Biphasic Insulin Aspart in Type 2 Diabetes Mellitus: An Evidence-Based Medicine Review

S.C.L. Gough; J. Tibaldi

Clin Drug Invest. 2007;27(5):299-324.

Abstract and Introduction

The efficacy benefits of biphasic insulin aspart formulation (BIAsp 30) in patients with diabetes mellitus have been reported in several studies. BIAsp 30 has been shown to be more effective in terms of glycaemic control than standard biphasic human insulin 30 (BHI 30). In addition to gauging the treatment in terms of clinical evidence of benefits provided, it is also important to evaluate the strength of the evidence supporting the therapeutic improvements offered by BIAsp 30. In this paper, we evaluated the strength of the available data that relate to the use of BIAsp 30 in the treatment of patients with type 2 diabetes based on a comprehensive literature review. Selected publications that provided relevant data were obtained via a literature search and from the manufacturer, Novo Nordisk. These were graded in terms of the strength of the evidence they provided using the Oxford Centre for Evidence-Based Medicine (CEBM) system in the following categories: (i) twice-daily use versus basal insulin; (ii) twice-daily use versus other treatments; (iii) once-daily use; (iv) thrice-daily use; (v) use in combination with thiazolidinediones; and (vi) use in comparison with BHI 30. A total of 30 publications for BIAsp 30 were identified and graded. For the majority of categories (four out of six), the evidence supporting the use of BIAsp 30 was given an overall CEBM grade of A (highest quality); evidence supporting clinical efficacy in the other two categories (twice-daily use versus basal insulin and thrice-daily BIAsp 30 administration) was graded B.

In most of the studies examined, the efficacy of BIAsp 30 was evaluated in terms of glycaemic control (glycosylated haemoglobin [HbA_1c] reduction, proportion of patients achieving HbA_1c target of <6.5% or <7%, fasting blood glucose, blood glucose profile and/or prandial and postprandial glucose increments). In some studies, efficacy was further evaluated using plasma insulin and glucose infusion rates, plasma C-peptide levels, mean serum fructosamine levels, postprandial hyperlipidaemia, overall well-being, treatment satisfaction and quality of life. Safety was evaluated using physical and laboratory investigations and assessment of incidence of adverse events, including, in many of the studies reviewed, specific evaluation of those events known to be associated with antidiabetic treatment, hypoglycaemia and weight gain. Strong evidence was provided for better glycaemic control with BIAsp 30 without increases in the incidence of major hypoglycaemia or nocturnal hypoglycaemic episodes. Overall, weight gain with BIAsp 30 was minimal and not significantly greater than with basal insulin or BHI 30.

Thus, we can confirm that the reported efficacy and tolerability of BIAsp 30 in the treatment of diabetes based on a variety of clinical endpoints is supported by a good body of evidence relating to its use in different dosage regimens and in comparison with other insulin treatment regimens.

Diabetes mellitus is one of the most serious global healthcare problems, with the global prevalence set to rise from 171 million cases in 2000 to 366 million by 2030.^[1] Moreover, the prevalence of type 2 diabetes, which accounts for around 90% of cases, is rising in both adults and children.^[2,3] Complications associated with diabetes add to the burden, although they may be avoided or delayed with maintenance of near-normal glycaemic control.^[4,5] Postprandial glucose excursions make a major contribution to overall glycaemic control and may be involved in the development of diabetes complications, particularly cardiovascular complications.^[6] Indeed, the impact of postprandial glucose control on overall glycaemic control appears to increase as glycosylated haemoglobin (HbA_1c) values approach American Diabetes Association (ADA) target levels of <7% and American College of Endocrinology (ACE) and International Diabetes Federation (IDF) targets of =6.5%.^[7,8]

In patients with uncontrolled type 2 diabetes, early initiation of insulin therapy is recommended to supplement the inability of oral antidiabetic drugs alone to prevent deterioration of metabolic control. While an intensive insulin regimen can effectively reduce and delay complications,^[9,10] for some patients such multiple injection regimens can be a burden on their lifestyle, which may impact on adherence. Since patients who retain some capacity for insulin secretion may not require such an intensive approach, many may prefer a once- or twice-daily regimen using biphasic premixed insulin. In addition, with this approach both prandial and basal aspects of glucose regulation are addressed and dosage errors may be reduced by avoiding self-mixing of insulin preparations.

Previously, biphasic human insulin 30 (BHI 30), comprising 30% soluble human insulin and 70% insulin suspension isophane (neutral protamine Hagedorn [NPH] insulin), has been the most widely used premix preparation. However, BHI 30 shares many of the limitations of unmodified human insulin, and the delayed absorption of the soluble insulin component results in limited postprandial glucose control. Additionally, adherence to the recommended 30- to 45-minute preprandial injection interval for human insulin may not be observed.^[11] Insulin analogues were developed to address the difficulties associated with human insulin. Rapid-acting analogues (e.g. insulin aspart) have a shorter onset and duration of action and can be given immediately before meals.^[12]

A biphasic formulation of insulin aspart has been developed, comprising 30% rapid-acting soluble insulin aspart and 70% intermediate-acting protaminated insulin aspart (BIAsp 30; also known as BIAsp 70/30 in the US). This insulin formulation has a more rapid onset of action than BHI 30,^[13] allowing it to be given closer to a meal (within 0–10 minutes before or after starting the meal). In contrast to what is often considered characteristic of premixed insulins, BIAsp 30 produces a protracted decline in glucose-lowering activity after initial rapid onset, without a second separate insulin peak.^[14]

The aim of the current paper is to review the literature and evaluate (using the Oxford Centre for Evidence-Based Medicine [CEBM] approach) the strength of the available published evidence on the use of BIAsp 30 in patients with type 2 diabetes in various categories.

