- Email: [email protected]
Study design and baseline characteristics of patients in the PRESENT study
diabetes research and clinical practice 81s (2008) s3–s9
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Review
Study design and baseline characteristics of patients in the PRESENT study Marina Shestakova a,*, Ole Molskov Bech b, Munther S. Momani c a
Institute of Diabetes, Moscow, Russia Novo Nordisk, International Operations, Clinical Development Centre, China c Department of Endocrinology, Al-Habib Medical Centre, Riyadh, Saudi Arabia b
article info
abstract
Keywords:
PRESENT (Physicians’ Routine Evaluation of Safety & Efficacy of NovoMix1 30 Therapy) is a 6-
Biphasic insulin aspart 30
month observational study of safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) in
Glycaemic control
31,044 type 2 diabetes patients from 15 countries. The aim of this article is to describe the
Hypoglycaemia
study protocol and assess baseline characteristics of patients in various countries according
Observational study
to diabetes duration (<5 years, 5 to 10 years, 10 to 20 years and 20 years), to improve treatment decisions in clinical practice. Glycaemic control was similar across all groups: HbA1c 9.3–9.4%; fasting plasma glucose 11.3–11.6 mmol/L; postprandial glucose 15.9– 16.3 mmol/L. Major hypoglycaemia was reported by 5% of all patients, minor hypoglycaemia increased with diabetes duration (25.4–30.3%); overall hypoglycaemia rate was 6.7 events/ patient/year. Complications increased with diabetes duration; the most reported were hypertension (40.6–71.0%) and hyperlipidaemia (39.4–56.6%). Of patients 38% previously received OADs only, 28% insulin only, 19% insulin with OADs, and 13% received no therapy. Glycaemic control appeared independent of diabetes duration. HbA1c was well above targets and the clinical inertia was quite apparent; even patients with diabetes for <5 years had high HbA1c levels. Patients suffered high rates of complications and hypoglycaemia before starting BIAsp 30 therapy. # 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . 2.1. Study design . . . . . . . . . . . . . . . 2.2. Study population . . . . . . . . . . . . 2.3. Inclusion and exclusion criteria 2.4. Endpoints. . . . . . . . . . . . . . . . . . 2.5. Statistical analyses . . . . . . . . . .
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* Corresponding author at: Institute of Diabetes, Federal Scientific Centre of Endocrinology, Federal Agency of Rosmedtechnology, Dmitryia Uljanova, No. 11, 117036 Moscow, Russia. Tel.: +7 495 124 45 00; fax: +7 495 124 45 00. E-mail address: [email protected] (M. Shestakova). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.06.008
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3.
4.
1.
diabetes research and clinical practice 81s (2008) s3–s9
Results . . . . . . . . . . . . . . . . . . . 3.1. Baseline characteristics . 3.2. Complications . . . . . . . . 3.3. Pre-study treatment . . . 3.4. Glycaemic control . . . . . 3.5. Safety . . . . . . . . . . . . . . . 3.6. BIAsp 30 regimen. . . . . . Discussion . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . References . . . . . . . . . . . . . . . .
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Introduction
The clinical importance of glycaemic control in patients with type 2 diabetes is well established [1], and the progressive nature of type 2 diabetes makes insulin initiation a necessary therapeutic step for many patients. Each 1% increase in HbA1c is estimated to raise the risk of diabetes-related mortality by 25% [2]. Many studies have shown that control of postprandial glucose (PPG) plays a significant role in overall glycaemic control [3,4]. Indeed, as HbA1c levels approach euglycaemia, the contribution of PPG to overall glycaemic control becomes greater than that of fasting plasma glucose (FPG) [4]. Furthermore, postprandial hyperglycaemia has been shown to increase the risk of macrovascular and microvascular complications independently of FPG [5–7]. Thus, regular revision of therapy and adequate control of PPG is important, not only to lower overall glycaemia in terms of HbA1c, but in reducing the risk of long-term complications of type 2 diabetes. It has been suggested that premixed insulin formulations might be a good treatment regimen for initiation of insulin therapy in patients with type 2 diabetes [8]. Premixed insulin formulations consist of soluble insulin, which addresses mealtime glucose excursions; and intermediate-acting insulin, which can control basal glucose levels (e.g. biphasic insulin aspart 30 [BIAsp 30], insulin lispro mix 75/25 [Mix 75/25]). The pharmacokinetic and pharmacodynamic profiles of premixed insulin analogues are more physiological than those of premixed human insulins; analogue premixes show more rapid and higher peak insulin levels, faster and higher maximum serum insulin concentrations, and a greater postprandial plasma glucose lowering effect than human premixes [9,10]. The use of premixed insulin analogues before main meals is a more efficient way to maintaining optimal glycaemic control than long- or intermediate-acting insulins in patients with type 2 diabetes [11–13]. One such premixed insulin analogue formulation is biphasic insulin aspart 30 (BIAsp 30; NovoMix1 30, Novo Nordisk, Copenhagen, Denmark), containing 30% soluble rapid-acting insulin aspart and 70% protamine-crystallised insulin aspart. Inadequate glycaemic control may sometimes be due to lack of educational resources, as well as evidence-based data from clinical practice. Therefore, it is important to raise awareness among clinicians and provide them with data reflecting clinical practice, so that they can make the best treatment decisions in relation to their patients. Data from observational studies provide information from everyday
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clinical practice; they complement the results of randomised controlled trials (RCTs), but also reveal a ‘more realistic picture’ of a particular clinical population, especially if it is a very heterogeneous population with chronic diseases. Observational studies that include patients with type 2 diabetes can indicate whether improvements in glycaemic control associated with particular treatments reported in RCTs are transferable into ‘real-life’ clinical practice [14,15]. The aim of the Physicians’ Routine Evaluation of Safety & Efficacy of NovoMix1 30 Therapy (PRESENT) study was to evaluate efficacy and safety of BIAsp 30 in patients with type 2 diabetes in routine clinical practice. The gradual decline in betacell function in patients with type 2 diabetes requires individually tailored treatment regimens according to the stage of disease progression for each patient. This paper therefore describes the study protocol and presents baseline characteristics of patients being prescribed BIAsp 30 in various countries, according to their treatment duration, with the view of using this information to aid treatment decisions in clinical practice.
