Insulin Analogs and Glycosylated Hemoglobin Target of Less Than 7% in Type 2 Diabetes: A Systematic Review of Randomized Trials

Abstract

Background:

We conducted a systematic review of randomized controlled trials (RCTs) that evaluated the effectiveness of insulin regimens with insulin analogs to reach the glycosylated hemoglobin (HbA1c) target of <7% in patients with type 2 diabetes.

Methods:

RCTs involving insulin regimens (basal, prandial, biphasic, and basal-bolus) with insulin analogs in type 2 diabetes were identified through electronic searches [MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and The Cochrane Library] through September, 2010. We included any study arm of RCTs if they were at least 12 weeks in duration and reported HbA1c as an outcome.

Results:

We identified 55 RCTs, with 96 arms and 33,244 patients, that reported the HbA1c target, and 32 RCTs, with 32 arms and 5,559 patients, that did not report the target. The missing targets were calculated with an algorithm that explained 88% of variability between studies. Overall, the proportion of patients at target (HbA1c <7%) was 37.2% [95% confidence interval (CI), 31.5–43.1%] with basal insulin, 35.3% (28.9–42.1%) with biphasic insulin, 37.5% (27.7–47.9%) with prandial insulin, and 51.2% (41.4–61.1%) for basal-bolus insulin, with high heterogeneity (I² >80% for all).

Conclusions:

The HbA1c target <7% can be achieved in a proportion of patients ranging from 35% to 51%, depending on the particular insulin regimen. At least one half of patients with type 2 diabetes receiving insulin analogs do not reach the HbA1c target.

Introduction

T ight glycemic control, to maintain a glycosylated hemoglobin (HbA1c) concentration of 7% or less, is recommended for most patients with type 2 diabetes to minimize the risk of vascular complications, but fewer than half of U.S. adults with type 2 diabetes reach this target.¹ Insulin analogs are increasingly used in the treatment of type 2 diabetes, with the aim to offer a better replication of the pattern of basal and postprandial endogenous secretion of insulin.² According to the National Health Interview Survey, 28% of patients with type 2 diabetes are using insulin, either alone (16%) or in combination with oral antidiabetic drugs (12%).³ In a systematic review of 30,588 patients with type 2 diabetes using insulin analogs, we found that the HbA1c target <7% can be achieved in a percentage ranging from 40% to 54% depending on the particular insulin regimen.⁴ Since then, several new studies have emerged (7 trials with 10 arms); moreover, there were at least 32 randomized controlled trials (RCTs) that were excluded from the previous analysis based on the absence of reported HbA1c target at the end of intervention. Therefore, we undertook this subsequent systematic review of the available evidence assessing the role of insulin analogs to achieve the recommended HbA1c target of <7% in type 2 diabetes.

Methods

We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist for reporting systematic reviews and meta-analyses.⁵

Data sources and searches

We updated our previous systematic review and continued the search through September, 2010. Reports of RCTs of insulin analogs in type 2 diabetes patients were identified through systematic literature search of MEDLINE, EMBASE, The Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). The main search terms were type 2 diabetes, hemoglobin A1c, long-acting insulin analogs, short-acting insulin analogs, biphasic insulin analogs, glargine, detemir, neutral protamine lispro, lispro, aspart, glulisine, randomized controlled trials, and clinical trials. We also reviewed reference lists of included articles, the U.S. Food and Drug Administration and European Medicines Agency websites for the insulin analogs, and websites of public registries of clinical trials (ClinicalTrials.gov and ClinicalStudyResults.org).

Study selection

For a study to be included in the systematic review, it had to be (1) a RCT that evaluated different insulin regimens (basal, biphasic, prandial, or basal-bolus) with insulin analogs in type 2 diabetes and (2) reported HbA1c as an outcome measure. Because being a RCT was a prerequisite for inclusion, any other arm of a given RCT that assessed human insulin or oral drugs was excluded. So, many RCTs could only have one arm. We included crossover trials with at least 12 weeks of follow-up before and after the crossover phase. The search had no language restriction; we excluded reviews, editorials, comments, letters, and abstracts. Trials were rejected if the intervention time was <3 months or the number of patients in any arm was less than 30 patients.

Data extraction and quality assessments

Titles, abstracts, and articles were reviewed independently by two authors (D.G. and K.E.), and any disagreements were resolved by consensus. Methodological quality was scored using criteria set out by Jadad et al.⁶ This 5-point quality scale included points for randomization (described as randomized, 1 point; table of random numbers or computer-generated randomization, additional 1 point), double-blind (described as double-blind, 1 point; use of masking such as identical placebo, additional 1 point), and follow-up (the numbers and reasons for withdrawal in each group are stated; 1 point) in the report of an RCT. We gave an additional point if the analysis was by intention-to-treat. We considered scores of 2 or less as low quality, and a score of 3 or more as high quality, because none but one of the studies were double-blinded, which is difficult with this type of intervention.

Insulin regimens

We evaluated four insulin regimens: (1) Basal insulin consisted of long-acting insulin analogs (glargine, detemir, and lispro NPL); (2) biphasic insulin consisted of premixed insulin analogs (lispro 25/75, lispro 50/50, aspart 30/70, aspart 50/50, aspart 70/30, with the numbers denoting the percentage of the rapid-acting to the long-acting component, respectively); (3) prandial insulin consisted of short-acting insulin analogs (lispro, aspart, glulisine); and (4) basal-bolus insulin consisted of any combination of prandial and basal insulin analogs. Humalog NPL is not available in the United States at present.

Data synthesis and analyses

The proportion of patients with HbA1c <7% at the end of treatment was the primary outcome. Statistically, binomial proportion lacks consensus over the calculation of the confidence intervals. We transformed the proportions into a quantity suitable for the usual fixed and random effects summaries (the Freeman–Tukey variant of the arcsine square root transformed proportion).⁷ The pooled proportion is calculated as back-transformation of the weighted mean of the transformed proportions, using inverse arcsine variance weights for the fixed effects model and DerSimonian–Laird weights⁸ for the random effects model. We used the calculated proportions for descriptive purposes, because claim for superiority can be drawn from meta-analysis of comparative trials. Meta-regression models to check for prognostic factors of response, were fitted by using the SAS proc Mixed procedure.