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Summary of Oxford Centre for Evidence-Based Medicine (CEBM) Grades of Recommendation and American Diabetic Association (ADA) Levels of Evidence Relating to the Quality of Available Published Data
Grade/level of evidence	Description
Oxford CEBM grades of recommendation (Oxford CEBM 2005^[19])
A	Consistent level 1 studies (e.g. a systematic review or well conducted RCT)
B	Consistent level 2 or 3 studies or extrapolations from level 1 studies (e.g. individual cohort studies or case-control studies)
C	Level 4 studies or extrapolations from level 2 or 3 studies (e.g. case series studies)
D	Level 5 evidence or troublingly inconsistent or inconclusive studies of any level (e.g. expert opinion or bench research)
ADA levels of evidence^[20]
A	Clear evidence from well conducted, generalisable RCTs that are adequately powered or supportive evidence from well conducted RCTs
B	Supportive evidence from well conducted cohort studies or supporting evidence from a well conducted case-control study
C	Supportive evidence from poorly controlled or uncontrolled studies or conflicting evidence with the weight of evidence supporting the recommendation
E	Expert consensus or clinical experience

RCT = randomised controlled trial.

Summary of Oxford Centre for Evidence-Based Medicine (CEBM) Grades of Recommendation and American Diabetic Association (ADA) Levels of Evidence Relating to the Quality of Available Published Data
Grade/level of evidence	Description
Oxford CEBM grades of recommendation (Oxford CEBM 2005^[19])
A	Consistent level 1 studies (e.g. a systematic review or well conducted RCT)
B	Consistent level 2 or 3 studies or extrapolations from level 1 studies (e.g. individual cohort studies or case-control studies)
C	Level 4 studies or extrapolations from level 2 or 3 studies (e.g. case series studies)
D	Level 5 evidence or troublingly inconsistent or inconclusive studies of any level (e.g. expert opinion or bench research)
ADA levels of evidence^[20]
A	Clear evidence from well conducted, generalisable RCTs that are adequately powered or supportive evidence from well conducted RCTs
B	Supportive evidence from well conducted cohort studies or supporting evidence from a well conducted case-control study
C	Supportive evidence from poorly controlled or uncontrolled studies or conflicting evidence with the weight of evidence supporting the recommendation
E	Expert consensus or clinical experience

RCT = randomised controlled trial.

