Once Daily Lancet v371 n9618

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Once-daily basal insulin glargine versus thrice-daily prandial

insulin lispro in people with type 2 diabetes on oralhypoglycaemic agents APOLLO: an open randomisedcontrolled trialReinhard G Bretzel*, Ulrike Nuber, Wolfgang Landgraf, David R Owens, Clare Bradley, Thomas Linn*

SummaryBackgroundAs type 2 diabetes mellitus progresses, oral hypoglycaemic agents often fail to maintain blood glucosecontrol and insulin is needed. We investigated whether the addition of once-daily insulin glargine is non-inferior tothree-times daily prandial insulin lispro in overall glycaemic control in adults with inadequately controlled type 2diabetes mellitus taking oral hypoglycaemic agents.

Methods In the 44-week, parallel, open study that was undertaken in 69 study sites across Europe and Australia,418 patients with type 2 diabetes mellitus that was inadequately controlled by oral hypoglycaemic agents wererandomly assigned to either insulin glargine taken once daily at the same time every day or to insulin lisproadministered three times per day. The primary objective was to compare the change in haemoglobin A1cfrom baselineto endpoint (week 44) between the two regimens. Randomisation was done with a central randomisation service.Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00311818.

Findings205 patients were randomly assigned to insulin glargine and 210 to insulin lispro. Mean haemoglobin A 1cdecrease in the insulin glargine group was 17% (from 87% [SD 10] to 70% [07]) and 19% in the insulin lisprogroup (from 87% [10] to 68% [09]), which was within the predefined limit of 04% for non-inferiority(difference=0157; 95% Cl 0008 to 0322). 106 (57%) patients reached haemoglobin A1cof 7% or less in the glarginegroup and 131 (69%) in the lispro group. In the glargine group, the fall in mean fasting blood glucose (43 [SD 23]

mmol/Lvs

18 [23] mmol/L; p


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The basal insulin analogue glargine has a long duration

of action (about 24 h), with little or no discernible peak ininsulin concentration in the blood and a lower variabilitybetween patients than there is with neutral protamineHagedorn (NPH) insulin or ultralente insulin.1417Furthermore, an injection of insulin glargine once a daycan confer glycaemic control equivalent to NPH insulinin patients with type 2 diabetes mellitus,18,19 but with alower rate of hypoglycaemia.1822The short-acting insulinanalogue lispro, which is given three times a day atmealtimes, also compares favourably with NPH insulinin terms of improvements in haemoglobin A1c, and hassimilar rates of hypoglycaemia.23Until recently, opinionon how or when to start insulin treatment in type 2diabetes mellitus was divided.6 However, combination

therapy of oral hypoglycaemic agents with a basal insulinanalogue like insulin glargine can be regarded as aneffective first choice for introducing insulin as part of astepwise approach, adapting to the progressive -cellfailure. The introduction of insulin glargine once a day(at bedtime or before breakfast) has several advantages,including a substantial improvement in glycaemiccontrol, fewer episodes of hypoglycaemia than withconventional NPH insulin, a reduction of daily insulinrequirements when combined with oral hypoglycaemicagents,1822 and less weight gain.24The United KingdomInsulin Initiation Study (UKIIS) group25 and theInternational Diabetes Federation (IDF)5concur with thisregimen, which is well accepted in clinical practice.

However, there is ongoing debate as to whether andwhen it is most beneficial to treat patients: to targetpostprandial blood glucose concentrations withmeal-related insulin, or continue to target fasting bloodglucose concentrations with basal insulin that is restrictedonly by hypoglycaemia. Several studies have shown thatfasting blood glucose concentrations correlateequivalently or better with overall glycaemic control onthe basis of haemoglobin A1cconcentrations,

2629whereasothers have shown that postprandial blood glucoseconcentrations are a better predictor of haemoglobin A 1cvalues and glycaemic control.23,30Monnier and colleagues31provided an explanation for such opposing views by

showing that postprandial blood glucose contributesmore to glycaemic control in patients with mild ormoderate hyperglycaemia than in those with poorlycontrolled diabetes mellitus, in whom fastinghyperglycaemia is the main contributor to overallhyperglycaemia.

The APOLLO study (A Parallel design comparing anOral antidiabetic drug combination therapy with eitherLantus once daily or Lispro at mealtime in type 2 diabetespatients failing Oral treatment) aimed to establishwhether the addition of once-daily insulin glarginetargeting fasting blood glucose is non-inferior tothree-times daily prandial insulin lispro targetingpostprandial blood glucose in overall glycaemic controlin adults with inadequately controlled type 2 diabetes

mellitus taking oral hypoglycaemic agents. In addition to

glycaemic control, patient satisfaction with treatment isan important consideration in deciding between availabletreatments for this disease. Therefore we investigatedwhether people given insulin glargine plus oralhypoglycaemic agents were more satisfied with theirtreatment regimen than were those given insulin lisproplus oral hypoglycaemic agents.