2.
Materials and methods
2.1.
Study design
This 6-month, prospective, open-label, non-interventional, uncontrolled, multi-national observational study investigated the efficacy, safety and convenience of using BIAsp 30 in patients with type 2 diabetes. Physicians who prescribed BIAsp 30 in daily clinical practice took part in the evaluation.
2.2.
Study population
Patients with type 2 diabetes inadequately controlled on current therapy (HbA1c 7.0%) were prescribed BIAsp 30 as monotherapy, or in combination with oral antidiabetic drugs (OADs), in accordance with the approved labelling. It was entirely at the physicians’ discretion to initiate, continue, or stop the therapy with BIAsp 30, and to individualise the treatment pattern in terms of the dose and injection regimen, according to the patient’s best interest. Due to the nature of an observational study, no special investigational procedures or intervention, other than those routinely used in clinical practice, were planned for the patients, except the collection of clinical data. Data were collected at baseline and after approximately 3 and 6 months of treatment (Table 1), except in China (baseline and 3 months) and Sri Lanka (baseline only).
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Table 1 – Data to be collected at baseline, 3 and 6 months of the study Visit number Month Demographics Diabetes duration Medical history Current diabetes therapy FPG PPG after breakfast HbA1c Weight, BMI, height ADRs Number of hypoglycaemic episodes Satisfaction questions DTSQ (optional)
1 Baseline U U U U U U U U U
2 3 (2 weeks)
3 6 (2 weeks)
U U U U (optional) U U U U
U U U U U U U U U
U
ADRs, adverse drug reactions; BMI, body mass index; DTSQ, diabetes treatment satisfaction questionnaire; FPG, fasting plasma glucose; PPG, postprandial plasma glucose.
The PRESENT study was carried out in 15 countries: China, India, Iraq, Jordan, Lebanon, Romania, Russia, Saudi Arabia and the Gulf countries (Kuwait, Qatar, UAE), South Africa, South Korea, Sri Lanka and Turkey. However, data from Sri Lanka were excluded from this paper. For the purpose of this review, patients were stratified according to diabetes duration into four groups: <5 years, 5 to 10 years, 10 to 20 years and 20 years.
2.3.
Endpoints
Efficacy was examined by change in glycated haemoglobin A1c (HbA1c), FPG, and PPG 90–120 min after breakfast over the study period. Based on patient recollection and their clinical records over the previous 3 months, safety was assessed by the incidence of overall, nocturnal (00:00–06:00 h), and diurnal (06:00–00:00 h) hypoglycaemic episodes, major (when patients were not able to treat themselves), and minor (patients were able to treat themselves) hypoglycaemic episodes, and incidence of serious and non-serious adverse drug reactions (ADRs) (excluding hypoglycaemic episodes). Weight was also recorded at baseline visit. Physicians’ satisfaction with efficacy, safety and patients’ compliance with BIAsp 30 was examined by a questionnaire. Also patient satisfaction with the treatment compared with the previous treatment (as perceived by the physician) was assessed, as well as patient satisfaction with the prescribed insulin injection device (as perceived by the physician).
2.5.
3.
Results
3.1.
Baseline characteristics
Inclusion and exclusion criteria
No inclusion and exclusion criteria were defined for the study. All patients with type 2 diabetes who were inadequately controlled on their current therapy and who were prescribed BIAsp 30 (as monotherapy or in combination with OADs) were eligible.
2.4.
were presented according to category and severity using summary statistics and event rates per patient per year. The data were presented for the overall cohort and the subgroups based on patients’ diabetes duration (<5 years, 5 to 10 years, 10 to 20 years and 20 years). All the statistical analyses were performed using SAS1 version 9.1.3 (SAS Institute, Cary, NC, USA).
Statistical analyses
Patient baseline demographics, current diabetes therapy, and efficacy and safety outcomes were presented as descriptive statistics (mean S.D.). Hypoglycaemic episodes and ADRs
A total of 2013 physicians from 1182 sites participated between September 2004 and June 2006, and a total of 31,044 patients were included in the baseline safety analysis cohort. The largest subgroup of patients was from China (N = 11,662) comprising 34.7% of the total cohort, followed by South Korea (N = 5828, 17.3%) and India (N = 3559, 10.6%); the remaining countries contributed with less than 10% of patients of the total cohort each (Table 2). Baseline patient characteristics are shown in Table 3. Mean age of the total cohort was 54.6 11.9 years and increased with increasing diabetes duration. In contrast, mean weight (71.5 14.3 kg) and body mass index (BMI; 26.1 4.6 kg/m2) did not appear to vary greatly across the diabetes duration groups.
3.2.