Summary of Studies of Twice-Daily Biphasic Insulin Aspart 30 Versus Basal Insulin and Versus Other Treatments in Patients with Type 2 Diabetes Mellitus
Ref. (type)	Type of study	Details of study	Study message	Study endpoints	Oxford Grading System
Versus basal insulin
Moses et al.^[21] (Ab)	r, op, pg	233 insulin-naive pts from INITIATE study^[7] 28 weeks (4-week run-in, 24 weeks treatment)	1, 5-anhydroglucitol may be a useful marker of glycaemic control that may allow identification of pts who would benefit from intensive mealtime glycaemic control to achieve target levels of overall glycaemia	Serum 1,5-anhydroglucitol (marker of short-term glycaemic control) Reduction in HbA_1c at 28 weeks	2a
Raskin et al.^[7] (FP)	r, pg, mc	233 pts randomised, 209 completed (INITIATE study) 28 weeks (4-week run-in, 24 weeks treatment)	Initiating insulin therapy with BIAsp 30 bid was more effective in achieving HbA_1c targets than insulin glargine qd in pts with type 2 diabetes poorly controlled with oral antidiabetic drugs, particularly in pts with HbA_1c >8.5%; minor hypoglycaemia was more frequent in the BIAsp 30 group	Reduction in HbA_1c, FBG, daily BG profile and PPG at 28 weeks Safety: hypoglycaemia, weight gain and other AEs	1b
Luzio et al.^[22] (FP)	r	12 pts 2?×?24h study periods	Plasma insulin bioavailability and glucose lowering response were 28% and 34% greater, respectively (p < 0.001 and p < 0.05), after equivalent SC doses of BIAsp 30 (as two split doses) vs a single dose of insulin glargine	Pharmacokinetic/dynamic assessments: AUCs of glucose infusion rate, plasma insulin and C-peptide levels over 24 hours	2a
Christiansen et al.^[23] (FP)	r, db, pg, mn	403 pts 16 weeks	BIAsp 30 bid reduced PPG exposure to a significantly greater extent, and was at least as effective at reducing HbA_1c, compared with NPH insulin; both treatments were well tolerated. Pts on NPH alone who were switched to BIAsp 30 bid achieved a significantly greater reduction in HbA_1c than those switched to NPH bid	Reduction in HbA_1c and change in mean daily BG at 16 weeks Safety: hypoglycaemic events and other AEs	1b
Brod et al.^[24] (Ab)	r, mc	233 insulin-naive pts from INITIATE study^[7] 28 weeks (4-week run-in, 24 weeks treatment)	There were no differences in treatment satisfaction between qd insulin glargine and bid BIAsp 30 injection regimens	Treatment satisfaction (DTSQ and ITSQ) and proportion of pts achieving HbA_1c =6.5% at 24 weeks	2c
Ligthelm^[25] (Ab)	obs	34 pts 6mo	Well-being scores did not differ across treatment groups (insulin glargine qd, BIAsp 30 bid or tid) at 6mo, suggesting that increasing the number of daily insulin injections did not have a detrimental impact on pts' well-being; improvements in glycaemic control were concurrently achieved. In some pts qd insulin was insufficient to achieve good glycaemic control	Changes in HbA_1c and well-being scores (based on answers to 5 lifestyle questions) at 28 weeks	2c
Kann et al.^[26] (Ab)	r, op, pg	255 insulin-naive pts 26 weeks	Commencing insulin with bid BIAsp 30 + metformin can reduce HbA_1c and mean prandial glucose increment to a greater extent than insulin glargine qd + glimepiride	Reduction in HbA_1c and changes in mean prandial increment (average over 3 meals) and FBG at 26 weeks; AEs, hypoglycaemic episodes and weight gain	1b
Versus other treatments
Garber et al.^[27] (FP)	op, mc	100 pts 48 weeks	Progressive titration of BIAsp 30 (when added to oral antidiabetic drug therapy) allows a high percentage of pts with type 2 diabetes unsuccessfully treated with oral antidiabetic drugs and basal insulin alone to reach glycaemic targets: HbA_1c <7% attained by 41%, 70% and 77% of pts with BIAsp 30 qd, bid or tid, respectively; HbA_1c =6.5% attained by 21%, 52% and 60%, respectively^a	Proportion of pts achieving HbA_1c target of =6.5%, reduction in HbA_1c, FBG, and mean daily BG Safety: AEs and hypoglycaemic episodes	2b
Kvapil^[28] (FP)	r, op, pg, mn	329 pts 16 weeks	In poorly controlled pts with type 2 diabetes, addition of BIAsp 30 bid to metformin produced lower HbA_1c levels compared with the addition of glibenclamide, particularly with HbA_1c =9% at baseline	Reduction in HbA_1c and changes in mean BG profiles at 16 weeks Other assessments: weight, TGs and HDL-C, AEs, hypoglycaemia	1b
Wan Mohamad^[29] (Ab)	r, op, pg, mc	192 pts 24 weeks	In pts with type 2 diabetes not well controlled with oral antidiabetic drugs, the addition of BIAsp 30 qd or bid significantly improved glycaemic control without additional safety concerns	Reduction in HbA_1c at endpoint, proportion of pts achieving HbA_1c target of <7.0%, hypoglycaemia and AEs	1b
Ushakova et al.^[30] (Ab)	r, op, mc	308 pts 16 weeks	BIAsp 30 bid + metformin and BIAsp 30 tid achieved significantly better glycaemic control than oral antidiabetic drug monotherapy in pts with poorly controlled type 2 diabetes. Satisfaction with treatment showed a tendency to be higher in insulin treatment groups vs oral antidiabetic drug group	Reduction in HbA_1c, proportion of pts achieving HbA_1c target of <7%, change in mean BG and mean PPG increment at 16 weeks	1b
Niskanen et al.^[31] (FP)	r, op, co, mc	137 pts 12 weeks	BIAsp 30 and biphasic insulin lispro 25 provided comparable glycaemic control in pts with type 2 diabetes with similar safety profiles	Reduction in HbA_1c, change in mean daily BG at 12 weeks; AEs and hypoglycaemic episodes	1b

a Percentage HbA_1c values cited are those from Garber et al.^[27]
Ab = abstract; AE = adverse event; AUCs = areas under the concentration-time curve; BG = blood glucose; BIAsp 30 = biphasic insulin aspart 30 (30% soluble and 70% protamine-bound insulin aspart); bid = twice daily; co = crossover; db = double-blind; DTSQ = Diabetes Treatment Satisfaction Questionnaire; FBG = fasting blood glucose; FP = full paper; HbA_1c = glycosylated haemoglobin; HDL-C = high-density lipoprotein-cholesterol; ITSQ = Insulin Treatment Satisfaction Questionnaire; mc = multicentre; mn = multinational; NPH = neutral protamine Hagedorn insulin (insulin suspension isophane); obs = observational study; op = open-label; pg = parallel group; PPG = postprandial glucose; pts = patients; qd = once daily; r = randomised; SC = subcutaneous; TGs = triglycerides; tid = three times daily.