MethodsPatientsThe study was undertaken at 69 study sites across Europeand Australia between June 25, 2003, and May 31, 2005.Male and female patients were eligible for enrolment ifthey were aged between 18 and 75 years, had type 2

diabetes mellitus for 1 year or more with haemoglobin A1cconcentrations between 75% and 105%, were on oralhypoglycaemic agents (excluding alpha-glucosidaseinhibitors) for at least 6 months with stable doses for3 months or more before study entry, had fasting bloodglucose concentrations of 67 mmol/L or more, and hadbody-mass index of 35 kg/m2 or less. All participantswere willing to monitor blood glucose themselves.

Patients meeting any of the following criteria were notincluded in the study: treatment with any insulin in thepast 4 weeks before study entry; positive for glutamic-acid-decarboxylase (GAD) antibodies; diabetic retinopathywith surgical treatment in the 3 months before studyentry; clinically relevant cardiovascular, gastrointestinal,hepatic, neurological, endocrine, or haematologicaldisease; history of drug or alcohol misuse; impairedhepatic function, as shown by alanine aminotransferaseor aspartate aminotransferase greater than three timesthe upper limit of normal; or impaired renal function, asshown by serum creatinine greater than 177 mol/L.Patients who were pregnant were also excluded from thestudy.

The study was approved by ethics committees of theparticipating centres and was undertaken in accordancewith the Declaration of Helsinki. All patients providedwritten informed consent for their participation beforestudy entry.

ProceduresIn this open-label study, randomisation to the twotreatment groups was done with a central randomisationservice that was generated by the eCRF programme(InForm). The randomisation schedule was stratified bycentre and co-treatment with metformin on a 1:1 basis.

At the baseline visit, patients were randomly assignedto either insulin glargine (Sanofi-Aventis DeutschlandGmbH, Frankfurt, Germany) taken once daily at thesame time every day or to insulin lispro (Lilly DeutschlandGmbH, Bad Homburg, Germany) given three times perday immediately before breakfast, lunch, and dinner(preferably at 06000900 h, 12001400 h, and 18002100 h).Insulin glargine was given with the OptiSet injection


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(Sanofi-Aventis) device and insulin lispro with theHumalog Pen (Lilly Deutschland GmbH). The startingdose for insulin glargine was 10 U and for insulin lisprothe dose was 4 U before every meal. In both groups, thedose of oral hypoglycaemic agents was kept stable duringthe 4-week screening period and the 44-week treatmentphase. During the screening period, patients who werepretreated with sulphonylurea hypoglycaemia agentseither changed to the equivalent dose of glimepiride (2, 3,or 4 mg, decided by the investigator) or remained on their

present glimepiride dose. Glimepiride was given in themorning, before breakfast (preferably 06000900 h).Thereafter, the dose of glimepiride or other oralhypoglycaemic agents remained unchanged throughoutthe study.

Participants were trained to self-monitor their bloodglucose with the same type of blood-glucose meter (AccuCheck, Roche Diagnostics, Mannheim, Germany)provided by the sponsor, and to self-inject insulin withthe OptiSet pen (glargine) or the Humalog Pen (lispro).At start of screening, at week 20, and at week 44 (studyendpoint), a previously validated diabetes treatmentsatisfaction questionnaire (DTSQ) was given to thepatients.32,33The questionnaire was linguistically validatedin eight languages that were appropriate for the

participating centres. It consisted of eight items which

were all measured by a 7-point numeric rating scalefrom 0 to 6. The treatment satisfaction score wascalculated as the sum of six items (items one andfoureight) with higher scores on the 036 scaleindicating greater patient satisfaction with theirtreatment. By contrast, for items two (perceived frequencyof hyperglycaemia: How often have you felt that yourblood sugars have been unacceptably high recently?)and three (perceived frequency of hypoglycaemia: Howoften have you felt that your blood sugars have beenunacceptably low recently?), higher scores on the06 scale indicate perception of more frequenthyperglycaemia or hypoglycaemia.33

During the treatment phase, insulin doses were

adjusted by a forced titration regimen (panel) to a targetfasting blood glucose less than 55 mmol/L in the insulinglargine group, and a preprandial blood glucose of lessthan 55 mmol/L and a postprandial blood glucose ofless than 75 mmol/L in the insulin lispro group, inaccordance with the insulin titration algorithms proposedby the European Diabetes Policy Group.34Insulin doseswere titrated every week according to self-monitoredcapillary blood glucose measurements. The insulin doseand injection time was recorded in each patients diary.Fasting, preprandial, and postprandial blood glucoseconcentrations, as well as hypoglycaemic episodes, werealso recorded.

Participants visited the research site at baseline andwere contacted by telephone at week 3, 5, 7, and 10 todiscuss dose changes. Patients were to test glucosewhenever they had symptoms that might be related tohypoglycaemia and to record the results. Additionally,participants tested their blood glucose at eight pointsthroughout the day (before and 2 h after breakfast, lunch,and dinner; at bedtime; and at 0300 h) starting 2 daysbefore visits at week 2, 8, 20, 28, 36, and 44. When glucoseconcentrations in the target range were obtained,investigators were allowed to stop titration or temporarilyreduce the dose when they believed further titrationwould be hazardous. After the forced titration phase,diary checks were part of the subsequent study visits at

the research site (at week 12, 16, 20, 24, 28, 32, 36, 40,and 44).