Complications
A significant proportion of patients suffered from diabetic complications, and the percentage of patients with complications increased with increasing diabetes duration (Fig. 1). Of the macrovascular complications, hypertension was the most commonly reported complication (40.6–71.0% of patients), followed by hyperlipidaemia (39.4–56.6%). The most commonly reported microvascular complication was neuropathy (16.2–57.7%), followed by retinopathy (10.9–48.7%).
3.3.
Pre-study treatment
Around 38% of patients had previously received OAD therapy only, 28% received insulin only, and 19% insulin with OADs; however, some patients (2%) did not provide information on
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Table 2 – Baseline patient characteristics according to diabetes duration Country
Total cohort, N (%)
Diabetes duration <5 years
China India Iraq Jordan Lebanon Romania Russia Saudi Arabia and Gulf countries South Africa South Korea Turkey
11,662 3,559 1,888 349 551 912 2,150 2,226 1,473 5,828 3,041
(34.7) (10.6) (5.6) (1.0) (1.6) (2.7) (6.4) (6.6) (4.4) (17.3) (9.0)
5867 817 213 59 54 329 424 312 530 1485 556
(55.1%) (7.7%) (2.0%) (0.6%) (0.5%) (3.1%) (4.0%) (2.9%) (5.0%) (13.9%) (5.2%)
5 to <10 years 3767 1157 385 100 131 273 628 562 377 1810 909
(37.3%) (11.5%) (3.8%) (1.0%) (1.3%) (2.7%) (6.2%) (5.6%) (3.7%) (17.9%) (9.0%)
10 to <20 years 1374 1151 470 89 201 231 696 656 323 1854 1105
(16.9%) (14.1%) (5.8%) (1.1%) (2.5%) (2.8%) (8.5%) (8.0%) (4.0%) (22.7%) (13.6%)
20 years 150 238 292 28 80 48 175 169 82 634 253
(7.0%) (11.1%) (13.6%) (1.3%) (3.7%) (2.2%) (8.1%) (7.9%) (3.8%) (29.5%) (11.8%)
Gulf countries = Kuwait, Qatar, UAE.
Table 3 – Baseline patient characteristics of subgroups in the PRESENT study according to diabetes duration Total cohort
N Age (years, mean (S.D.)) Male/Female (%) Weight (kg, mean (S.D.)) BMI (kg/m2, mean (S.D.)) Diabetes duration (years, mean (S.D.)) Previous therapy: OAD only/insulin only/insulin + OAD/no OAD no Insulin
31,044 54.6 (11.9) 52/48 71.5 (14.3) 26.1 (4.6) 8.0 (6.5) 48/30/20/–
Diabetes duration <5 years
5 to <10 years
10 to <20 years
10,646 50.2 (11.9) 44/56 70.3 (13.6) 25.4 (4.3) 2.1 (1.4) 40/19/9/32
10,099 55.1(10.9) 48/52 71.2 (13.7) 26.1 (4.4) 6.7 (1.4) 47/25/17/10
8150 58.6 (10.6) 52/48 72.0 (14.8) 26.6 (4.8) 13.3 (2.7) 39/31/23/6
20 years 2149 63.7 (10.3) 52/48 71.3 (15.1) 26.5 (4.8) 23.9 (4.6) 28/39/27/3
BMI, body mass index; CHD, coronary heart disease; OAD, oral antidiabetic drug.
previous treatment (Table 3). Thirty-seven percent of patients were using human insulin, and only 3% were using insulin analogue; the mean pre-study total daily all insulin dose was 37.7 17.69 U. The study showed that more intensive treatment is used with increasing diabetes duration.
3.4.
patients (90%) were using FlexPen1, a disposable, pre-filled insulin injection device (Novo Nordisk). The BIAsp 30 dose per body weight increased with diabetes duration, from 0.43 0.19 U/kg in patients with diabetes of less than 5 years’ duration to 0.54 0.23 U/kg in patients who had had diabetes for 20 years or more (Table 6).
Glycaemic control
Glycaemic control of the overall cohort was poor: mean HbA1c was 9.4%; mean FPG 11.5 mmol/L; and mean PPG 16.2 mmol/L. Mean values of these measures were similar across all four groups stratified by diabetes duration (Table 4).
3.5.
Safety
Around 5% of patients had experienced major hypoglycaemia during the 3 months prior to the study across all diabetes duration groups; the range for minor hypoglycaemia during the 3 months prior to the study was 25.4–30.3%, increasing with diabetes duration. Around 16–29% of patients experienced nocturnal, and 23–27% diurnal hypoglycaemia, increasing with diabetes duration. Similarly, the mean overall rate of hypoglycaemia also increased from 6.4 to 8.0 events/patient/ year (Table 5).
3.6.
BIAsp 30 regimen
At baseline, the majority of patients (86%) started using BIAsp 30 twice-daily, 11% once-daily and 3% three times daily; most
Fig. 1 – Proportion of patients reporting complications at baseline.
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Table 4 – Glycaemic control in subgroups of the PRESENT study according to diabetes duration Total cohort
N HbA1c (% Hb, mean (S.D.)) FPG (mmol/L, mean (S.D.)) PPG (mmol/L, mean (S.D.))