Summary of Studies of Twice-Daily Biphasic Insulin Aspart 30 Versus Basal Insulin and Versus Other Treatments in Patients with Type 2 Diabetes Mellitus
Ref. (type)	Type of study	Details of study	Study message	Study endpoints	Oxford Grading System
Versus basal insulin
Moses et al.^[21] (Ab)	r, op, pg	233 insulin-naive pts from INITIATE study^[7] 28 weeks (4-week run-in, 24 weeks treatment)	1, 5-anhydroglucitol may be a useful marker of glycaemic control that may allow identification of pts who would benefit from intensive mealtime glycaemic control to achieve target levels of overall glycaemia	Serum 1,5-anhydroglucitol (marker of short-term glycaemic control) Reduction in HbA_1c at 28 weeks	2a
Raskin et al.^[7] (FP)	r, pg, mc	233 pts randomised, 209 completed (INITIATE study) 28 weeks (4-week run-in, 24 weeks treatment)	Initiating insulin therapy with BIAsp 30 bid was more effective in achieving HbA_1c targets than insulin glargine qd in pts with type 2 diabetes poorly controlled with oral antidiabetic drugs, particularly in pts with HbA_1c >8.5%; minor hypoglycaemia was more frequent in the BIAsp 30 group	Reduction in HbA_1c, FBG, daily BG profile and PPG at 28 weeks Safety: hypoglycaemia, weight gain and other AEs	1b
Luzio et al.^[22] (FP)	r	12 pts 2?×?24h study periods	Plasma insulin bioavailability and glucose lowering response were 28% and 34% greater, respectively (p < 0.001 and p < 0.05), after equivalent SC doses of BIAsp 30 (as two split doses) vs a single dose of insulin glargine	Pharmacokinetic/dynamic assessments: AUCs of glucose infusion rate, plasma insulin and C-peptide levels over 24 hours	2a
Christiansen et al.^[23] (FP)	r, db, pg, mn	403 pts 16 weeks	BIAsp 30 bid reduced PPG exposure to a significantly greater extent, and was at least as effective at reducing HbA_1c, compared with NPH insulin; both treatments were well tolerated. Pts on NPH alone who were switched to BIAsp 30 bid achieved a significantly greater reduction in HbA_1c than those switched to NPH bid	Reduction in HbA_1c and change in mean daily BG at 16 weeks Safety: hypoglycaemic events and other AEs	1b
Brod et al.^[24] (Ab)	r, mc	233 insulin-naive pts from INITIATE study^[7] 28 weeks (4-week run-in, 24 weeks treatment)	There were no differences in treatment satisfaction between qd insulin glargine and bid BIAsp 30 injection regimens	Treatment satisfaction (DTSQ and ITSQ) and proportion of pts achieving HbA_1c =6.5% at 24 weeks	2c
Ligthelm^[25] (Ab)	obs	34 pts 6mo	Well-being scores did not differ across treatment groups (insulin glargine qd, BIAsp 30 bid or tid) at 6mo, suggesting that increasing the number of daily insulin injections did not have a detrimental impact on pts' well-being; improvements in glycaemic control were concurrently achieved. In some pts qd insulin was insufficient to achieve good glycaemic control	Changes in HbA_1c and well-being scores (based on answers to 5 lifestyle questions) at 28 weeks	2c
Kann et al.^[26] (Ab)	r, op, pg	255 insulin-naive pts 26 weeks	Commencing insulin with bid BIAsp 30 + metformin can reduce HbA_1c and mean prandial glucose increment to a greater extent than insulin glargine qd + glimepiride	Reduction in HbA_1c and changes in mean prandial increment (average over 3 meals) and FBG at 26 weeks; AEs, hypoglycaemic episodes and weight gain	1b
Versus other treatments
Garber et al.^[27] (FP)	op, mc	100 pts 48 weeks	Progressive titration of BIAsp 30 (when added to oral antidiabetic drug therapy) allows a high percentage of pts with type 2 diabetes unsuccessfully treated with oral antidiabetic drugs and basal insulin alone to reach glycaemic targets: HbA_1c <7% attained by 41%, 70% and 77% of pts with BIAsp 30 qd, bid or tid, respectively; HbA_1c =6.5% attained by 21%, 52% and 60%, respectively^a	Proportion of pts achieving HbA_1c target of =6.5%, reduction in HbA_1c, FBG, and mean daily BG Safety: AEs and hypoglycaemic episodes	2b
Kvapil^[28] (FP)	r, op, pg, mn	329 pts 16 weeks	In poorly controlled pts with type 2 diabetes, addition of BIAsp 30 bid to metformin produced lower HbA_1c levels compared with the addition of glibenclamide, particularly with HbA_1c =9% at baseline	Reduction in HbA_1c and changes in mean BG profiles at 16 weeks Other assessments: weight, TGs and HDL-C, AEs, hypoglycaemia	1b
Wan Mohamad^[29] (Ab)	r, op, pg, mc	192 pts 24 weeks	In pts with type 2 diabetes not well controlled with oral antidiabetic drugs, the addition of BIAsp 30 qd or bid significantly improved glycaemic control without additional safety concerns	Reduction in HbA_1c at endpoint, proportion of pts achieving HbA_1c target of <7.0%, hypoglycaemia and AEs	1b
Ushakova et al.^[30] (Ab)	r, op, mc	308 pts 16 weeks	BIAsp 30 bid + metformin and BIAsp 30 tid achieved significantly better glycaemic control than oral antidiabetic drug monotherapy in pts with poorly controlled type 2 diabetes. Satisfaction with treatment showed a tendency to be higher in insulin treatment groups vs oral antidiabetic drug group	Reduction in HbA_1c, proportion of pts achieving HbA_1c target of <7%, change in mean BG and mean PPG increment at 16 weeks	1b
Niskanen et al.^[31] (FP)	r, op, co, mc	137 pts 12 weeks	BIAsp 30 and biphasic insulin lispro 25 provided comparable glycaemic control in pts with type 2 diabetes with similar safety profiles	Reduction in HbA_1c, change in mean daily BG at 12 weeks; AEs and hypoglycaemic episodes	1b