We recorded haemoglobin A1c, fasting plasma glucose,GAD antibodies, clinical chemistry variables (creatinine,aspartate aminotransferase, alanine aminotransferase,sodium, and potassium), and lipid profile (totalcholesterol, HDL cholesterol, LDL cholesterol,triglycerides, and non-esterified fatty acid) with standardmethods at the central laboratory (INTERLAB, Munich,Germany). We did a routine physical examination at thebaseline and end visit. Asssessment of vital signs wasdone at every visit at the site.

The primary objective was to compare the change inhaemoglobin A

1c

from baseline to endpoint (week 44)between the oral hypoglycaemic agent combination

Panel:Dose titration algorithm and monitoring

Insulin glargine

Titration monitoring

Starting dose: 10 U per day. Direct investigator contact.

Additional calls to adjust insulin

Insulin dose titration algorithm

Starting dose: 10 U per day. If self-monitored fasting blood

glucose for 2 consecutive days with no severe hypoglycaemia

is:

>89 mmol/L: add 8 U per day




55 mmol/L: no further titration

Insulin lispro

Titration monitoring

Starting dose: 4 U per day. Direct investigator contact.

Additional calls to adjust insulin dose if haemoglobin A1c>7%

Insulin dose titration algorithm

Preprandial blood glucose:

>111 mmol/L: add 3 U before main meal



103 mmol/L: add 2 U before main meal

>75103 mmol/L: add 1 U before main meal 75 mmol/L: no further titration


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611 patients prescreened

477 patients screened

436 continuation of previous OHA treatment with change from from sulphonylurea to glimepiride

418 patients randomised

205 received insulin glargine once daily plus continuation of

previous OHA

210 received insulin lispro three -times daily plus continuation

of previous OHA

204 in intention-to-treat population 208 in intention-to-treat population

12 discontinued 1 new or worsening of adverse event 1 poor treatment compliance 4 patients wish not to continue in the study 2 lost to follow-up 4 other reasons

16 discontinued 2 new or worsening of adverse event 1 little efficacy 1 poor treatment compliance 4 patients wish not to continue in the study 3 lost to follow-up 2 protocol violation 2 hypoglycaemia

1 other reason

186 in per-protocol population 191 in per-protocol population

174 completed 175 completed

3 never received any study drug

18 failed change to glimepiride

134 non-eligible HbA1c

concentrations

41 screening failures

415 in safety analysis population

2 no follow-up of HbA1c

17 withdrawn because of major protocol violations27 events in total 9 incorrect sample date of HbA

1cvalue

9 insufficient duration of insulin treatment 5 metformin treatment not in accordance with stratification

3 corticosteroid use >7 days 1 study drug other than randomised

1 no follow-up of HbA1c

18 withdrawn because of major protocol violations28 events in total 6 incorrect sample date of HbA

1cvalue

6 insufficient duration of insulin treatment 7 metformin treatment not in accordance with stratification

4 corticosteroid use >7 days 2 interruption of study drug >7 days 2 study drug other than randomised 1 newly added metformin between visit 1 and randomisation

Figure :Trial profileHbA1c=haemoglobin A1c. OHA=oral hypoglycaemic agents.


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therapy with either insulin glargine once daily or insulin

lispro at mealtimes. The secondary objectives includedthe proportion of participants achieving a haemo-globin A1cof 65% or less or 70% or less, the change infasting blood glucose during the treatment period, andproportion reaching a fasting blood glucose of55 mmol/L or less. We also compared baseline toendpoint changes in nocturnal blood glucose andblood-glucose profiles at eight points throughout the day(including mean daytime and mean daily blood glucoseconcentration), and the percentage of patients withnocturnal, severe, and symptomatic hypoglycaemia.Hypoglycaemia was defined as an event with or withoutsymptoms consistent with hypoglycaemia, not needingthe assistance of another person, and associated with

blood glucose concentrations less than 33 mmol/L.Severe hypoglycaemia was defined as an event withsymptoms consistent with hypoglycaemia, requiring theassistance of another person, associated with a bloodglucose concentration less than 20 mmol/L, or recoveryafter oral carbohydrate, intravenous glucose, or glucagonadministration. Nocturnal hypoglycaemia was defined ashypoglycaemia, occurring while the individual was asleepand before getting up in the morning. Wheneverparticipants awoke during the night and had symptomsof hypoglycaemia, self-monitoring blood glucose wasdone and documented in the patients diary.