In 32 trials (39 arms and 5,559 patients) that qualified for inclusion/exclusion criteria, the proportion of patients with HbA1c <7% at the end of treatment was not reported. We used the available information from the 55 trials (96 arms and 33,244 patients) that reported the proportion of patients with HbA1c <7% for developing an algorithm for the estimate of the proportion of patients with HbA1c <7% (p) starting from the mean value of HbA1c reported at the end of treatment. The algorithm was a linear regression model relating the logit of the success rate [log(p/(1−p)], with the HbA1c at the end of the treatment. Following there is the resulting equation to predict the logit of the success rate: log(p/1−p)=11.68167−164.3119×HbA1c−end. This equation explained the 88% of the variability between studies, and just little deviance between observed and predicted success rates were reported. The proportion of patients at target (p) was then given by simple mathematical transformations.

Heterogeneity of the effect across studies was assessed by the Q² statistics, which is distributed as a chi-squared statistic. A p value <0.10 was used to indicate lack of homogeneity among effects. I² statistics were also provided to quantify the percentage of total variation across studies that were attributable to heterogeneity rather than to chance.⁹ A value greater than 50% represented substantial heterogeneity.

Results

The process of selecting the RCTs utilized in the final analyses from the 2,700 citations originally identified is described in Fig. 1. We found 87 studies (refs. 10 –96), with a total of 135 arms, that satisfied the inclusion/exclusion criteria. Most trials were multinational and sponsored by industry. Publication years ranged from 1997 to 2010. All studies were randomized controlled trials (Table 1): Among these, most were parallel group and 8 were crossover studies. All studies were of open-label design except one. Trial duration ranged from 12 to 134 weeks. The trials enrolled a total of 38,803 patients (range, 41 to 2,493 patients per arm); baseline HbA1c ranged from 7.2% to 10.6%. Scores of methodological quality ranged from 1 to 6 (median score 3).

FIG. 1.

Process of selecting the randomized controlled trials (RCTs) used in the final analyses from the 2,700 citations originally identified. RCT, randomized controlled trial.

Table 1.