Summary of Studies of Once-Daily Use of Biphasic Insulin Aspart 30 in Patients with Type 2 Diabetes Mellitus
Ref. (type)	Type of study	Details of study	Study message	Study endpoints	Oxford Grading System
Garber et al.^[27] (FP)	op, mc	100 pts 48 weeks	BIAsp 30, when progressively titrated from qd to bid to tid, enables a high percentage of pts to achieve glycaemic targets when added to oral antidiabetic drug therapy in type 2 diabetes unsuccessfully treated with oral antidiabetic drugs and basal insulin only	Proportion of pts achieving HbA_1c target of =6.5%, reduction in HbA_1c, FBG and mean daily BG Safety: AEs and hypoglycaemic episodes	2b
Kilo et al.^[32] (FP)	r, op, pg	140 pts 12 weeks	Pts with type 2 diabetes can safely and effectively commence insulin therapy using qd injections of BIAsp 30, BHI 30 or NPH insulin, each in combination with metformin. All three combinations were effective in improving glycaemic control (HbA_1c decreases of 1.1–1.3%)	Reduction in HbA_1c, FBG and mean daily BG at 12 weeks Safety: AEs and hypoglycaemia	1b
Wan Mohamad^[29] (Ab)	r, op, pg, mc	192 pts 24 weeks	In pts with type 2 diabetes not well controlled with oral antidiabetic drugs, the addition of BIAsp 30 qd or bid significantly improved glycaemic control while not posing additional safety concerns to the pts	Reduction in HbA_1c at endpoint, proportion of pts achieving HbA_1c target of <7.0%, hypoglycaemia and AEs	1b
Lund et al.^[33] (Ab)	r	96 pts (non-obese) 12mo	Combining BIAsp 30 with oral antidiabetic drugs resulted in near-optimal glycaemic control in non-obese pts with type 2 diabetes uncontrolled by oral antidiabetic drug combination therapy. BIAsp 30 + oral antidiabetic drugs can be initiated qd (pre-dinner), but most pts needed >1 daily injection to achieve glycaemic target after 1 year	Reduction in HbA_1c and proportion of pts achieving HbA_1c target of <6.5% at 3 and 12mo	1b
Kabadi & Kabadi^[34] (FP)	r	46 pts 6mo	Combining once-daily BIAsp 30 with glimepiride and/or metformin resulted in desirable glycaemic control (HbA_1c <7.0%) in pts with lapse of glycaemic control with oral antidiabetic drugs	Reduction in HbA_1c, FBG, insulin dose, weight gain and hypoglycaemia	1b

Ab = abstract; AE = adverse event; BG = blood glucose; BIAsp 30 = biphasic insulin aspart 30 (30% soluble and 70% protamine-bound insulin aspart); BHI = biphasic human insulin; bid = twice daily; FBG = fasting blood glucose; FP = full paper; HbA_1c = glycosylated haemoglobin; mc = multicentre; NPH = neutral protamine Hagedorn insulin (insulin suspension isophane); op = open-label; pg = parallel group; pts = patients; qd = once daily; r = randomised; tid = three times daily.

Summary of Studies of Three Times Daily Use of Biphasic Insulin Aspart 30 in Patients with Type 2 Diabetes Mellitus
Ref. (type)	Type of study	Details of study	Study message	Study endpoints	Oxford Grading System
Garber et al.^[27] (FP)	op, mc	100 pts 48 weeks	BIAsp 30, when progressively titrated, enabled a high percentage of pts to achieve glycaemic targets when added to oral antidiabetic drug therapy in type 2 diabetes unsuccessfully treated with oral antidiabetic drugs and basal insulin only. HbA_1c <7% attained by 41%, 70% and 77% of pts with BIAsp 30 qd, bid or tid, respectively; HbA_1c =6.5% attained by 21%, 52% and 60%, respectively^a	Proportion of pts achieving HbA_1c target of =6.5%, reduction in HbA_1c, FBG, and mean daily BG Safety: AEs and hypoglycaemic episodes	2b
Ushakova et al.^[30] (Ab)	r, op, mc	308 pts 16 weeks	BIAsp 30 tid and BIAsp 30 bid + metformin significantly improved glycaemic control in pts with poorly controlled type 2 diabetes. Slight increase in bodyweight and incidence of minor hypoglycaemia in insulin treatment groups did not influence pts' treatment satisfaction	Reduction in HbA_1c, proportion of pts achieving HbA_1c target of <7%, change in mean BG and mean PPG increment at 16 weeks	1b
Ligthelm^[25] (Ab)	obs	34 pts 6mo	HbA_1c and well-being scores improved in pts receiving qd glargine, BIAsp 30 bid or BIAsp 30 tid at 6mo (at 2–3 mo, pts on qd glargine not meeting glycaemic targets were switched to BIAsp bid or tid). Well-being did not differ between treatment groups at 6mo, suggesting that increasing the number of daily insulin injections did not have a detrimental impact on pts' well-being	Changes in HbA_1c and well-being scores (based on answers to five lifestyle questions) at 28 weeks	2c

a % HbA_1c values cited are those from Garber et al.^[27]
Ab = abstract; AE = adverse event; BG = blood glucose; BIAsp 30 = biphasic insulin Aspart 30 (30% soluble and 70% protamine-bound insulin aspart); bid = twice daily; BHI = biphasic human insulin; FBG = fasting blood glucose; HbA_1c = glycosylated haemoglobin; mc = multicentre; obs = observational study; op = open-label; PPG = postprandial glucose; pts = patients; qd = once daily; r = randomised; tid = three times daily.