An investigator examined patients and recordedadverse events at every visit or during telephone contact,instructing patients to report any events occurringduring the study period. For the purposes of the study,the period of observation for each individual extendedfrom the time that the patient gave informed consentuntil 7 days after the last dose of study drug. The termadverse event referred to any unfavourable andunintended sign, symptom, syndrome, or illness thatdeveloped or worsened during the study. A seriousadverse event was defined as one that at any dose(including overdose) resulted in death, was lifethreatening, required inpatient admission to hospital orextension of existing admission, resulted in persistentor substantial disability or incapacity, was a congenital

anomaly or birth defect, or was an important medicalevent.

Statistical analysisThe primary analysis was per protocol, and included allpatients without any major protocol violations. Figure 1shows the criteria for inclusion in the per-protocolpopulation. With the assumption of an equivalenceregion of 04% and standard deviation of 13% for thedifferences of haemoglobin A1c reduction between thetwo groups, one-sided therapeutic non-inferiority can beshown with an error of =0025 (one-sided) and =02with 167 participants per group (total of 334 participants).With an expected non-evaluable rate of 20% (ie, notsuitable for per-protocol analysis), a total of 420 individuals

(210 in each treatment group) were randomly assigned.We planned to recruit this sample in roughly 70 centres.The recommended minimum number of individuals percentre was four, with a maximum of 20.

The intention-to-treat population was defined aspatients who, after randomisation, had received at leastone dose of insulin study drug and had both baselinehaemoglobin A1cand at least one haemoglobin A1cvalueduring the treatment period. Statistical testing was done

at a significance level of =005. The primary effi cacyanalysis was done as a two-step procedure. The firsthypothesis tested was the non-inferiority of insulinglargine versus insulin lispro. The subsequent superioritytesting of the difference in haemoglobin A1cwas done forthe intention-to-treat population.

We tested the hypotheses with analyses of covariance(ANCOVA) with treatment group, country, and intake ofmetformin at baseline as fixed variables, and baselinehaemoglobin A1c as a covariate to compare changes inhaemoglobin A1c. We calculated adjusted mean changesin haemoglobin A1c and corresponding two-sided95% CIs. For secondary effi cacy variables, ANCOVAanalyses were done. We compared categorical variablesbetween treatment groups by Cochran-Mantel-Haenszel

Insulin glargine plus OHAs Insulin lispro plus OHAs

Intention-to-treatpopulation(n=204)

Per-protocolpopulation(n=186)

Intention-to-treatpopulation(n=208)

Per-protocolpopulation(n=191)

Men 107 (52%) 102 (55%) 122 (59%) 113 (59%)

Women 97 (48%) 84 (45%) 86 (41%) 78 (41%)

Age (years) 600 (90) 597 (90) 597 (90) 597 (90)

Weight (kg) 839 (149) 841 (150) 844 (149) 842 (149)

BMI (kg/m) 292 (37) 292 (36) 294 (35) 293 (35)

Duration of diabetes (years) 90 (68) 91 (68) 85 (61) 86 (63)

Duration of OHA treatment(years)

70 (58) 72 (59) 70 (55) 71 (56)

Metformin treatment 155 (76%) 141 (76%) 153 (74%) 143 (75%)

HbA1c(%) 870 (096) 873 (097) 867 (097) 867 (097)

FBG (mmol/L) 103 (20) 104 (20) 99 (23) 98 (22)

C-Peptide (mmol/L) 356 (22) 352 (20) 360 (21) 358 (22)

Previous treatment with

Sulfonylureas 186 (91%) 172 (92%) 189 (91%) 174 (91%)

Metformin 159 (78%) 145 (78%) 157 (76%) 147 (77%)

Alpha glucosidase inhibitors 4 (2%) 3 (2%) 6 (3%) 5 (3%)

Thiazolidinediones 4 (2%) 4 (2%) 5 (2%) 5 (3%)

Coexisting disorders related to diabetes*

Retinopathy 21 (10%) 21 (11%) 21 (10%) 20 (11%)

Neuropathy 45 (22%) 40 (22%) 58 (28%) 53 (28%)

Nephropathy 13 (6%) 12 (7%) 16 (8%) 15 (8%)

Macroangiopathy 25 (12%) 25 (13%) 23 (11%) 23 (12%)

Data are median (IQR), mean (SD), or number (%).OHAs=oral hypoglycaemic agents. BMI=body-mass index.

FBG=fasting blood glucose. HbA1c

=haemoglobin A1c

. *The presence of retinopathy, neuropathy, macroangiopathy, or

nephropathy was determined by the investigator.

Table :Demographics and baseline characteristics of the study population


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tests, controlling for country and intake of metformin atbaseline. We analysed time-dependent variables with theKaplan-Meier method. Statistical testing was done bylogrank test.

The rate of patients with hypoglycemic episodes andnumber of episodes were analysed with a Cochran-Mantel-Haenszel test on the basis of the insulin safety population(figure 1). The number of hypoglycaemic events per patientand per patient year was summarised as a quantitativevariable. Comparisons between treatment groups were

done by an analysis of variance (ANOVA) model. Analyses

were also undertaken for the following subtypes ofhypoglycaemic events: nocturnal, severe, symptomatic,and asymptomatic. Additionally, hypoglycaemic events(overall, nocturnal, and symptomatic) that were confirmedby blood glucose concentration of 33 mmol/L or less wereanalysed by patient and event.