Characteristics of the Studies Included in the Analysis

Studies (author, year, reference)	N	Length weeks	Insulin regimen	Design	OADs	Naive	Start HbA1c	Statistics	Quality score
Reported target, 55 RCTs
Bastyr, 2000 10	41	12	Prandial	R, O, P	Su	Yes	10.0%	No ITT	1
Riddle, 2003 12	367	24	Basal	R, O, P	Su+Met	Yes	8.6%	ITT	4
Malone, 2003 21	296	16	Biphasic	R, O, P	Met	Yes	9.17%	ITT	2
Malone, 2004 13	105	16	Biphasic, basal	R, O, CO	Met	Yes	8.7, 8.7%	No ITT	3
Raskin, 2005 14	233	24	Biphasic, basal	R, O, P	Met+Pio	Yes	9.7, 9.8%	ITT	2
Heine, 2005 15	260	24	Basal	R, O, P	Su+Met	Yes	8.3%	ITT	4
Janka, 2005 16	177	24	Basal	R, O, P	Su+Met	Yes	8.85%	No ITT	3
Malone, 2005 17	97	16	Biphasic, basal	R, O, CO	Met	No	8.5, 8.5%	ITT	2
Davies, 2005 18	4,961	24	Basal, 2 arms	R, O, P	Big/Su	No	8.9, 8.9%	ITT	3
Kann, 2006 19	255	24	Biphasic, basal	R, O, P	Glimepiride	Mix	9.2, 8.9%	ITT	2
Jacober, 2006 20	60	16	Biphasic, basal	R, O, CO	Met/Su/Tzd	Yes	9.2%	No ITT	2
Kazda, 2006 21	162	16	Biph, basal, prandial	R, O, P	No	Yes	8.1, 8.1, 8,2%	ITT	2
Kennedy, 2006 22	5,721	24	Basal, 4 arms	R, O, P	Su, Met, Tzd	Yes	8.9%	ITT	3
Hermansen, 2006 23	227	24	Basal	R, O, P	Met, Su, α-g	Yes	8.6%	ITT	3
Rosenstock, 2006 24	104	24	Basal	R, O, P	Met+Su	Yes	8.8%	ITT	4
Gernstein, 2006 25	206	24	Basal	R, O, P	Met+Su, no tzd	Yes	8.6%	ITT	2
Standl, 2006 26	624	24	Basal, 2 arms	R, O, P	Glimepiride	Yes	8.8%	FAS	1
Holman, 2007 27	708	52	Biph, basal, prandial	R, O, P	Met+Su	Yes	8.6, 8.4, 8.6%	ITT	4
Ushakova, 2007 28	200	16	Biphasic, 2 arms	R, O, P	Met	Yes	10.4, 10.4%	ITT	2
Robbins, 2007 29	315	24	Biphasic, basal	R, O, P	Met	No	7.8, 7.8%	ITT	4
Barnett, 2007 30	138	16	Basal	R, O, CO	Met or Su	Yes	8.9%	ITT	3
Nauck, 2007 31	248	52	Biphasic	R, O, P	Met, Su	Yes	8.6%	Per protoc	4
Esposito, 2008 32	116	36	Basal, 2 arms	R, O, P	Met, Su	Yes	8.8, 8.7%	ITT	4
Bretzel, 2008 33	418	48	Prandial, basal	R, O, P	Met, Su	Yes	8.7, 8.7%	ITT	4
Hirao, 2008 34	117	24	Biphasic, prandial	R, O, P	No	Yes	10.6, 10.6%	No ITT	2
Hollander, 2008 35	319	52	Basal-bolus, 2 arms	R, O, P	Tzd	No	8.6, 8.8%	ITT	3
Rosenstock, 2008 36	582	52	Basal, 2 arms	R, O, P	Met, Su, Tzd	Yes	8.6%	ITT	4
Rosenstock, 2008 37	374	24	Biphasic, basal-bolus	R, O, P	No Su	No	8.8, 8.9%	Complete	4
Bergenstal, 2008 38	273	24	Basal-bolus, 2 arms	R, O, P	No	No	8.1, 8.3%	ITT	3
Yang, 2008 39	321	24	Biphasic, 2 arms	R, O, P	No	Yes	9.5%	ITT	4
Lankisch, 2008 40	316	24	Basal/plus, 2 arms	R, O, P	All	No	7.3%	FAS	2
Liebl, 2009 41	715	16	Biphasic, basal-bolus	R, O, P	No	No	8.4, 8.5%	ITT	2
Raskin, 2009 42	102	34	Biphasic	R, O, P	Met, Pio	Yes	8.1%	ITT	3
Raz, 2009 43	1,115	134	Basal, prandial	R, O, P	No	No	8.3, 8.4%	ITT	4
Riddle, 2009 44	56	24	Basal-bolus	R, O, P	All	No	8.3%	ITT	4
Russell-jones, 2009 45	232	24	Basal	R, O, P	Glimep+Met	No	8.2%	ITT	4
Kawamori, 2009 46	257	16	Prandial, 2 arms	R, O, P	Su+Met/No	Yes	9.0%	ITT	2
Bicklé, 2009 47	103	36	Basal	R, O, P	Su+Met	Yes	7.6%	FAS	2
Buse, 2009 48	2091	24	Basal, biphasic	R, O, P	Met/Su/Tzd	Yes	9.1%, 9.0%	ITT	4
Blonde 2009 49	243	20	Basal, 2 arms	R, O, P	MET/Su/Tzd	Yes	7.9%	ITT	3
Raskin, 2009 50	385	24	Basal-bolus, 2 arms	R, O, P	No	No	8.4%	ITT	3
Cucinotta, 2009 51	603	36	Biphasic, 3 arms	R, O, P	Metformin	No	8.9, 8.9, 8.7%	ITT	2
Rosenstock, 2009 52	223	24	Basal	R, O, P	SU/Met/Tzd	No	8.5%	ITT	2
Gross, 2009 53	203	24	Prandial	R, O, P	SU/Met/Tzd	Yes	8.2%	ITT	2
Oyer, 2009 54	4875	24	Biphasic, 3 arms	R, O, P	No Su	Yes	9.9%	ITT	2
Strojek, 2009 55	480	24	Basal, biphasic	R, O, P	Met+Glimep	Yes	8.5%	ITT	2
Fritsche, 2009 56	153	52	Basal-bolus	R, O, P	Met (56%)	No	8.6%	ITT	3
Fogelfeld, 2009 57	442	24	Basal, 2 arms	R, O, P	Su/Met-Tzd	Yes	8.80%	ITT	3
Heise, 2010 58	122	26	Basal	R, O, P	Su/Met/Tzd	Yes	8.6%	FAS	3
Kalra, 2010 59	155	26	Basal, biphasic	R, O, P	Met+Glimep	Yes	8.4%	ITT	3
Swinnen, 2010 60	964	24	Basal, 2 arms	R, O, P	Met+Su/Tzd	Yes	8.7%	Complete	3
Diamant, 2010 61	223	26	Basal	R, O, P	Met±Su	Yes	8.3%	ITT	4
Strojek, 2010 62	471	24	Basal, 2 arms	R, O, P	Met+SU±Tzd	Yes	8.67%	ITT	3
Rosenstock, 2010 63	237	52	Biphasic	R, O, P	Met/Tzd	No	8.7%	Per protoc	3
Jain, 2010 64	484	36	Biphasic, basal-bolus	R, O, P	Met/Su/Tzd	Yes	9.5, 9.3%	Per protoc	2
Calculated target, 32 RCTs
Anderson,1997 65	772	24	Prandial	R, O, CO	No	No	8.7%	ITT	3
Roach, 1999 66	89	24	Biphasic	R, O, CO	No	No	9.2%	No ITT	2
Yki-yarvinen, 2000 67	213	52	Basal	R, O, P	Su/Met or both	Yes	9.1%	No ITT	2
Rosenstock, 2001 68	259	28	Basal	R, O, P	No	No	8.6%	ITT	3
Ross, 2001 69	70	28	Prandial	R, O, P	No	Yes	10.3%	ITT	3
Herz, 2002 70	72	16	Prandial	R, O, P	Glimepiride	Yes	9.8%	No ITT	2
Massi-Benedetti, 2003 71	235	52	Bassal	R, O, P	Yes	Yes	8,56	ITT	3
Fritsche, 2003 72	463	24	Basal, 2 arms	R, O, P	Glimepiride	Yes	9.1%	ITT	4
Roach, 2003 73	116	16	Biphasic, 2 arms	R, O, CO	No	No	No data	No ITT	1
Tigoviste, 2003 74	85	16	Biphasic	R, O, P	No	Yes	9.85%	No ITT	1
Christiansen, 2003 75	201	16	Biphasic	R, O, P	No	Mixed	8.8%	ITT	3
Kilo, 2003 76	46	12	Biphasic	R, O, P	Metformin	Yes	9.5%	No ITT	2
Forst, 2003 77	75	24	Prandial	R, O, P	No	Yes	7.5%	No ITT	2
Schernthaner, 2004 78	40	24	Biphasic	R, O, P	No	No	8.4%	No ITT	2
Niskanen, 2004 79	266	12	Biphasic, 2 arms	R, O, CO	No	No	8.5%	ITT	3
Boehm, 2004 80	58	108	Biphasic	R, O, P	No	No	No data	No ITT	1
Bretzel, 2004 81	75	12	Prandial	R, O, P	No	No	78%	ITT	3
Raslova 2004 82	195	22	Basal-bolus	R, O, P	No	No	8.1%	ITT	3
Abrahamian, 2005 83	89	24	Biphasic	R, O, P	No	No	9.8%	ITT	2
Raz, 2005 84	190	18	Biphasic, 2 arms	R, O, P	No	Yes	9.5, 9.6%	ITT	3
Haak, 2005 85	341	26	Basal-bolus	R, O, P	No	No	7.9%	ITT	3
Eliaschewitz, 2006 86	231	24	Basal	R, O, P	Glimepiride	Yes	9.0%	ITT	3
Philis-Tsimikas, 2006 87	338	20	Basal, 2 arms	R, O, P	Met/su/Tzd	Yes	9.1, 8.9%	ITT	3
Yki-Jarvinen, 2006 88	55	36	Basal	R, O, P	Metformin	Yes	9.13%	ITT	4
Ligthelm, 2006 89	196	16	Biphasic	R, O, P	No	No	91%	ITT	3
Kvapil, 2006 90	215	16	Biphasic, 2 arms	R, O, P	Metformin/No	Yes	9.6, 9.3%	ITT	3
Yokohama, 2006 91	31	24	Basal-bolus	R, O, P	No	No	7.2%	No ITT	2
Yki-Jarvinen, 2007 92	121	24	Basal	R, O, P	Su/Met/Both	Yes	8.7%	ITT	4
Pan, 2007 93	220	24	Basal	R, O, P	Glimepiride	Yes	9.0%	No ITT	2
Bunck, 2009 94	33	52	Basal	R, O, P	Metformin	Yes	7.4%	No ITT	3
Milicevic, 2009 95	68	24	Biphasic	R, O, P	No	Yes	9.7%	No ITT	3
Lund, 2009 96	103	52	Biphasic, 2 arms	R, DB, P	Metformin/No	Yes	8.15, 8.07%	ITT	6

OADs, oral antidiabetic drugs; HbA1c, glycosylated hemoglobin; R, randomized; O, open; DB, double-blind; P, parallel; CO, cross-over; Met, metformin; Su, sulfonylurea; Tzd, thiazolidinedione; Pio, pioglitazone; Glimep, glimepiride; α-g, α-glucosidase inhibitor; Big, biguanide.