Summary of Studies of Three Times Daily Use of Biphasic Insulin Aspart 30 in Patients with Type 2 Diabetes Mellitus
Ref. (type)	Type of study	Details of study	Study message	Study endpoints	Oxford Grading System
Garber et al.^[27] (FP)	op, mc	100 pts 48 weeks	BIAsp 30, when progressively titrated, enabled a high percentage of pts to achieve glycaemic targets when added to oral antidiabetic drug therapy in type 2 diabetes unsuccessfully treated with oral antidiabetic drugs and basal insulin only. HbA_1c <7% attained by 41%, 70% and 77% of pts with BIAsp 30 qd, bid or tid, respectively; HbA_1c =6.5% attained by 21%, 52% and 60%, respectively^a	Proportion of pts achieving HbA_1c target of =6.5%, reduction in HbA_1c, FBG, and mean daily BG Safety: AEs and hypoglycaemic episodes	2b
Ushakova et al.^[30] (Ab)	r, op, mc	308 pts 16 weeks	BIAsp 30 tid and BIAsp 30 bid + metformin significantly improved glycaemic control in pts with poorly controlled type 2 diabetes. Slight increase in bodyweight and incidence of minor hypoglycaemia in insulin treatment groups did not influence pts' treatment satisfaction	Reduction in HbA_1c, proportion of pts achieving HbA_1c target of <7%, change in mean BG and mean PPG increment at 16 weeks	1b
Ligthelm^[25] (Ab)	obs	34 pts 6mo	HbA_1c and well-being scores improved in pts receiving qd glargine, BIAsp 30 bid or BIAsp 30 tid at 6mo (at 2–3 mo, pts on qd glargine not meeting glycaemic targets were switched to BIAsp bid or tid). Well-being did not differ between treatment groups at 6mo, suggesting that increasing the number of daily insulin injections did not have a detrimental impact on pts' well-being	Changes in HbA_1c and well-being scores (based on answers to five lifestyle questions) at 28 weeks	2c

Summary of Studies of Biphasic Insulin Aspart 30 in Combination with Thiazolidinediones in Patients with Type 2 Diabetes Mellitus
Ref. (type)	Type of study	Details of study	Study message	Study endpoints	Oxford Grading System
Raz et al.^[35] (Ab); Raz et al.^[36] (FP)	r, op, pg, mc	281 pts 18 weeks	BIAsp 30 + pioglitazone provided improved glycaemic control compared with BIAsp 30 monotherapy or pio- glitazone + glibenclamide combination therapy. HbA_lc levels achieved with BIAsp 30 + pioglitazone were significantly lower than with glibenclamide + pioglitazone (mean -0.64%; p = 0.005) or with BIAsp 30 monotherapy (-0.60%; p = 0.008). BIAsp 30 + pioglitazone was “a better treatment option than adding pioglitazone to existing and failing SU therapy in this population of poorly controlled patients with type 2 diabetes'^[36]	HbA_1c, FBG, BG profiles, lipid profiles, hypoglycaemia and AEs at 18 weeks	1b, 1b
Raskin et al.^[7] (FP)	r, pg, mc	233 pts randomised, 209 completed 28 weeks	In pts with type 2 diabetes poorly controlled with oral antidiabetic drugs, initiating insulin with BIAsp 30 bid was more effective in achieving HbA_1c targets than glargine qd. Reductions in HbA_1c from baseline continued to be significantly greater in the BIAsp 30 group irrespective of pioglitazone use: BIAsp 30 vs glargine: -2.6% vs -2.13% (p < 0.05) with pioglitazone, and -2.89 vs -2.46 (p < 0.05) without pioglitazone	Reduction in HbA_1c, FBG, daily BG profile and PPG at 28 weeks Safety: hypoglycaemia, weight gain and other AEs	1b
Raz et al.^[37] (FP)	r, op, pg, mc	49 pts 6 weeks	In pts with type 2 diabetes whose BG level was poorly controlled with glibenclamide monotherapy, switching to BIAsp 30 + rosiglitazone was effective and well tolerated and provided an alternative to adding rosiglitazone to existing glibenclamide treatment. BIAsp 30 may be associated with greater improvements in short-term metabolic control	Change in mean daily BG, prandial BG, HbA_1c, fructosamine and FBG at 6 weeks Safety: AEs, hypoglycaemia	1b

Ab = abstract; AE = adverse event; BG = blood glucose; BIAsp 30 = biphasic insulin aspart 30 (30% soluble and 70% protamine-bound insulin aspart); bid = twice daily; FBG = fasting blood glucose; FP = full paper; HbA_1c = glycosylated haemoglobin; mc = multicentre; op = open-label; pg = parallel group; PPG = postprandial glucose; pts = patients; qd = once daily; r = randomised; SU = sulphonylurea.