We used ANCOVA to compare changes in every itemof the DTSQ and the treatment satisfaction compositescore that was made up of six items. We entered treatmentgroup, language, and present intake of oral hypoglycaemicagents as fixed factors; corresponding scores at screeningwere entered as covariates.

This study is registered with ClinicalTrials.gov, numberNCT00311818.

Role of the funding sourceThe sponsor coordinated the study, monitoredinvestigator sites, collected and managed the data, andundertook the statistical analyses. UN wrote the studyprotocol. The corresponding author had full access to allthe data in the study and had the final responsibility forthe decision to submit for publication.

ResultsFigure 1 shows the trial profile. 412 patients were in theintention-to-treat population (204 in insulin glarginegroup and 208 in insulin lispro group). A total of35 patients were excluded owing to major protocoldeviations during the study (figure 1); thus theper-protocol population consisted of 377 patients (186 ininsulin glargine group and 191 in insulin lispro group),who were included in our analyses.

Table 1 shows the demographics and baselinecharacteristics of the per-protocol and intention-to-treatpopulations. After randomisation, most patients receivedmetformin therapy throughout the study (156 [76%] and153 [74%] in the insulin glargine and insulin lispro treatment groups, respectively). Most patients in bothtreatment groups were given glimepiride, with only 11(6%) patients assigned to insulin glargine and 14 (7%) toinsulin lispro not receiving glimepiride. Patient

demographics and glycaemic control (haemoglobin A1cand fasting blood glucose) were much the same betweenthe two groups at baseline (table 1).

The mean decreases in haemoglobin A1cwere similarbetween the insulin glargine and the insulin lisprogroups (172%, from 87% [SD 10] to 70% [07];p


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significantly different, showing non-inferiority (=0137%

[95% CI 0022 to 0297]; p=00908).Compared with baseline, 106 (57%) patients in theinsulin glargine group reached haemoglobin A1cconcentration of 7% or less and 131 (69%) in the lisprogroup of the per-protocol population (116 [58%] vs138 [68%] in the intention-to-treat population). Ahaemoglobin A1c concentration between 65% and 7%was achieved by 51 (27%) in the glargine group and58 (30%) in the lispro group of those treated per protocol(54 [27%] vs61 [30%] in the intention-to-treat population).Optimum haemoglobin A1cconcentrations less than 65%were reached by 55 (30%) in the glargine group and73 (38%) in the lispro group in the per-protocol population(62 [31%] vs77 [38%] in the intention-to-treat population).

At baseline, no patient had a fasting blood glucoseconcentration of 55 mmol/L or less, but more patientsreached this target with insulin glargine than with insulinlispro at study endpoint (71 [38%] vs 11 [6%] in theper-protocol population). The intention-to-treat analysisconfirmed the significance of the result (72 [35%] vs11 [5%]; p


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lispro (all p


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glargine group vs28 [12%] with insulin lispro). Only one

event of hypoglycaemia in the insulin lispro group wasconsidered related to the study drug.

DiscussionOur results suggest that treatment with once-daily insulinglargine is non-inferior to three-times daily insulin lisproin achieving overall glycaemic control as represented byhaemoglobin A1cin patients with type 2 diabetes mellitusthat is poorly controlled by oral hypoglycaemic agents.We noted similar significant reductions in haemoglobin A1cover the 44-week treatment period in both groups.

In practice, monotherapy fails to achieve or maintainthe glycaemic target of haemoglobin A1cof 7% or less inmost patients with type 2 diabetes mellitus, emphasising

the need to introduce additional therapeutic optionswithout undue delay.8,35,36Our findings show that patientswere able to reach this target with the addition of insulinto existing treatment with oral hypoglycaemic agents.When target haemoglobin A1ccould not be obtained withinsulins glargine or lispro, addition of the other insulincould be helpful in reaching the target.

However, the treatment regimens showed differenteffects on circadian regulation of blood glucose. Decreasesin fasting and nocturnal blood glucose were significantlygreater with insulin glargine than with the insulin lisproregimen. A much greater proportion of patients achieveda fasting blood glucose concentration of 55 mmol/L orless with insulin glargine than with insulin lispro.Conversely, insulin lispro was associated with lowerpostprandial concentrations, especially after lunch anddinner. These findings are consistent with those recordedin a previous study of people with type 2 diabetes mellituswhich is inadequately controlled by treatment with oralhypoglycaemic agents. Insulin lispro substantiallyreduced postprandial blood glucose, whereas NPHinsulin reduced fasting blood glucose with a greaterreduction of haemoglobin A1cin the lispro group.