All results are given in Table 2; they are presented for the four insulin regimens (basal, biphasic, prandial, and basal-bolus) and divided for reported targets (arms in which the proportion of patients with HbA1c <7% was reported), calculated target (arms in which the proportion of patients with HbA1c <7% was not reported but calculated with the algorithm), and pooled data (both reported and calculated). There were 45, 26, 9, and 13 arms that reported the proportion of patients at target with basal, biphasic, prandial, and basal-bolus insulin, respectively. The proportion of patients with HbA1c <7% was 42.5%, 46.5%, 39.6%, and 52.2%, respectively. Heterogeneity was high for all regimens (I² >50%).

Table 2.

Analysis for the 87 Trials with 135 Arms

Insulin regimen	Arms	N	Final HbA1c Median (interquartile)	Target: HbA1c <7% pooled (95% CI)	I²	P value
Basal
Reported target	45	19447	7.25 (7.06–7.44)	42.5% (36.6%–48.3%)	95.7%	0.01
Calculated target	12	2168	7.83 (7.5–8.10)	29.8% (18.5%–41.2%)	94.6%
Pooled	57	21615	7.34 (7.1–7.7)	37.2% (31.5%–43.1%)	96.1%
Biphasic
Reported target	29	9792	7.3 (7.0–7.53)	44.9% (39.2%–50.7%)	89.3%	<0.001
Calculated target	20	1832	8.1 (7.7–8.3)	21.2% (14.4%–28.9%)	89.6%
Pooled	49	11624	7.49 (7.1–8.0)	35.3% (28.9%–42.1%)	85.7%
Prandial
Reported target	9	1605	7.31 (7.05–7.7)	39.6% (28.6%–51.3%)	94.6%	0.5
Calculated target	4	992	7.6 (7.05–8.1)	33.3% (8.4%–65.0%)	96.8%
Pooled	13	2597	7.3 (7.05–7.76)	37.5% (27.7%–47.9%)	96.6%
Basal-bolus
Reported target	13	2400	7.0 (6.8–7.1)	52.2% (42.2%–62.7%)	92.1%	0.2
Calculated target	3	567	7.46 (6.8–7.56)	45.7% (8.4%–86.3%)	89.7%
Pooled	16	2967	7.02 (6.8–7.25)	51.2% (41.4%–61.1%)	93.7%

The I² parameter represents the percentage of total variation across studies that is attributable to heterogeneity rather than chance. P value refers to the difference of post-treatment (final) HbA1c values between published and estimated target.

HbA1c, glycosylated hemoglobin; CI, confidence interval.

Additional 37 arms (12, 20, 4, and 3, for basal, biphasic, prandial and basal-bolus insulin, respectively) with a total of 5,426 patients did not report the target. The overall proportion of patients at target for both basal and biphasic regimens was 30% and 53% less in comparison with the pooled estimate provided by the analysis of reported target; on the other hand, there were smaller differences for the prandial and basal-bolus regimens between reported and calculated targets. The median of final HbA1c level was higher for the basal and the biphasic insulin regimens in the arms with calculated target as compared with the arms with reported target. There was no difference in terms of variability attributable to heterogeneity across studies.

The proportion of patients at target in the pooled data (both reported and calculated) was closer to that observed in arms with reported target than that in arms with calculated target, owing to the greater number of arms (and patients) that reported the target.

Discussion

Insulin analogs are modified human insulins developed to address the limitations of human insulin preparations.² Conversion of the insulin market to analogs, estimated to be 40%–45% in 2005, was projected to reach saturation within 2010.⁹⁷ On the basis of the present analysis extended to 135 arms with 38,803 patients, we found that insulin analogs currently adopted in the clinical management of type 2 diabetes resulted in different proportions of patients achieving the recommended HbA1c target of <7%. The proportion of patients at target within the four insulin regimens derived by the arms with reported target ranged from the least value of 39.6% with the prandial to the highest value of 52.2% with the basal-bolus regimen. These figures were quite similar to those reported in the previous analysis,⁴ which makes it unlikely that further future studies will change them consistently. On the other hand, the proportions changed substantially, at least for basal and biphasic insulin regimens, by taking into account the studies that did not report the target. For the basal and biphasic insulin regimens, the calculated targets were between 30% and 50% lower than the reported targets. Because the algorithm we developed used the final HbA1c for calculating the target, this difference could be almost entirely explained by the higher posttreatment HbA1c values observed in the 39 arms. The mean difference between final HbA1c level ranged from 0.29% for the prandial to 0.8% for the biphasic regimen; this fully explained the differences in the proportion of patients at target between calculated and reported targets.

Selective outcome reporting occurs too often in medical studies, perhaps as a consequence of the situation that negative or less-than expected results are less likely to be published or reported than positive or fully expected results: Meta-analyses based on these studies are subject to some degree of publication bias because they may be drawing conclusions on less than all of the data.⁹⁸ This might have occurred in trials selected for the present analysis. Taking into consideration the biphasic regimen, for example, only 21% (on the average) of the 1,832 patients included in the 20 arms were at target, a deluding result as compared with the average 46% of patients at target with this regimen in the 29 arms with reported targets. Insulin is the most effective of diabetes medications in lowering glycemia. It can, when used in adequate doses, decrease any level of elevated HbA1C to, or close to, the therapeutic goal. Unlike the other blood glucose-lowering medications, there is no maximum dose of insulin beyond which a therapeutic effect will not occur.⁹⁹ We have no plausible explanation for the difference between reported and calculated target with basal or biphasic insulin regimens. Some study characteristics, including year of publication, quality score, starting HbA1c, insulin titration, and concomitant use of oral drugs, did not explain the difference, which seems inherent to the protocol of the particular study.