Summary of Studies Comparing Biphasic Insulin Aspart 30 with Biphasic Human Insulin 30 in Patients with Type 2 Diabetes Mellitus
Ref. (type)	Type of study	Details of study	Study message	Study endpoints	Oxford Grading System
Boehm et al.^[39] (FP)	r, op, pg	125 pts 2 years (3-month trial + 21-month extension); 76% completed 24-month treatment period	The frequency of major hypoglycaemic episodes was lower with BIAsp 30 bid than with BHI 30 bid during the second year of treatment; no significant difference between treatment groups in HbA_1c levels after 24mo	Safety: hypoglycaemic episodes, AEs, weight gain at 2 years	1b
Iwamoto^[38] (Ab)	r, op, pg, mc	428 pts 48 weeks	Overall glycaemic control with BIAsp 30 bid immediately before meals was as effective as BHI 30 bid 30 minutes before meals in type 2 diabetes. The frequency of hypoglycaemic episodes was similar in both treatment groups	HbA_1c at 24 weeks, pre- and postprandial BG, total daily insulin dose; AEs, hypoglycaemia	1b
McSorley et al.^[41] (FP)	r, db, co	13 pts 4 weeks	Pre-meal injection of BIAsp 30 bid resulted in significantly lower PPG excursions compared with BHI 30 after breakfast and dinner	24h BG profile, serum insulin and C-peptide levels, insulin AUC_2, AUC_24, C_max and t_max, prandial and nocturnal BG excursions, average 24h BG	1b
Hermansen et al.^[42] (FP)	r, op, co	61 pts Single dose 3 days	BIAsp 30 improves PPG control compared with biphasic insulin lispro 25 and conventional BHI 30	5h insulin and BG profiles, prandial glucose excursions; AEs and hypoglycaemia	1b
McNally et al.^[44] (Ab)	r, db, co, mc	160 insulin-treated pts 40 weeks (2?×? 16-week treatment periods and 8-week run in)	No difference in the mean frequency of reported hypoglycaemic events during treatment with BIAsp 30 bid and BHI 30 bid (although fewer major hypoglycaemic episodes with BIAsp 30) and no difference in HbA_1C between the two treatments. There was no difference in patient satisfaction between the two treatments. Rates of nocturnal hypoglycaemia were significantly lower when using BIAsp 30 than when using BHI 30, with no difference in overall control	Frequency of pts with BG <3.5 mmol/L, hypoglycaemia, HbA_1c, satisfaction at 8 and 16 weeks	1b
Lammert et al.^[45] (Ab)	r, op, pg	NA 24mo	BIAsp 30 bid was projected to result in additional QALYS and reduced healthcare costs associated with major hypoglycaemic events versus BHI 30. The higher acquisition costs of BIAsp 30 led to increased overall costs, but the incremental cost/QALY fell within the range generally considered to be cost effective in each country	QALYs based on rates of major hypoglycaemic events	1b
Schmoelzer et al.^[46] (FP)	r, op, co	12 pts Single dose 2 days (separated by 6-day washout period)	BIAsp 30 resulted not only in an improvement in glucose tolerance but also in a significant reduction of postprandial hyperlipidaemia compared with BHI 30	Postprandial (0–8h) serum BG, insulin, C-peptide, lipid profiles, HbA_1c, insulin sensitivity (HOMA index) and plasma retinyl palmitate	2a
Kapitza et al.^[43] (FP)	r, op, co	31 pts Single dose 4 test day visits	BIAsp 30 injected immediately before a meal provided superior control of PPG compared with BHI 30 injected 15 min before or immediately before the meal. BIAsp 30 injected after the meal provided PPG control comparable to BHI 30 injected 15 min before or immediately before the meal. Thus, BIAsp 30 offers the advantage of increased flexibility of timing of injection as well as the opportunity to adjust insulin dose after eating according to the amount of food ingested	PPG, AUC₄, C_max	1b
Yamada et al.^[40] (Ab)	r, op, mc	52 Japanese pts 2mo	No difference in short-term glycaemic control between BIAsp 30 and BHI 30, but BIAsp 30 was superior to BHI 30 in terms of its effect on QOL	Reduction in HbA_1c, insulin-therapy-related QOL	2c
Kilo et al.^[32] (FP)	r, op, pg	140 pts 12 weeks	Pts with type 2 diabetes can safely and effectively commence insulin therapy using qd injections of BIAsp 30, BHI 30 or NPH insulin, each in combination with metformin. All three combinations were effective in improving glycaemic control (HbA_1c decreases of 1.1–1.3%)	Reduction in HbA1c, FBG and mean daily BG at 12 weeks; AEs and hypoglycaemia	1b
Ray et al.^[47] (FP)	Economic model using baseline clinical data from INITIATE study^[7] (r, mc)	Baseline cohort characteristics and treatment effects taken from the INITIATE study^[7]	Based on data from the INITIATE study, long-term treatment with BIAsp 30 was projected to be cost effective in the management of pts with type 2 diabetes compared with insulin glargine in the US	Life expectancy, quality-adjusted life expectancy, QALYs based on 4-week efficacy and safety data from INITIATE	1b
Valentine et al.^[48] (FP)	Validated predictive model using baseline clinical data from INITIATE study^[7] (r, mc)	Baseline cohort characteristics and treatment effects taken from the INITIATE study^[7]	Projections based on the INITIATE study showed that BIAsp 30 therapy was associated with a substantially reduced cumulative incidence of diabetes-related complications (especially retinopathy and nephropathy) vs insulin glargine therapy over a patient's lifetime (35 years)	Lifetime cost of treatment based on incidence of diabetes-related complications, QALYs and ICERs	1b

Ab = abstract; AE = adverse event; AUC _x = area under the concentration time curve from time zero to time x; BG = blood glucose; BIAsp 30 = biphasic insulin aspart 30 (30% soluble and 70% protamine-bound insulin aspart); bid = twice daily; BHI 30 = biphasic human insulin 30; C _max = maximum plasma concentration; co = crossover; db = double-blind; FBG = fasting blood glucose; FP = full paper; HbA_1c = glycosylated haemoglobin; HOMA = homeostasis model assessment; ICERs = incremental cost-effectiveness ratios; mc = multicentre; NA = not available; NPH = neutral protamine Hagedorn insulin (insulin suspension isophane); op = open-label; pg = parallel group; PPG = postprandial glucose; pts = patients; qd = once daily; QALYs = quality-adjusted life-years; QOL = quality of life; r = randomised; t _max = time to reach C_max.