23In thatstudy, the fasting blood glucose at the end of treatmentwas 85 (SD 24) mmol/L in patients given NPH insulincompared with 61 (14) mmol/L in those given glarginein our study. In view of the discussion about whether

fasting or postprandial blood glucose concentrations havea greater effect on haemoglobin A1cin patients with poorcontrol, we would expect that one therapeutic regimenwould be better than the other. However, targeting fastingblood glucose or postprandial blood glucose were bothequally effective in improving haemoglobin A1c. Moreover,we recorded no differences in the adherence to titrationtargets when we compared maximum (baseline) orminimum (endpoint) haemoglobin A1cconcentrations forinsulin glargine and insulin lispro treatment. Thus, ourdata suggest that the reduction of haemoglobin A1c ismore dependent on targeted insulin therapy per se ratherthan on a specific glucose profile.

Tight glycaemic control is known to increase the risk ofhypoglycaemia, representing a major barrier to sustained

good glycaemic control with insulin therapy.9,12Therefore,

an insulin regimen that is associated with a reduced riskof hypoglycaemia can ease the introduction and titrationof insulin therapy. Our results show that, despite similarimprovements in glycaemic control between the twoinsulin regimens, the addition of insulin glargine toexisting treatment with oral hypoglycaemic agents wasassociated with a much lower incidence of overallhypoglycaemia than was noted when insulin lispro wasadded. Although it could be suggested that asymptomatichypoglycaemia might have been detected more often inthe lispro group than in the glargine group simplybecause they were monitoring their blood glucoseconcentrations more often preprandially, symptomatichypoglycaemia was also significantly less with insulin

glargine than with insulin lispro. The incidence waslower for all categories of hypoglycaemia in the insulinglargine than in the lispro group, apart from nocturnalhypoglycaemia which did not differ significantly betweengroups, showing the low overall incidence ofhypoglycaemia in the night compared with daytime.

The low rate of hypoglycaemia with the basal insulinregimen that we recorded supports the feasibility ofcontinued titration to achieve target glycaemicconcentrations in even more patients than we noted inour study. Improvement in glycaemic control and lowincidence of hypoglycaemia were obtained with similarinsulin doses in both treatment regimens. In the groupgiven basal insulin, doses at the end of the study weresimilar to those obtained from previous insulin glarginestudies.1822

Other barriers to achieving recommended targets forglycaemic control include the diffi culty of managingseveral injections and the associated requirement forself-monitoring blood glucose many times throughoutthe day.10,11,37Therefore, simple but effective regimens areespecially important when starting insulin therapy inpatients with type 2 diabetes mellitus. The regimen ofinsulin glargine plus oral hypoglycaemic agents in thisstudy needed only one daily injection and a singleblood-glucose test before breakfast to guide therapycompared with the three injections required with insulin

lispro administration, necessitating several tests forblood glucose throughout the day. Study participantstaking insulin glargine reported greater overall treatmentsatisfaction, with specific improvements in convenienceof treatment, than did those taking insulin lispro. Patientstaking insulin glargine also reported a greater reductionin perceived frequency of hyperglycaemia and a smallerincrease in perceived frequency of hypoglycaemia thandid those taking insulin lispro. These ratings togetherwith a lower prevalence of hypoglycaemia with insulinglargine than with insulin lispro despite similarreductions in HbA1c show that the glargine regimen ismore acceptable to patients than is the lispro regimen.

The APOLLO study represents a long-term, directcomparison between two different insulin analogue


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treatment strategies. Previous studies have compared

insulin glargine and NPH insulin for safety withintreatment strategies involving basal insulin.1822,3841Holman and colleagues42 recently published 1-yearinterim data from their 4-T study comparing the additionof biphasic, prandial, and basal insulin to oral therapywhen glycaemic control was less than optimum. Thestudy design and overall baseline characteristics of thepatients were similar to those in the APOLLO study. Bothstudies noted a lower risk of hypoglycaemia with basalthan with prandial-insulin supplementation. Thereduction of haemoglobin A1c in both these treatmentgroups was less in the 4-T study than in the APOLLOstudy. Furthermore, twice as many patients in thebasal insulin cohort reached haemoglobin A1cof less than

7% in this study compared with the 4-T study despiteapparently equivalent insulin doses between the twostudies and despite insulin detemir needing to be giventwice daily in a third of patients in the 4-T study.Compliance with the structured titration algorithm usein our study in combination with only once daily insulinglargine partly accounts for the difference in glycaemicoutcome.

The use of the incretin mimetic exenatide is one of theemerging therapies for patients with type 2 diabetes whohave poor glycaemic control despite taking oralhypoglycaemic agents. Exenatide is injected once or twiceper day, lowers blood glucose concentration by mobilisinginsulin from the pancreas during meals, and has theadvantage compared with insulin therapy that it isassociated with a decrease of bodyweight. In a trialdirectly comparing insulin glargine and exenatide,43 theeffect of lowering blood glucose in both treatment groupswas identical, but was less than was recorded in theAPOLLO study. Patients receiving exenatide had a higherincidence of gastrointestinal symptoms than did thosereceiving glargine, and 95% of the exenatide group werereported to have withdrawn from the study because ofadverse events compared with 07% of those receivinginsulin glargine. Treatment satisfaction in patientsremaining in the exenatide group for at least 12 weekswas reported to be comparable with that of the glargine

group.44These findings accord with the consideration ofexenatide as an alternative treatment to the addition ofinsulin. However, more studies will be needed to establishthe effect of adverse events and to identify patients whoare most likely to benefit from exenatide or insulin.