Diabetes duration
32,466 9.4 (1.9) 11.5 (3.8) 16.2 (5.0)
<5 years
5 to <10 years
10 to <20 years
10,646 9.3 (2.0) 11.5 (3.9) 16.3 (5.1)
10,099 9.3(1.8) 11.3 (3.5) 15.9 (4.7)
8150 9.4 (1.8) 11.6 (3.8) 16.2 (4.9)
20 years 2149 9.3 (1.9) 11.4 (4.1) 16.1 (5.4)
FPG, fasting plasma glucose; PPG postprandial plasma glucose.
Table 5 – Hypoglycaemic events in subgroups of the PRESENT study according to diabetes duration Total cohort
N Major hypoglycaemia (% patients with events) Minor hypoglycaemia (% patients with events) Nocturnal hypoglycaemia (% patients with events) Daytime hypoglycaemia (% patients with events) Overall rate of hypoglycaemia (events/patient/year)
33,639 5.3 26.5 16.8 23.1 6.7
Diabetes duration <5 years
5 to <10 years
10 to <20 years
10,646 5.9 25.4 16.4 22.6 6.4
10,099 5.3 28.6 18.3 24.8 7.1
8150 4.9 26.8 16.5 23.0 6.8
20 years 2149 5.5 30.3 18.8 26.5 8.0
Table 6 – BIAsp 30 injection regimen at baseline and dose per body weight Injection regimen
Once daily (%) Twice daily Three times daily Mean BIAsp 30 dose (U/kg, mean (S.D.))
Total cohort
11.0 85.5 3.4 0.46 (0.20)
Diabetes duration <5 years
5 to <10 years
10 to <20 years
9.80 87.4 2.7 0.43 (0.19)
11.0 85.8 3.2 0.46 (0.19)
12.7 83.9 3.4 0.49 (0.21)
20 years 14.2 81.9 4.0 0.54 (0.23)
BIAsp, biphasic insulin aspart.
4.
Discussion
The PRESENT study is a 6-month, multi-national observational study of patients with type 2 diabetes inadequately controlled on current therapy. The study assesses efficacy, safety and physicians’ satisfaction with BIAsp 30 treatment in clinical practice. Over 30,000 patients from 15 countries took part. The BIAsp 30 dosing and injection regimen were entirely at the discretion of the physicians. There were no inclusion or exclusion criteria. Each country contributed less than 10% of the sample, apart from China (35%), South Korea (17%) and India (11%). As the largest group, providing more than a third of the cohort, came from China (N = 11,662) this sub-sample will also be analysed and reported separately, to ensure that this fact is not a confounding factor in the overall analysis. Baseline characteristics were examined according to four predefined groups stratified by diabetes duration. Not surprisingly, mean age increased from 50 years to 64 years with increasing diabetes duration. Mean weight (71.5 14.3 kg) and BMI (26.1 4.6 kg/m2) were fairly high but similar across all four groups. However, a large proportion of this sample comprised patients from China (35%)—a fact which may have reduced the mean weight and BMI of the total cohort. Many patients reported macrovascular and microvascular complications and these did increase with increasing diabetes
duration. For example, the percentage of patients with hypertension increased from 41% to 72%, the percentage with stroke nearly tripled (3 to 9%), and the microvascular complications quadrupled from the shortest to the longest diabetes duration groups. The high incidence of complications such as hypertension indicates long-term inadequate glycaemic control that may cause further problems in diabetes management. Conversely, improving glycaemic control has been shown to improve the rate of diabetic complications [16]. Had the patients been treated more adequately earlier, complications might have been fewer and less severe [17]. Glycaemic control at baseline was fairly poor across all four groups (mean HbA1c 9.4%), and there was very little variation in HbA1c, FPG or PPG according to diabetes duration. The International Diabetes Foundation recommends a target for HbA1c of 6.5% or lower [8], and the treatment goal for PPG is 7.8 mmol/L or lower and for FPG 6.1 mmol/L or lower [18,19]. In this study, patients’ glycaemic control was well above the recommended targets and did not differ according to diabetes duration. However, patients were included in the study if their glycaemic control was poor; so all patients in the study had poor glycaemic control at baseline. Before enrolling in the PRESENT study, 50% of patients were receiving insulin with or without OADs, but almost 40% were receiving OAD therapy only, despite poor glycaemic control. With increasing diabetes duration, the proportion of
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patients using insulin with or without OADs increased (from 28% to 67%), and the proportion of patients not receiving any therapy decreased (from 32% to 3%). The percentage of patients using OADs only increased from 40% (<5 years’ diabetes duration) to 47% by 5–10 years, but subsequently decreased (to 37% and 28%) in the longer duration groups. In comparison, the proportion of patients using OADs only was higher in the 1-2-3 study (72%) with mean diabetes duration of 11 years than in the PRESENT study [11]. The opposite was the case for insulin use; only 28% of patients were using insulin prior to the 1-2-3 study, whereas in the PRESENT study this number increased from 28% to 67% with increasing diabetes duration. Furthermore, 5% of patients in the PRESENT study experienced major hypoglycaemia in the previous 3 months and this did not differ greatly between the groups. The proportion of patients with minor hypoglycaemia increased from 25% to 30%, and the overall rate of hypoglycaemia increased from 6.4 to 8.0 events/patient/year with increasing diabetes duration. However, this may be explained by the fact that as diabetes duration increased, more patients were receiving insulin, and therefore the rate of hypoglycaemia increased. Several conclusions can be made from these findings: physicians may not be setting appropriate treatment targets, as patients appear to be left with inadequate glycaemic control for too long; patients are not achieving better control with more experience in the management of their diabetes; patients and physicians postpone insulin initiation for too long and are reluctant to intensify therapy accordingly. This may be due to several barriers to insulin therapy including needle anxiety, fear of hypoglycaemia, and weight gain. Education of patients and physicians about the importance of glycaemic control is therefore essential in order to limit long-term diabetes complications. The relatively high mean HbA1c at baseline (9.4%), high percentage of patients with complications and the high percentage of patients on OADs only indicate that many patients may have benefited from an earlier start on insulin. Upon enrolling in the PRESENT study, BIAsp 30 was started twice daily in the majority of patients, and resulted in significant improvements in patients’ glycaemic control. These in turn will help patients and physicians achieve the long-term benefits of early insulin initiation, intensification and attainment of glycaemic targets.