This study has limitations. The methodological quality of the trials ranged from low to high, and the degree of heterogeneity was high. In most cases, results were qualitatively similar across studies in terms of directions of effect, even in the presence of large I² values. Most trials had a short follow-up and firm conclusions cannot be drawn about the long-term comparative effectiveness of the various regimens, although trials with longer follow-up are present in the analysis. On the other hand, intermediate outcomes, such as HbA1c, are commonly used clinically to optimize glycemic control. Moreover, the different methods of HbA1c assay used in the various studies may introduce some confounding, although this may apply to similar analyses. Finally, this analysis focused on a HbA1c target of <7%; however, specific diabetic populations or specific situations may require targets more or less stringent. Therefore, targets from 6.5% to 8% may be suggested depending on, although not limited to age, life expectancy, co-morbid conditions, patient preferences, and medication adverse effects.^100,101 At the very end, the higher cost of insulin analogs, as compared with human insulins, may be a deterrent in some “real-world” situations. This study has also strengths. To our knowledge, it represents the first comprehensive analysis describing the attainment of the currently recommended HbA1c target of <7% in type 2 diabetes using insulin analogs for optimization of glycemic control; moreover, the high number of RCTs included (87 RCTs with 135 arms) and the huge number of patients investigated (38,803) makes unlikely the possibility that even missed (nonpublished) data may alter the proportion herein reported.

Our analysis of 38,803 type 2 diabetic patients using insulin analogs in type 2 diabetes indicates that the HbA1c target of <7% can be achieved in a proportion of patients ranging from 35% to 51%, depending on the particular insulin regimen. This poses the problem of how to manage the half of patients that are not at the HbA1c goal with the best, and ultimate, insulin regimen now available (basal-bolus) for controlling hyperglycemia in the real world of the diabetic patient.

Footnotes

Author Disclosure Statement

No conflict of interest exists for any of the authors.

References

Skyler

, Bergenstal

, Bonow

, Buse

, Deedwania

, Gale

, Howard

, Kirkman

, Kosiborod

, Reaven

, Sherwin

. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA Diabetes trials: A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care, 2009; 32:187–192.

Hirsch

. Insulin analogues. N Engl J Med, 2005; 352:174–183.

Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2005. Atlanta: Department of Health and Human Services, Centers for Disease Control and Prevention, 2005.

Giugliano

, Maiorino

, Bellastella

, Chiodini

, Esposito

. Treatment regimens with insulin analogues and haemoglobin A1c target of <7% in type 2 diabetes: A systematic review. Diab Res Clin Pract, 2010, 10.1016/j.diabres.2010.08.006

Liberati

, Altman

, Tetzlaff

, Mulrow

, Gøtzsche

, Ioannidis

, Clarke

, Devereaux

, Kleinjnen

, Moher

. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. Ann Intern Med, 2009; 151:W-65–W-94.

Jadad

, Moore

, Carroll

, Jenkinson

, Reynolds

, Gavaghan

, McQuay

. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clinical Trials, 1996; 17:1–12.

Stuart

, Ord

. Kendall's Advanced Theory of Statistics, 6th. London: Edward Arnold, 1994.

DerSimonian

, Laird

. Meta-analysis in clinical trials. Controlled Clinical Trials, 1986; 7:177–188.

Higgings

JPT

, Thompson

. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002; 21:1539–1558.

10.

Bastyr

3rd , Stuart

, Brodows

, Schwartz

, Graf

, Zagar

, Robertson

. Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group. Diabetes Care, 2000; 23:1236–1241.

11.

Riddle

, Rosenstock

, Gerich

. Insulin Glargine 4002 Study Investigators. The treat-to-target trial: Randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care, 2003; 26:3080–3086.

12.

Malone

, Beattie

, Campaigne

, Johnson

, Howard

, Milicevic

. Therapy after single oral agent failure: Adding a second oral agent or an insulin mixture? Diabetes Res Clin Pract, 2003; 62:187–195.

13.

Malone

, Kerr

, Campaigne

, Sachson

, Holcombe

. Lispro Mixture-Glargine Study Group. Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: A 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clin Ther, 2004; 26:2034–2044.

14.

Raskin

, Allen

, Hollander

, Lewin

, Gabbay

, Hu

, Bode

, Garber

. for the INITIATE Study Group. Initiating insulin therapy in type 2 diabetes: A comparison of biphasic and basal insulin analogs. Diabetes Care, 2005; 28:260–265.

15.

Heine

, Van Gaal

, Johns

, Mihm

, Widel

, Brodows

. GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: A randomized trial. Ann Intern Med, 2005; 143:559–569.

16.

Janka

, Plewe

, Riddle

, Kliebe-Frisch

, Schweitzer

, Yki-Järvinen

. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes. Diabetes Care, 2005; 28:254–259.

17.

Malone

, Bai

, Campaigne

, Reviriego

, Augendre-Ferrante

. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with type 2 diabetes. Diabet Med, 2005; 22:374–381.

18.

Davies

, Storms

, Shutler

, Bianchi-Biscay

, Gomis

. for the Atlantus Study Group. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes. Comparison of two treatment algorithms using insulin glargine. Diabetes Care, 2005; 28:1282–1288.

19.

Kann

, Wascher

, Zackova

, Moeller

, Medding

, Szocs

, Mokan

, Mrevlje

, Regulski

. Starting insulin therapy in type 2 diabetes: Twice-daily biphasic insulin Aspart 30 plus metformin versus once-daily insulin glargine plus glimepiride. Exp Clin Endocrinol Diabetes, 2006; 114:527–532.

20.

Jacober

, Scism-Bacon

, Zagar

. A comparison of intensive mixture therapy with basal insulin therapy in insulin-naïve patients with type 2 diabetes receiving oral antidiabetes agents. Diabetes Obes Metab, 2006; 8:448–455.

21.

Kazda

, Hülstrunk

, Helsberg

, Langer

, Forst

, Hanefeld

. Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy. J Diabetes Complications, 2006; 20:145–152.

22.

Kennedy

, Herman

, Strange

, Harris

. GOAL A1C Team. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes: The Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1C) trial. Diabetes Care, 2006; 29:1–8.

23.

Hermansen

, Davies

, Derezinski

, Martinez Ravn

, Clauson

, Home

. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care, 2006; 29:1269–1274.

24.

Rosenstock

, Sugimoto

, Strange

, Stewart

, Soltes-Rak

, Dailey

. Triple therapy in type 2 diabetes: Insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. Diabetes Care, 2006; 29:554–559.

25.

Gerstein

, Yale

, Harris

, Issa

, Stewart

, Dempsey

. A randomized trial of adding insulin glargine vs. avoidance of insulin in people with type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. Diabet Med, 2006; 23:736–742.

26.

Standl

, Maxeiner

, Raptis

. HOE901/4009 Study Group. Once-daily insulin glargine administration in the morning compared to bedtime in combination with morning glimepiride in patients with type 2 diabetes: an assessment of treatment flexibility. Horm Metab Res, 2006; 38:172–177.