Whether patients with type 2 diabetes and cardiovasculardisease benefit from a strategy of intensive glycaemiccontrol including insulin administration continues to bedebated. The blood glucose lowering part of the ACCORDtrial was stopped prematurely because of a 20% increasedrate of mortality in the intensive group, targeting ahaemoglobin A1cconcentration of less than 6%, comparedwith the standard group with a target of 7079%. 45In theAPOLLO trial, about a third of the participants reachedhaemoglobin A1c concentrations in the range of the

intensively-treated group. We noted that the rate of acute

cardiovascular events was 113 per 1000 patient years andno deaths occurred; overall 350 patient years were assessed.The protocols of both trials differ substantially from eachother in terms of the design and implementation of thestudyeg, the inclusion criteria, variety of study drug, thenumber of visits during the titration phase, and time ofobservation period per patient, all of which potentiallyexplain the different outcome of mortality.46More studieswill be needed to address the open issue of an optimumbalance between risks and benefits of intensive glycaemiccontrol in patients with diabetes who are at high risk forcardiovascular disease. It might be particularly importantto control potassium concentrations and autonomiccardiac activity when haemoglobin A1c is aggressively

lowered.The addition of insulin glargine to oral hypoglycaemic

agents is a simple and well-tolerated intervention that canbe helpful in overcoming major barriers to timely insulininitiation in settings of primary and secondary care.47Theuse of a simple self-administered titration algorithm isequally as effective at improving glycaemic control as istitration managed by the physician.48 Evidence from theAPOLLO study suggests that the addition of insulinglargine to therapies with oral hypoglycaemic agents canbe regarded as a first-line insulin initiation approach intype 2 diabetes mellitus, as has been recommended in ajoint consensus guideline by the American DiabetesAssociation and European Association for the Study ofDiabetes.6

ContributorsAll authors participated in various aspects of the study analysis andinterpretation of the data, and to the development of the report. Thefinal version was seen and approved by all authors. RGB was principalinvestigator and chairman of the steering committee and togetherwith UN contributed to the study concept and interpretation of thedata. WL was involved in the drafting and development of the report.DRO contributed to both the development of the report and thecritical discussion of the concept of analyses. CB advised on the useand interpretation of the diabetes treatment satisfactionquestionnaire and the discussion. TL contributed to data collection,development of the report, and was the leading author during thereviewing process.

Investigators of the APOLLO study

AustraliaJ Karrasch (Peninsula Clinical Research Centre, Kippa Ring),D Darnell (Central Coast Endocrinology, Gosford), D Roberts (LoganHospital, Department of Medicine, Meadowbrook).AustriaP Bratusch-Marrain (Krankenhaus Horn, Horn), T Egger(Donaufeldspital/SMZ Ost, Wien), H Kiss (Krankenhaus Oberwart,Oberwart), R Prager (Krankenhaus der Stadt Wien Lainz, Wien),G Roeggla (Krankenhaus Neunkirchen, Medizinische Abteilung,Neunkirchen), G Schernthaner (Medical Practice, Wien), J Thomas(Krankenhaus der Barmherzigen Schwestern, Wien), T Wascher(Universitatsklinik Graz, Graz).DenmarkN Holmegaard (Medicinsk afdeling, Thisted Sygehus Nord,Thisted), K Koelendorf (Medicinsk Afdeling, Roskilde Amtssygehus IKoge, Koge), S Madsbad (Klinik for endokrinologi, H:S Hvidovre,Hvidovre), N Moeller (Medicinsk afdeling M, Arhus Kommunehospital,Arhus), I Ramsgaard Hansen (Medicinsk Afdeling, Sygehus Fyn Nyborg,Nyborg), B Thorsteinsson (Medicinsk afdeling F, Hillerod).GermanyH Alawi (Medical Practice, Saarlouis), H Anderten (Medical

Practice, Hildesheim), K Busch (Medical Practice, Dortmund), E-M Fach(Medical Practice, Rosenheim), E Haak (Diabetes Zentrum


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Mergentheim, Bad Mergentheim), J Habbig (Medical Practice, Koln),A Hamann (Innere Medizin I Medizinische Klinik