Acknowledgements The PRESENT study was sponsored by Novo Nordisk International Operations. The authors would like to thank the patients and physicians for taking part in the study, and Dr. Eva Cyhlarova for assistance in the preparation of this manuscript.
Conflict of interest Marina Shestakova and Munther Momani have no conflict of interests to declare. Ole Molskov Bech is an employee of Novo Nordisk.
references
[1] UKPDS Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853. [2] American Diabetes Association, Implications of the United Kingdom prospective diabetes study, Diab. Care Suppl. 126 (2003) S28–S32. [3] I.M. El-Kebbi, D.C. Ziemer, C.B. Cook, D.L. Gallima, C.S. Barnes, L.S. Phillips, Utility of casual postprandial glucose levels in type 2 diabetes management, Diab. Care 27 (2004) 335–339. [4] L. Monnier, H. Lapinski, C. Colette, Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients, Diab. Care 26 (2003) 881–885. [5] DECODE, Study Group the European Diabetes Epidemiology Group, Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria, Arch. Intern. Med. 161 (2001) 397–405. [6] E. Selvin, S. Marinopoulos, G. Berkenblit, T. Rami, F.L. Brancati, N.P. Powe, Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus, Ann. Intern. Med. 141 (2004) 421–431. [7] Q. Qiao, J. Tuomilehto, K. Borch-Johnsen, Post-challenge hyperglycaemia is associated with premature death and macrovascular complications, Diabetologia 46 (Suppl. 1) (2003) M17–M21. [8] International Diabetes Federation, Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Available from http://www.idf.org/home/index.cfm?unode=B7462CCB3A4C-472C-80E4-710074D74AD3. Accessed January 21, 2008. [9] C. Weyer, L. Heinemann, T. Heise, Insulin aspart in a 30/70 premixed formulation: pharmacodynamic properties of a rapid acting insulin analog in stable mixture, Diabetes 20 (1997) 1612–1614. [10] P.T. McSorley, P.M. Bell, L.V. Jacobsen, A. Kristensen, A. Lindholm, Twice-daily biphasic insulin aspart 30 versus biphasic human insulin 30: a double-blind crossover study in adults with type 2 diabetes mellitus, Clin. Ther. 24 (2002) 530–539. [11] A.J. Garber, R. Ligthelm, J.S. Christiansen, A. Liebl, Premixed insulin treatment for type 2 diabetes: analogue or human? Diab. Obes. Metab. 9 (2007) 630–639. [12] C. Kapitza, K. Rave, K. Ostrowski, T. Heise, L. Heinemann, Reduced postprandial glycaemic excursion with biphasic insulin Aspart 30 injected immediately before a meal, Diab. Med. 21 (2004) 500–501. [13] A. Lindholm, L.V. Jacobsen, P.M. Bell, P.T. McSorley, A. Kristensen, Improved postprandial glucose control with biphasic insulin aspart 30 in Type 2 diabetes, Diab. Med. 18 (Suppl. 2) (2001) 83, Abstract P160. [14] S. Gough, Post-marketing surveillance: a UK/European perspective, Curr. Med. Res. Opin. 21 (2005) 565–570. [15] R.J. Ligthelm, V. Borzi, J. Gumprecht, R. Kawamori, Y. Wenying, P. Valensi, Importance of observational studies in clinical practice, Clin. Ther. 29 (2007) 1284–1292. [16] I.M. Stratton, A.I. Adler, H.A. Neil, D.R. Matthews, S.E. Manley, C.A. Cull, et al., Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study, BMJ 321 (2000) 405–412. [17] I. Lee, S.R. Lee, N. Lebedev, T. Kedijang, S. Tuna, A. Hassan, et al., Biphasic insulin aspart 30 improves treatment results
diabetes research and clinical practice 81s (2008) s3–s9
in patients with early type 2 diabetes with early type 2 diabetes poorly controlled on prior diabetes treatment: preliminary results from the PRESENT Study, Diabetes 56 (Suppl. 1) (2007) A567. [18] American Association of Clinical Endocrinologists, Medical guidelines for the management of diabetes mellitus: the
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AACE system of intensive diabetes self-management-2002 update, Endocr. Pract. 8 (Suppl. 1) (2002) 40–83. [19] American Association of Clinical Endocrinologists (AACE) Diabetes Guidelines. Available at: http://www.aace.com/ clin/guidelines/diabetes_2002.pdf. Accessed January 21, 2008.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/diabres
Review
Study design and baseline characteristics of patients in the PRESENT study Marina Shestakova a,*, Ole Molskov Bech b, Munther S. Momani c a
Institute of Diabetes, Moscow, Russia Novo Nordisk, International Operations, Clinical Development Centre, China c Department of Endocrinology, Al-Habib Medical Centre, Riyadh, Saudi Arabia b
article info
abstract
Keywords:
PRESENT (Physicians’ Routine Evaluation of Safety & Efficacy of NovoMix1 30 Therapy) is a 6-
Biphasic insulin aspart 30
month observational study of safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) in
Glycaemic control
31,044 type 2 diabetes patients from 15 countries. The aim of this article is to describe the
Hypoglycaemia
study protocol and assess baseline characteristics of patients in various countries according
Observational study
to diabetes duration (<5 years, 5 to 10 years, 10 to 20 years and 20 years), to improve treatment decisions in clinical practice. Glycaemic control was similar across all groups: HbA1c 9.3–9.4%; fasting plasma glucose 11.3–11.6 mmol/L; postprandial glucose 15.9– 16.3 mmol/L. Major hypoglycaemia was reported by 5% of all patients, minor hypoglycaemia increased with diabetes duration (25.4–30.3%); overall hypoglycaemia rate was 6.7 events/ patient/year. Complications increased with diabetes duration; the most reported were hypertension (40.6–71.0%) and hyperlipidaemia (39.4–56.6%). Of patients 38% previously received OADs only, 28% insulin only, 19% insulin with OADs, and 13% received no therapy. Glycaemic control appeared independent of diabetes duration. HbA1c was well above targets and the clinical inertia was quite apparent; even patients with diabetes for <5 years had high HbA1c levels. Patients suffered high rates of complications and hypoglycaemia before starting BIAsp 30 therapy. # 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2.