27.

Holman

, Thorne

, Farmer

, Davies

, Keenan

, Paul

, Levy

. for the 4-T Study Group. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med, 2007; 357:1716–1730.

28.

Ushakova

, Sokolovskaya

, Morozova

, Valeeva

, Zanozina

, Sazonova

, Zhadanova

, Starceva

, Kazakova

, Saifullina

. Comparison of biphasic insulin aspart 30 given three times daily or twice daily in combination with metformin versus oral antidiabetic drugs alone in patients with poorly controlled type 2 diabetes: A 16-week, randomized, open-label, parallel-group trial conducted in Russia. Clin Ther, 2007; 29:2374–84.

29.

Robbins

, Beisswenger

, Ceriello

, Goldberg

, Moses

, Pagkalos

, Milicevic

, Jones

, Sarwat

, Tan

. Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: A multinational, 24-week, randomized, open-label, parallel-group comparison. Clin Ther, 2007; 29:2349–2364

30.

Barnett

, Burger

, Johns

, Brodows

, Kendall

, Roberts

, Trautmann

. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: A multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther, 2007; 29:2333–2348.

31.

Nauck

, Duran

, Kim

, Johns

, Northrup

, Festa

, Brodows

, Trautmann

. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: A non-inferiority study. Diabetologia, 2007; 50:259–267.

32.

Esposito

, Ciotola

, Malorino

, Gualdiero

, Schisano

, Ceriello

, Beneduce

, Feola

, Glugliano

. Addition of neutral protamine lispro insulin or insulin glargine to oral type 2 diabetes regimens for patients with suboptimal glycemic control: A randomized trial. Ann Intern Med, 2008; 149:531–539.

33.

Bretzel

, Nuber

, Landgraf

, Owens

, Bradley

, Linn

. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): An open randomised controlled trial. Lancet, 2008; 371:1073–1084.

34.

Hirao

, Arai

, Yamauchi

, Takagi

, Kobayashi

. Japan Diabetes Clinical Data Management Study Group. Six-month multicentric, open-label, randomized trial of twice-daily injections of biphasic insulin aspart 30 versus multiple daily injections of insulin aspart in Japanese type 2 diabetic patients (JDDM 11) Diabetes Res Clin Pract, 2008; 79:171–176.

35.

Hollander

, Cooper

, Bregnhøj

, Pedersen

. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther, 2008; 30:1976–1987.

36.

Rosenstock

, Davies

, Home

, Larsen

, Koenen

, Schernthaner

. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia, 2008; 51:408–416.

37.

Rosenstock

, Ahmann

, Colon

, Scism-Bacon

, Jiang

, Martin

. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: Prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. Diabetes Care, 2008; 31:20–25.

38.

Bergenstal

, Johnson

, Powers

, Wynne

, Vlajnic

, Hollander

, Rendell

. Adjust to target in type 2 diabetes: Comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care, 2008; 31:1305–1310.

39.

Yang

, Ji

, Zhu

, Yang

, Chen

, Liu

, Yu

, Yan

. Biphasic insulin aspart 30 three times daily is more effective than a twice-daily regimen, without increasing hypoglycemia, in Chinese subjects with type 2 diabetes inadequately controlled on oral antidiabetes drugs. Diabetes Care, 2008; 31:852–856.

40.

Lankisch

, Ferlinz

, Leahy

, Scherbaum

. Introducing a simplified approach to insulin therapy in type 2 diabetes: A comparison of two single-dose regimens of insulin glulisine plus insulin glargine and oral antidiabetic drugs. Diabetes Obes Metab, 2008; 10:1178–1185.

41.

Liebl

, Prager

, Binz

, Kaiser

, Bergenstal

, Gallwitz

. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER Study: A randomized controlled trial. Diabetes Obes Metab, 2009; 11:45–52.

42.

Raskin

, Matfin

, Schwartz

, Chaykin

, Chu

, Braceras

, Wynne

. Addition of biphasic insulin aspart 30 to optimized metformin and pioglitazone treatment of type 2 diabetes mellitus: The ACTION Study (Achieving Control Through Insulin plus Oral ageNts) Diabetes Obes Metab, 2009; 11:27–32.

43.

Raz

, Wilson

, Strojek

, Kowalska

, Bozikov

, Gitt

, Jermendy

, Campaigne

, Kerr

, Milicevic

, Jacober

. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: The HEART2D trial. Diabetes Care, 2009; 32:381–386.

44.

Riddle

, Pencek

, Charenkavanich

, Lutz

, Wilhelm

, Porter

. Randomized comparison of pramlintide or mealtime insulin added to basal insulin treatment for patients with type 2 diabetes. Diabetes Care, 2009; 32:1577–1582.

45.

Russell-Jones

, Vaag

, Schmitz

, Sethi

, Lalic

, Antic

, Zdravkovic

, Ravn

, Simo

. on behalf of the Liraglutide Effect and Action in Daibetes 5 (LEAD-5) met+SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): A randomised controlled trial. Diabetologia, 2009; 52:2046–2055.

46.

Kawamori

, Iwamoto

, Kadowaki

, Iwasaki

, Kim

, Woo

, Baik

S-H

, Yoon

K-H

. Effects of insulin glulisine as mono- or add-on therapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab, 2009; 11:900–909.

47.

Blicklé

, Hancu

, Piletic

, Profozic

, Shestakova

, Dain

, Jacqueminet

, Grimaldi

. Insulin glargine provides greater improvements in glycaemic control vs. intensifying lifestyle management for people with type 2 diabetes treated with OADs and 7–8% A1c levels. The TULIP study. Diabetes Obes Metab, 2009; 11:379–386.

48.

Buse

, Wolffenbuttel

, Herman

, Shemonsky

, Jiang

, Fahrbach

, Scism-Bacon

, Martin

. DURAbility of basal versus lispro mix 75/25 insulin efficacy (DURABLE) trial 24-week results: Safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes. Diabetes Care, 2009; 32:1007–1013.

49.

Blonde

, Merilainen

, Karwe

, Raskin

. TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: An assessment of two different fasting plasma glucose targets-the TITRATE study. Diabetes Obes Metab, 2009; 11:623–631.

50.

Raskin

, Gylvin

, Weng

, Chaykin

. Comparison of insulin detemir and insulin glargine using a basal-bolus regimen in a randomized, controlled clinical study in patients with type 2 diabetes. Diabetes Metab Res Rev, 2009; 25:542–548.