Appendix

Oxford Centre for Evidence-Based Medicine Levels of Evidence (Oxford Centre for Evidence-Based Medicine 2005, Reproduced with Permission^[19])

Level^a	Therapy/prevention, aetiology/harm	Prognosis	Diagnosis	Differential diagnosis/symptom prevalence study	Economic and decision analyses
1a	SR (with homogeneity^b) of RCTs	SR (with homogeneity^b) of inception cohort studies; CDR^c validated in different populations	SR (with homogeneity^b) of level 1 diagnostic studies; CDR^c with 1b studies from different clinical centres	SR (with homogeneity^b) of prospective cohort studies	SR (with homogeneity^b) of level 1 economic studies
1b	Individual RCT (with narrow confidence interval^d)	Individual inception cohort study with >80% follow-up; CDR^c validated in a single population	Validating^e cohort study with good^f reference standards; or CDR^c tested within one clinical centre	Prospective cohort study with good follow-up^g	Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multiway sensitivity analyses
1c	All or none^h	All or none case series	Absolute SpPins and SnNoutsⁱ	All or none case series	Absolute better-value or worse-value analyses^j
2a	SR (with homogeneity^b) of cohort studies	SR (with homogeneity^b) of either retrospective cohort studies or untreated control groups in RCTs	SR (with homogeneity^b) of level >2 diagnostic studies	SR (with homogeneity^b) of 2b and better studies	SR (with homogeneity^b) of level >2 economic studies
2b	Individual cohort study (including low-quality RCT; e.g. <80% follow-up)	Retrospective cohort study or follow-up of untreated control pts in an RCT; derivation of CDR^c or validated on split-sample^k only	Exploratory^e cohort study with good^f reference standards; CDR^c after derivation, or validated only on split-sample^k or databases	Retrospective cohort study, or poor follow-up	Analysis based on clinically sensible costs or alternatives; limited review(s) of the evidence, or single studies; and including multiway sensitivity analyses
2c	'Outcomes' research; ecological studies	'Outcomes' research		Ecological studies	Audit or outcomes research
3a	SR (with homogeneity^b) of case-control studies		SR (with homogeneity^b) of 3b and better studies	SR (with homogeneity^b) of 3b and better studies	SR (with homogeneity^b) of 3b and better studies
3b	Individual case-control study		Non-consecutive study; or without consistently applied reference standards	Non-consecutive cohort study, or very limited population	Analysis based on limited alternatives or costs, poor quality estimates of data, but including sensitivity analyses incorporating clinically sensible variations
4	Case series (and poor quality cohort and case-control studies^l)	Case series (and poor quality prognostic cohort studies^m)	Case-control study, poor or non-independent reference standard	Case series or superseded reference standards	Analysis with no sensitivity analysis
5	Expert opinion without explicit critical appraisal, or based on physiology, bench research or 'first principles'	Expert opinion without explicit critical appraisal, or based on physiology, bench research or 'first principles'	Expert opinion without explicit critical appraisal, or based on physiology, bench research or 'first principles'	Expert opinion without explicit critical appraisal, or based on physiology, bench research or 'first principles'	Expert opinion without explicit critical appraisal, or based on economic theory or 'first principles'

^a Users can add a minus sign to denote the level that fails to provide a conclusive answer because of: either a single result with a wide CI (such that, for example, an ARR in an RCT is not statistically significant but whose CIs fail to exclude clinically important benefit or harm), or a systematic review with troublesome (and statistically significant) heterogeneity. Such evidence is inconclusive, and therefore can only generate grade D recommendations.
^b By homogeneity we mean a systematic review that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a '-' at the end of their designated level.
^c Clinical decision rule – these are algorithms or scoring systems that lead to a prognostic estimation or a diagnostic category.
^d See footnote 'a' above for advice on how to understand, rate and use trials or other studies with wide CIs.
^e Validating studies test the quality of a specific diagnostic test, based on prior evidence. An exploratory study collects information and trawls the data (e.g. using a regression analysis) to find which factors are 'significant'.
^f Good reference standards are independent of the test, and applied blindly or objectively to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study.
^g Good follow-up in a differential diagnosis study is >80%, with adequate time for alternative diagnoses to emerge (e.g. 1–6mo acute, 15 years chronic).
^h Met when all patients died before the treatment became available, but some now survive on it; or when some patients died before the treatment became available, but none now die on it.
ⁱ An 'Absolute SpPin' is a diagnostic finding whose Specificity is so high that a Positive result rules-in the diagnosis. An 'Absolute SnNout' is a diagnostic finding whose Sensitivity is so high that a Negative result rules-out the diagnosis.
^j Better-value treatments are clearly as good but cheaper, or better at the same or reduced cost. Worse-value treatments are as good and more expensive, or worse and equally or more expensive.
^k Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into 'derivation' and 'validation' samples.
^l By poor quality cohort study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded) objective way in both cases and controls and/or failed to identify or appropriately control known confounders.
^m By poor quality prognostic cohort study we mean one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was accomplished in <80% of study patients, or outcomes were determined in an unblinded, non-objective way, or there was no correction for confounding factors.
ARR = absolute risk reduction; CDR = clinical decision rule; CI = confidence interval; RCT = randomised controlled trial; SR = systematic review.

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Biphasic Insulin Aspart in Type 2 Diabetes Mellitus: An Evidence-Based Medicine Review

Abstract and Introduction

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