Introduction . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . 2.1. Study design . . . . . . . . . . . . . . . 2.2. Study population . . . . . . . . . . . . 2.3. Inclusion and exclusion criteria 2.4. Endpoints. . . . . . . . . . . . . . . . . . 2.5. Statistical analyses . . . . . . . . . .
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* Corresponding author at: Institute of Diabetes, Federal Scientific Centre of Endocrinology, Federal Agency of Rosmedtechnology, Dmitryia Uljanova, No. 11, 117036 Moscow, Russia. Tel.: +7 495 124 45 00; fax: +7 495 124 45 00. E-mail address: [email protected] (M. Shestakova). 0168-8227/$ – see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2008.06.008
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3.
4.
1.
diabetes research and clinical practice 81s (2008) s3–s9
Results . . . . . . . . . . . . . . . . . . . 3.1. Baseline characteristics . 3.2. Complications . . . . . . . . 3.3. Pre-study treatment . . . 3.4. Glycaemic control . . . . . 3.5. Safety . . . . . . . . . . . . . . . 3.6. BIAsp 30 regimen. . . . . . Discussion . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . References . . . . . . . . . . . . . . . .
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Introduction
The clinical importance of glycaemic control in patients with type 2 diabetes is well established [1], and the progressive nature of type 2 diabetes makes insulin initiation a necessary therapeutic step for many patients. Each 1% increase in HbA1c is estimated to raise the risk of diabetes-related mortality by 25% [2]. Many studies have shown that control of postprandial glucose (PPG) plays a significant role in overall glycaemic control [3,4]. Indeed, as HbA1c levels approach euglycaemia, the contribution of PPG to overall glycaemic control becomes greater than that of fasting plasma glucose (FPG) [4]. Furthermore, postprandial hyperglycaemia has been shown to increase the risk of macrovascular and microvascular complications independently of FPG [5–7]. Thus, regular revision of therapy and adequate control of PPG is important, not only to lower overall glycaemia in terms of HbA1c, but in reducing the risk of long-term complications of type 2 diabetes. It has been suggested that premixed insulin formulations might be a good treatment regimen for initiation of insulin therapy in patients with type 2 diabetes [8]. Premixed insulin formulations consist of soluble insulin, which addresses mealtime glucose excursions; and intermediate-acting insulin, which can control basal glucose levels (e.g. biphasic insulin aspart 30 [BIAsp 30], insulin lispro mix 75/25 [Mix 75/25]). The pharmacokinetic and pharmacodynamic profiles of premixed insulin analogues are more physiological than those of premixed human insulins; analogue premixes show more rapid and higher peak insulin levels, faster and higher maximum serum insulin concentrations, and a greater postprandial plasma glucose lowering effect than human premixes [9,10]. The use of premixed insulin analogues before main meals is a more efficient way to maintaining optimal glycaemic control than long- or intermediate-acting insulins in patients with type 2 diabetes [11–13]. One such premixed insulin analogue formulation is biphasic insulin aspart 30 (BIAsp 30; NovoMix1 30, Novo Nordisk, Copenhagen, Denmark), containing 30% soluble rapid-acting insulin aspart and 70% protamine-crystallised insulin aspart. Inadequate glycaemic control may sometimes be due to lack of educational resources, as well as evidence-based data from clinical practice. Therefore, it is important to raise awareness among clinicians and provide them with data reflecting clinical practice, so that they can make the best treatment decisions in relation to their patients. Data from observational studies provide information from everyday
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clinical practice; they complement the results of randomised controlled trials (RCTs), but also reveal a ‘more realistic picture’ of a particular clinical population, especially if it is a very heterogeneous population with chronic diseases. Observational studies that include patients with type 2 diabetes can indicate whether improvements in glycaemic control associated with particular treatments reported in RCTs are transferable into ‘real-life’ clinical practice [14,15]. The aim of the Physicians’ Routine Evaluation of Safety & Efficacy of NovoMix1 30 Therapy (PRESENT) study was to evaluate efficacy and safety of BIAsp 30 in patients with type 2 diabetes in routine clinical practice. The gradual decline in betacell function in patients with type 2 diabetes requires individually tailored treatment regimens according to the stage of disease progression for each patient. This paper therefore describes the study protocol and presents baseline characteristics of patients being prescribed BIAsp 30 in various countries, according to their treatment duration, with the view of using this information to aid treatment decisions in clinical practice.