51.

Cucinotta

, Smirnova

, Christiansen

, Kanc

, le Devehat

, Wojciechowska

, Lopez de al Torre

, Liebl

. Three different premixed combinations of biphasic insulin aspart—comparison of the efficacy and safety in a randomized controlled clinical trial in subjects with type 2 diabetes. Diabetes Obes Metab, 2009; 11:700–708.

52.

Rosenstock

, Eliaschewitz

, Heilmann

, Muchmore

, Hayes

, Belin

. Comparison of prandial AIR inhaled insulin alone to intensified insulin glargine alone and to AIR insulin plus intensified insulin glargine in patients with type 2 diabetes previously treated with once-daily insulin glargine. Diabetes Technol Ther, 2009; 11,Suppl 2:S63–S73.

53.

Gross

, Nakano

, Colon-Vega

, Ortiz-Carasquillo

, Ferguson

, Althouse

, Tobian

, Berclaz

P-Y

, Milicevic

. Initiation of prandial insulin therapy with AIR inhaled insulin or insulin lispro in patients with type 2 diabetes: A randomized noninferiority trial. Diabetes Technol Ther, 2009; 11,Suppl 2:S27–S34.

54.

Oyer

, Shepherd

, Coulter

, Bhargava

, Brett

, Chu

, Trippe

. A1c control in a primary care setting: Self-titrating an insulin analog pre-mix (INITIATE plus trial) Am J Med, 2009; 122:1043–1049.

55.

Strojek

, Bebakar

, Khutsoane

, Pesic

, Smahelová

, Thomsen

, Kalra

. Once-daily initiation with biphasic insulin aspart 30 versus insulin glargine in patients with type 2 diabetes inadequately controlled with oral drugs: an open-label, multinational RCT. Curr Med Res Opin, 2009; 25:2887–2894.

56.

Fritsche

, Larbig

, Owens

, Häring

H-U

. on behalf of the GINGER study group. Comparison between a basal-bolus and a premixed insulin regimen in individuals with type 2 diabetes—Results of the GINGER study. Diabetes Obes Metab, 2010; 12:115–123.

57.

Fogelfeld

, Dharmalingam

, Robling

, Jones

, Swanson

, Jacober

. A Randomized, treat-to-target trial comparing insulin lispro protamine suspension and insulin detemir in insulin-naïve patients with type 2 diabetes. Diabetic Med, 2010; 27:181.

58.

Heise

, Mathieu

, Hey-Hadavi

, Strack

, Lawrence

. Glycemic control with preprandial versus basal insulin in patients with type 2 diabetes mellitus poorly controlled by oral antidiabetes agents. Diabetes Technol Ther, 2010; 12:135–141.

59.

Kalra

, Plata-Que

, Kumar

, Mumtaz

, Søndergaard

, Kozlovski

, Bebakar

WMW

. Initiation with once-daily BIAsp 30 results in superior outcome compared to insulin glargine in Asians with type 2 diabetes inadequately controlled by oral anti-diabetic drugs. Diab Res Clin Pract, 2010; 88:282–288.

60.

Swinnen

, Dain

, Aronson

, Davies

, Gerstein

, Pfeiffer

, Snoek

, DeVries

, Hoekstra

, Holleman

. A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs. Diabetes Care, 2010; 33:1176–1178.

61.

Diamant

, Van Gaal

, Stranks

, Northrup

, Cao

, Taylor

, Trautmann

. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): An open-label randomised trial. Lancet, 2010; 375:2234–2243.

62.

Strojek

, Shi

, Carey

, Jacober

. Addition of insulin lispro protamine suspension or insulin glargine to oral type 2 diabetes regimens: A randomized trial. Diabetes Obes Metab, 2010; 12:916–922.

63.

Rosenstock

, Lorber

, Gnudi

, Howard

, Bilheimer

, Chang

, Petrucci

, Boss

, Richardson

. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: A multicentre randomised trial. Lancet, 2010; 375:2244–2253

64.

Jain

, Mao

, Escalante-Pulido

, Vorokhobina

, Lopez

, Ilag

. Prandial-basal insulin regimens plus oral antihyperglycaemic agents to improve mealtime glycaemia: Initiate and progressively advance insulin therapy in type 2 diabetes. Diabetes Obes Metab, 2010; 12:967–975.

65.

Anderson JH

, Brunelle

, Keohane

, Koivisto

, Trautmann

, Vignati

, DiMarchi

. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Arch Intern Med, 1997; 157:1249–1255.

66.

Roach

, Yue

, Arora

. Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Humalog Mix25 Study Group. Diabetes Care, 1999; 22:1258–1261.

67.

Yki-Järvinen

, Dressler

, Ziemen

. HOE 901/300s Study Group Less nocturnal hypoglycemia better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care, 2000; 23:1130–1136.

68.

Rosenstock

, Schwartz

, Clark

Jr , Park

, Donley

, Edwards

. Basal Insulin Therapy in Type 2 Diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care, 2001; 24:631–636.

69.

Ross

, Zinman

, Campos

, Strack

. Canadian Lispro Study Group. A comparative study of insulin lispro and human regular insulin in patients with type 2 diabetes mellitus and secondary failure of oral hypoglycemic agents. Clin Invest Med, 2001; 24:292–98.

70.

Herz

, Sun

, Milicevic

, Erickson

, Fövènyi

, Grzywa

, Pelikanova

. Comparative efficacy of preprandial or postprandial humalog® Mix75/25 versus glyburide in patients 60 to 80 years of age with type 2 diabetes mellitus. Clin Ther, 2002; 24:73–86.

71.

Massi Benedetti

, Humburg

, Dressler

, Ziemen

. A one-years, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes. Horm Metab Res, 2003; 35:189–196.

72.

Fritsche

, Schweitzer

, Häring

. 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med, 2003; 138:952–959.

73.

Roach

, Arora

, Campaigne

, Mattoo

, Rangwala

. The India Mix25/Mix50 Study Group. Humalog Mix50TM before carbohydrate-rich meals in type 2 diabetes mellitus. Diabetes Obes Metab, 2003; 5:311–316.

74.

Tigoviste

, Strachinariu

, Farcasiu

, Milicevic

, Teodirescu

. Humalog Mix 25 in patients with type 2 diabetes which do not achieve acceptable glycemic control with oral agents: Results from a phase III, randomized, parallel study. Rom J Intern Med, 2003; 41:152–62.

75.