Universitaetsklinikum Heidelberg, Heidelberg), T Hampel (MedicalPractice, Schwedt), S Jung (Diabeteszentrum, Simmern), V Jung(Medical Practice, Waldkraiburg), P Kann (Philipps-UniversitaetMarburg, Marburg), M Kiper (Medical Practice, Berlin), C Klein(Medical Practice, Kunzing), D Klein (Medical Practice, Koln), V Koch(Medical Practice, Wetter-Wengern), K Langer (Klinikum DarmstadtDiabetologie, Darmstadt), T Linn (Medizinische Klinik und PoliklinikIII Universitaet Giessen, Giessen), E Lohr (Medical Practice, Essen),C Marck (Medical Practice, Pohlheim), H-J Marks (Medical Practice,Siegen), S Maxeiner (Medical Practice, Bad Kreuznach), B Maykemper(Medical Practice, Lollar), K Milek (Asklepiosklinik Hohenmoelsen,Hohenmolsen), F Odemar (Klinikum Bernburg, Bernburg), B Paschen(Medical Practice, Hamburg), A Segner (Medical Practice,St.Ingbert-Oberwuerzbach), I Strotmann (Institut fuer klinischeForschung und Entwicklung, Rotenburg/Fulda), M Stuendel (MedicalPractice, Berlin), S Vidal (Diabetes Zentrum Mergentheim,Bad Mergentheim), U Wendisch (Medical Practice, Hamburg),

V Wenzl-Bauer (Medical Practice, Rehlingen).ItalyG Bolli (DIMISEM, Universita, Perugia), S Del Prato (Universitadi Pisa, Medicina Interna e Scienze Endocrine e Metaboliche, Pisa),A Galluzzo (Clinica Medica, Cattedra di Endocrinologia, Palermo),S Gambardella (Cattedra Malattie del Ricambio, Complesso IntegratoColumbus, Roma), G Pagano (Ospedale Molinette, Medicina Interna,Torino), C Rotella (Div Un. Endocrinologia e Malattie Metaboliche,Firenze), D Fedele (Ospedale Geriatrico, Padova), A Pontiroli (ClinicaMedica, Ospedale S Paolo, Milano).NetherlandsP Biemond (Ziekenhuis Franciscus, Interne geneeskunde,Roosendaal), T Cleophas (Albert Schweitzer Ziekenhuis, LocatieSliedrecht, Interne geneeskunde, Sliedrecht), J van Hoogenhuijze(Medisch Centrum Haaglanden, Locatie Antoniushove, Internegeneeskunde, Leidschendam), R van Leendert (Albert SchweitzerZiekenhuis, Locatie Zwijndrecht, Interne geneeskunde, Zwijndrecht),B van Ouwerkerk (Albert Schweitzer Ziekenhuis, Locatie Dordrecht,Interne geneeskunde, Dordrecht).

NorwayM Baekken (Ullevaal University Hospital, Oslo), K Furuseth(Solli klinikk, Jessheim), K Gisholt (Dr. Gisholts Kontor,Spesialistsenteret, Nesttun), K Hoye (Norsk Helseklinikk Hamar AS,Hamar), F Moen (Sykehuset innlandet I Gjovik, Gjovik), U Schafroth(Sykehuset I Vestfold (Siv), Tonsberg).PolandA Czech (Katedra i Klinika Chorob Wewnetrznych iDiabetologii A.M., Warszawa), T Kasperska-Czyzyk (III Oddzial ChorobWewnetrznych i Diabetologii, Warszawa), A Nowakowski (Katedra iKlinika Endokrynologii A.M. w Lublinie, Lublin),E Semetkowska-Jurkiewicz ( Regional Centre of Diabetology, Gdansk),B Wierusz-Wysocka (Pracownia Edukacji Diabetologicznej KatedryProfilaktyki Zdrowotnej A.M. w Poznaniu, Poznan).SpainM Angeles Anton (Hospital Txagorritxu, Vitoria), A Becerra(Ambulatorio San Blas, Madrid), A Calderon (Centro de Salud Rosa deLuxemburgo, Madrid), L Enriquez (Hospital San Pedro de Alcantara,Caceres), S Tenes (Hospital La Plana, Villareal).SwitzerlandF Cattaneo (Medical Practice, Lugano), B Felix

(Kantonspital Bruderholz, Bruderholz), D Gloor (Kantonsspital Liestal,Liestal), N Noth (Medical Practice Endokrinologie-Diabetologie,Unterseen), K Scheidegger (Medical Practice, St Gallen).

Conflict of interest statementRGB served as a consultant to or gave lectures organised by Bayer,Develogen, GSK, Lilly, MSD, Novo Nordisk, and Sanofi-Aventis. UN wasan employee of Sanofi-Aventis, left the company after completion of thestudy, and is a consultant for clinical studies. WL is an employee ofSanofi-Aventis. DRO served as a consultant for Sanofi-Aventis, MSD,Pfizer, Novo Nordisk, Roche, and Novartis, and gave lectures at varioussymposia sponsored by these companies. CB is a copyright holder of thediabetes treatment satisfaction questionnaire and director of HealthPsychology Research (HPR) that licenses questionnaires topharmaceutical companies. CB has served as consultant forSanofi-Aventis and other companies, has given lectures at symposiasponsored by Sanofi-Aventis, served on an advisory board for Lilly, and

received research grants from Sanofi-Aventis and Lilly. TL has receivedan unrestricted research grant from Sanofi-Aventis.

AcknowledgmentsThe study was sponsored by Sanofi-Aventis (Paris, France). We thank

Marlis Herbold, Karl-Heinz Theobald, and Martin Larbig for support inreviewing the report.

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