasic insulin lispro 50/50 vs
Twice-daily biphasic insulin lispro 50/50 vs. basal–bolus therapy: Glycaemic control
Participants were insulin-naïve people with type 2 diabetes who had suboptimal glycaemic control on maximal doses of oral antidiabetes drugs.
Biphasic insulin lispro 50/50 (n=14)
HbA1c (%) 14 13 12 11 10 9 8 7 6 5
Basal–bolus therapy* (n=14)
At entry
Time (months) 4
Both the premix group and basal bolus group showed significant reduction in HbA1c over the 12 weeks.
Presenter notes:
Objective: The aim of this study was to evaluate twice-daily injections of biphasic insulin lispro vs. basal–bolus (BB) therapy with regard to quality-of-life (QOL) and glycaemic control in insulin-naive patients with type 2 diabetes.
Methods: Twenty-eight patients with type 2 diabetes were randomized to receive either twice-daily 50/50 premixed insulin lispro (Mix50 group) or BB (NPH insulin at bedtime and preprandial insulin lispro) therapy (BB group) for 12 weeks. Glycosylated haemoglobin (HbA1C), 1,5-anhydroglucitol (1,5 AG), blood plasma glucose level, body mass index (BMI), daily total insulin dosage and insulin therapy–related QOL (ITR-QOL) were studied.
Results: ITR-QOL scores were significantly higher in the Mix50 than in the BB group (103.1 ±9.8 vs ± 19.4; p < 0.05). HbA1c improved in both groups (from 11.1± 2.1 to 6.9 ± 1.0% with Mix50 vs. from 11.0 ±2.3 to 6.6 ±0.8% with BB therapy).
Conclusion: These results suggest that twice-daily injections of premixed rapid-acting insulin analogue therapy could achieve good glycaemic control and improved QOL scores compared with BB therapy in insulin-naive type 2 diabetes.
*NPH plus mealtime insulin lispro.
NPH=neutral protamine Hagedorn.
Masuda H et al (2008) Diabetes Obes Metab 10: 1261–5

31. Twice-daily biphasic insulin lispro 50/50 vs
Twice-daily biphasic insulin lispro 50/50 vs. basal–bolus therapy: Insulin therapy-related quality of life questionnaire scores
Score **
***
120
100 80 60 40 20
Total score
Social activities
Physical function
Daily activities
Therapy-related feelings
Biphasic insulin lispro 50/50 (n=14).
Basal–bolus therapy* (n=14).
These results might suggest that twice-daily injections of premixed rapid-acting insulin analogue therapy could achieve good glycaemic control and better QOL compared with basal–bolus therapy in insulin-naïve type 2 diabetes.
Presenter notes:
Objective: The aim of this study was to evaluate twice-daily injections of biphasic insulin lispro vs. basal–bolus (BB) therapy with regard to quality-of-life (QOL) and glycaemic control in insulin-naive patients with type 2 diabetes.
Methods: Twenty-eight patients with type 2 diabetes were randomized to receive either twice-daily 50/50 premixed insulin lispro (Mix50 group) or BB (NPH insulin at bedtime and preprandial insulin lispro) therapy (BB group) for 12 weeks. Glycosylated haemoglobin (HbA1C), 1,5-anhydroglucitol (1,5 AG), blood plasma glucose level, body mass index (BMI), daily total insulin dosage and insulin therapy–related QOL (ITR-QOL) were studied.
Results: ITR-QOL scores were significantly higher in the Mix50 than in the BB group (103.1 ±9.8 vs ± 19.4; p < 0.05). HbA1c improved in both groups (from 11.1± 2.1 to 6.9 ± 1.0% with Mix50 vs. from 11.0 ±2.3 to 6.6 ±0.8% with BB therapy).
Conclusion: These results suggest that twice-daily injections of premixed rapid-acting insulin analogue therapy could achieve good glycaemic control and improved QOL scores compared with BB therapy in insulin-naive type 2 diabetes.
*NPH plus mealtime insulin lispro. **P≤0.05; ***P=NS.
NPH=neutral protamine Hagedorn; NS=not significant; QOL=quality of life.
Masuda H et al (2008) Diabetes Obes Metab 10: 1261–5

32. Advantages of three-times daily “mid-mix” premixed insulins
A three-times daily “mid-mix” regimen comprehensively addresses the postprandial glucose peaks associated with the three main meals.
Compared with a basal–bolus regimen, a three-times daily “mid-mix” regimen may be simpler to teach, and the single delivery device may benefit people who find it difficult to cope with the demands of frequent injections, glucose monitoring and necessary dose adjustments.

33. Summary
There is evidence that biphasic insulin lispro 50/50 is associated with glycaemic benefits compared with biphasic human insulin 30/70, without a detrimental effect on rates of hypoglycaemia.
There are data demonstrating similar glycaemic effects of basal–bolus and “mid-mix” insulin regimens, which are relevant when choosing between these regimens.

34. Is this for every patient?
Basal bolus a successful regimen
Carb awareness
4-5 injections a day
Insulin dose adjustments
Frequent BG monitoring
4-5 injections
Regimen complexity
Patient
mental capacity
Fear of hypos
Frequent BG measurements
CHO awareness
More injections -> more likely to skip injections
Body weight (not just young women)
Tiring, long-tem commitment
Not all patients want flexibility
Best regimen for the right patient
Donnelly LA et al (2007) Q J Med 100: 345–50

35. In “Real World” Practice, Is Basal–Bolus Always The Gold Standard?
High injection frequency can lead to poor adherence, causing inadequate glycaemic control in insulin treated type 2 patients.1
Noncompliance in insulin treated type 2 patients is associated with increased all-cause mortality.2
Many people with type 2 diabetes on basal–bolus therapy have suboptimal glycaemic control. In one large study*, almost two thirds of people failed to achieve HbA1c ≤7% (≤53 mmol/mol).3
Poor adherence to the diabetic regimen is widely acknowledged as a potential cause of poor metabolic control. In this Scottish study by Donnelly et al between 1995 and 2001 adherence to insulin was a significant predictor of HbA1c, in other words better adherence to insulin was associated with lower HbA1c. In addition, there was an inverse linear relationship between adherence and number of injections.
Currie and colleagues found that noncompliance (noncompliance was defined as missing more than one scheduled visit or having at least one
provider code for not taking medications as prescribed) was independently associated with increased all-cause mortality in insulin treated type 2 patients.
*This was a multinational, 52-week, open-label, parallel-group, non-inferiority, treat-to-target trial, designed to compare the efficacy and safety profiles of detemir and glargine as the basal insulin component of a basal–bolus regimen in people with type 2 diabetes. Insulin aspart was used as the bolus insulin. The intention-to-treat population included 319 participants.
Donnelly LA et al (2007) Q J Med 100: 345–50
Currie CJ et al (2012) Diabetes Care 35(6):
Hollander P et al (2008) Clin Ther 30: 1976–87

36. Summary:
There is no panacea – we need to discuss and tailor the insulin regimen to the individual.

37. UKHMG00717(1) October 2015