2.
Materials and methods
2.1.
Study design
This 6-month, prospective, open-label, non-interventional, uncontrolled, multi-national observational study investigated the efficacy, safety and convenience of using BIAsp 30 in patients with type 2 diabetes. Physicians who prescribed BIAsp 30 in daily clinical practice took part in the evaluation.
2.2.
Study population
Patients with type 2 diabetes inadequately controlled on current therapy (HbA1c 7.0%) were prescribed BIAsp 30 as monotherapy, or in combination with oral antidiabetic drugs (OADs), in accordance with the approved labelling. It was entirely at the physicians’ discretion to initiate, continue, or stop the therapy with BIAsp 30, and to individualise the treatment pattern in terms of the dose and injection regimen, according to the patient’s best interest. Due to the nature of an observational study, no special investigational procedures or intervention, other than those routinely used in clinical practice, were planned for the patients, except the collection of clinical data. Data were collected at baseline and after approximately 3 and 6 months of treatment (Table 1), except in China (baseline and 3 months) and Sri Lanka (baseline only).
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diabetes research and clinical practice 81s (2008) s3–s9
Table 1 – Data to be collected at baseline, 3 and 6 months of the study Visit number Month Demographics Diabetes duration Medical history Current diabetes therapy FPG PPG after breakfast HbA1c Weight, BMI, height ADRs Number of hypoglycaemic episodes Satisfaction questions DTSQ (optional)
1 Baseline U U U U U U U U U
2 3 (2 weeks)
3 6 (2 weeks)
U U U U (optional) U U U U
U U U U U U U U U
U
ADRs, adverse drug reactions; BMI, body mass index; DTSQ, diabetes treatment satisfaction questionnaire; FPG, fasting plasma glucose; PPG, postprandial plasma glucose.
The PRESENT study was carried out in 15 countries: China, India, Iraq, Jordan, Lebanon, Romania, Russia, Saudi Arabia and the Gulf countries (Kuwait, Qatar, UAE), South Africa, South Korea, Sri Lanka and Turkey. However, data from Sri Lanka were excluded from this paper. For the purpose of this review, patients were stratified according to diabetes duration into four groups: <5 years, 5 to 10 years, 10 to 20 years and 20 years.
2.3.
Endpoints
Efficacy was examined by change in glycated haemoglobin A1c (HbA1c), FPG, and PPG 90–120 min after breakfast over the study period. Based on patient recollection and their clinical records over the previous 3 months, safety was assessed by the incidence of overall, nocturnal (00:00–06:00 h), and diurnal (06:00–00:00 h) hypoglycaemic episodes, major (when patients were not able to treat themselves), and minor (patients were able to treat themselves) hypoglycaemic episodes, and incidence of serious and non-serious adverse drug reactions (ADRs) (excluding hypoglycaemic episodes). Weight was also recorded at baseline visit. Physicians’ satisfaction with efficacy, safety and patients’ compliance with BIAsp 30 was examined by a questionnaire. Also patient satisfaction with the treatment compared with the previous treatment (as perceived by the physician) was assessed, as well as patient satisfaction with the prescribed insulin injection device (as perceived by the physician).
2.5.
3.
Results
3.1.
Baseline characteristics
Inclusion and exclusion criteria
No inclusion and exclusion criteria were defined for the study. All patients with type 2 diabetes who were inadequately controlled on their current therapy and who were prescribed BIAsp 30 (as monotherapy or in combination with OADs) were eligible.
2.4.
were presented according to category and severity using summary statistics and event rates per patient per year. The data were presented for the overall cohort and the subgroups based on patients’ diabetes duration (<5 years, 5 to 10 years, 10 to 20 years and 20 years). All the statistical analyses were performed using SAS1 version 9.1.3 (SAS Institute, Cary, NC, USA).
Statistical analyses
Patient baseline demographics, current diabetes therapy, and efficacy and safety outcomes were presented as descriptive statistics (mean S.D.). Hypoglycaemic episodes and ADRs
A total of 2013 physicians from 1182 sites participated between September 2004 and June 2006, and a total of 31,044 patients were included in the baseline safety analysis cohort. The largest subgroup of patients was from China (N = 11,662) comprising 34.7% of the total cohort, followed by South Korea (N = 5828, 17.3%) and India (N = 3559, 10.6%); the remaining countries contributed with less than 10% of patients of the total cohort each (Table 2). Baseline patient characteristics are shown in Table 3. Mean age of the total cohort was 54.6 11.9 years and increased with increasing diabetes duration. In contrast, mean weight (71.5 14.3 kg) and body mass index (BMI; 26.1 4.6 kg/m2) did not appear to vary greatly across the diabetes duration groups.
3.2.
Complications
A significant proportion of patients suffered from diabetic complications, and the percentage of patients with complications increased with increasing diabetes duration (Fig. 1). Of the macrovascular complications, hypertension was the most commonly reported complication (40.6–71.0% of patients), followed by hyperlipidaemia (39.4–56.6%). The most commonly reported microvascular complication was neuropathy (16.2–57.7%), followed by retinopathy (10.9–48.7%).