Christiansen

, Vaz

, Metelko

, Bogoev

, Dedov

. Twice daily biphasic insulin aspart improves postprandial glycaemic control more effectively than twice daily NPH insulin, with low risk of hypoglycaemia, in patients with type 2 diabetes. Diabetes Obes Metab, 2003; 5:446–454.

76.

Kilo

, Mezitisb

, Jainc

, Merseyd

, McGille

, Raskin

. Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin. J Diabetes Complications, 2003; 17:307–313.

77.

Forst

, Eriksson

, Strotmann

, Bai

, Brunelle

, Gulliya

, Gack

, Gudat

. Metabolic effects of mealtime insulin lispro in comparison to glibenclamide in early type 2 diabetes. Exp Clin Endocrinol Diabetes, 2003; 111:97–103.

78.

Schernthaner

, Kopp

H-P

, Ristic

, Muzyka

, Peter

, Mitteregger

. Metabolic control in patients with type 2 diabetes using humalog Mix50 injected three times daily: crossover comparison with human insulin 30/70. Horm Metab Res, 2004; 36:188–193.

79.

Niskanen

, Jensen

, Råstam

, Nygaard-Pedersen

, Erichsen

, Vora

. Randomized, multinational, open-label, 2-period,crossover comparison of biphasic insulin aspart 30 and biphasic insulin lispro 25 and pen devices in adult patients with type 2 diabetes mellitus. Clin Ther, 2004; 26:531–540.

80.

Boehm

, Vazb

, Brondstedb

, Home

. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur J Inter Med, 2004; 15:496–502.

81.

Bretzel

, Arnolds

, Medding

, Linn

. A direct efficacy and safety comparison of insulin aspart, uman soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes. Diabetes Care, 2004; 27:1023–1027.

82.

Rašlová

, Bogoev

, Raz

, Leth

, Gall

M-A

, Hancu

. Insulin detemir and insulin aspart: A promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract, 2004; 66:193–201.

83.

Abrahamian

, Ludvik

, Schernthaner

, Prager

, Zellenka

, Knudsen

, Wascher

. Improvement of glucose tolerance in type 2 diabetic patients: traditional vs modern insulin regimens (results from the Austrian Biaspart Study) Horm Metab Res, 2005; 37:684–689.

84.

Raz

, Stranks

, Filipczak

, Joshi

, Lertoft

, Rastam

, Chow

, Shaban

. Efficacy and safety of biphasic insulin aspart 30 combined with pioglitazone in type 2 diabetes poorly controlled on glibenclamide (glyburide) monotherapy or combination therapy: An 18-week, randomized, open-label study. Clin Ther, 2005; 27:1432–1443.

85.

Haak

, Tiengo

, Draeger

, Suntum

, Waldhausl

. Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab, 2005; 7:56–64.

86.

Eliaschewitz

, Calvo

, Valbuena

, Ruiz

, Aschner

, Villena

, Ramiriez

, Jimenez

. HOE 901/4013 LA Study Group. Therapy in type 2 diabetes: Insulin glargine vs. NPH insulin both in combination with glimepiride. Arch Med Res, 2006; 37:495–501.

87.

Philis-Tsimikas

, Charpentier

, Clauson

, Ravn

, Roberts

, Thorsteinsson

. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther, 2006; 28:1569–1581.

88.

Yki-Järvinen

, Kauppinen-Mäkelin

, Tiikkainen

, Vähätalo

, Virtamo

, Nikkilä

, Tulokas

, Hulme

, Hardy

, McNulty

. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetologia, 2006; 49:442–451.

89.

Ligthelm

, Mouritzen

, Lynggaard

, Landin-Olsson

, Fox

, le Devehat

, Romero

, Liebl

. Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus regimen with four daily injections. A randomised open-label parallel group four months comparison in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes, 2006; 114:511–519.

90.

Kvapil

, Swatko

, Hilberg

, Shestakova

. Biphasic insulin aspart 30 plus metformin: An effective combination in type 2 diabetes. Diabetes Obes Metab, 2006; 8:39–48.

91.

Yokoyama

, Tada

, Kamikawa

, Kanno

, Yokota

, Kuramitsu

. Effect of conversion from bedtime NPH insulin to morning insulin glargine in type 2 diabetic patients on basal-prandial insulin therapy. Diabetes Res Clin Pract, 2006; 73:35–40.

92.

Yki-Järvinen

, Juurinen

, Alvarsson

, Bystedt

, Caldwell

, Davies

, Lahdenpera

, Nijpels

, Vahatalo

. Initiate insulin by aggressive titration and education (INITIATE): a randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups. Diabetes Care, 2007; 30:1364–1369.

93.

Pan

, Sinnassamy

, Chung

, Kim

. LEAD Study Investigators Group. Insulin glargine versus NPH insulin therapy in Asian type 2 diabetes patients. Diabetes Res Clin Pract, 2007; 76:111–118.

94.

Bunck

, Diamant

, Cornér

, Eliasson

, Malloy

, Shaginian

, Deng

, Kendall

, Taskinen

M-R

, Smith

, Yki-Jarvinen

, Heine

. One-year treatment with exenatide improves β-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: A randomized, controlled trial. Diabetes Care, 2009; 32:762–768.

95.

Milicevic

, Hancu

, Car

, Ivanyi

, Schwarzenhofer

, Jermendy

. Effect of two starting insulin regimens in patients with type II diabetes not controlled on a combination of oral antihyperglycemic medications. Exp Clin Endocrinol Diabetes, 2009; 117:223–229.

96.

Lund

, Tarnow

, Frandsen

, Nielsen

, Hansen

, Pedersen

, Parving

H-H

, Vaag

. Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes: 12 month, randomised, double blind trial. BMJ, 2009; 339:b4324

97.

Hauber

, Gale

EAM

. The market in diabetes. Diabetologia, 2006; 49:247–252.

98.

McGauran

, Wieseler

, Kreis

, Schüler

, Kölsch

, Kaiser

. Reporting bias in medical research: A narrative review. Trials, 2010; 11:37.

99.

Nathan

, Buse

, Davidson

, Ferrannini

, Holman

, Sherwin

, Zinman

. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 2009; 32:193–203.

100.

Qaseem

, Vijan

, Snow

, Cross

, Weiss

, Owens

. for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Glycemic control and type 2 diabetes mellitus: the optimal hemoglobin A1c targets. A guidance statement from the American College of Physicians. Ann Intern Med, 2007; 147:417–422.

101.

Pogach

, Engelgau

, Aron

. Measuring progress toward achieving hemoglobin A1c goals in diabetes care: Pass/fail or partial credit. JAMA, 2007; 297:520–523.