3.3.
Pre-study treatment
Around 38% of patients had previously received OAD therapy only, 28% received insulin only, and 19% insulin with OADs; however, some patients (2%) did not provide information on
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Table 2 – Baseline patient characteristics according to diabetes duration Country
Total cohort, N (%)
Diabetes duration <5 years
China India Iraq Jordan Lebanon Romania Russia Saudi Arabia and Gulf countries South Africa South Korea Turkey
11,662 3,559 1,888 349 551 912 2,150 2,226 1,473 5,828 3,041
(34.7) (10.6) (5.6) (1.0) (1.6) (2.7) (6.4) (6.6) (4.4) (17.3) (9.0)
5867 817 213 59 54 329 424 312 530 1485 556
(55.1%) (7.7%) (2.0%) (0.6%) (0.5%) (3.1%) (4.0%) (2.9%) (5.0%) (13.9%) (5.2%)
5 to <10 years 3767 1157 385 100 131 273 628 562 377 1810 909
(37.3%) (11.5%) (3.8%) (1.0%) (1.3%) (2.7%) (6.2%) (5.6%) (3.7%) (17.9%) (9.0%)
10 to <20 years 1374 1151 470 89 201 231 696 656 323 1854 1105
(16.9%) (14.1%) (5.8%) (1.1%) (2.5%) (2.8%) (8.5%) (8.0%) (4.0%) (22.7%) (13.6%)
20 years 150 238 292 28 80 48 175 169 82 634 253
(7.0%) (11.1%) (13.6%) (1.3%) (3.7%) (2.2%) (8.1%) (7.9%) (3.8%) (29.5%) (11.8%)
Gulf countries = Kuwait, Qatar, UAE.
Table 3 – Baseline patient characteristics of subgroups in the PRESENT study according to diabetes duration Total cohort
N Age (years, mean (S.D.)) Male/Female (%) Weight (kg, mean (S.D.)) BMI (kg/m2, mean (S.D.)) Diabetes duration (years, mean (S.D.)) Previous therapy: OAD only/insulin only/insulin + OAD/no OAD no Insulin
31,044 54.6 (11.9) 52/48 71.5 (14.3) 26.1 (4.6) 8.0 (6.5) 48/30/20/–
Diabetes duration <5 years
5 to <10 years
10 to <20 years
10,646 50.2 (11.9) 44/56 70.3 (13.6) 25.4 (4.3) 2.1 (1.4) 40/19/9/32
10,099 55.1(10.9) 48/52 71.2 (13.7) 26.1 (4.4) 6.7 (1.4) 47/25/17/10
8150 58.6 (10.6) 52/48 72.0 (14.8) 26.6 (4.8) 13.3 (2.7) 39/31/23/6
20 years 2149 63.7 (10.3) 52/48 71.3 (15.1) 26.5 (4.8) 23.9 (4.6) 28/39/27/3
BMI, body mass index; CHD, coronary heart disease; OAD, oral antidiabetic drug.
previous treatment (Table 3). Thirty-seven percent of patients were using human insulin, and only 3% were using insulin analogue; the mean pre-study total daily all insulin dose was 37.7 17.69 U. The study showed that more intensive treatment is used with increasing diabetes duration.
3.4.
patients (90%) were using FlexPen1, a disposable, pre-filled insulin injection device (Novo Nordisk). The BIAsp 30 dose per body weight increased with diabetes duration, from 0.43 0.19 U/kg in patients with diabetes of less than 5 years’ duration to 0.54 0.23 U/kg in patients who had had diabetes for 20 years or more (Table 6).
Glycaemic control
Glycaemic control of the overall cohort was poor: mean HbA1c was 9.4%; mean FPG 11.5 mmol/L; and mean PPG 16.2 mmol/L. Mean values of these measures were similar across all four groups stratified by diabetes duration (Table 4).
3.5.
Safety
Around 5% of patients had experienced major hypoglycaemia during the 3 months prior to the study across all diabetes duration groups; the range for minor hypoglycaemia during the 3 months prior to the study was 25.4–30.3%, increasing with diabetes duration. Around 16–29% of patients experienced nocturnal, and 23–27% diurnal hypoglycaemia, increasing with diabetes duration. Similarly, the mean overall rate of hypoglycaemia also increased from 6.4 to 8.0 events/patient/ year (Table 5).
3.6.
BIAsp 30 regimen
At baseline, the majority of patients (86%) started using BIAsp 30 twice-daily, 11% once-daily and 3% three times daily; most
Fig. 1 – Proportion of patients reporting complications at baseline.
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Table 4 – Glycaemic control in subgroups of the PRESENT study according to diabetes duration Total cohort
N HbA1c (% Hb, mean (S.D.)) FPG (mmol/L, mean (S.D.)) PPG (mmol/L, mean (S.D.))
Diabetes duration
32,466 9.4 (1.9) 11.5 (3.8) 16.2 (5.0)
<5 years
5 to <10 years
10 to <20 years
10,646 9.3 (2.0) 11.5 (3.9) 16.3 (5.1)
10,099 9.3(1.8) 11.3 (3.5) 15.9 (4.7)
8150 9.4 (1.8) 11.6 (3.8) 16.2 (4.9)
20 years 2149 9.3 (1.9) 11.4 (4.1) 16.1 (5.4)
FPG, fasting plasma glucose; PPG postprandial plasma glucose.
Table 5 – Hypoglycaemic events in subgroups of the PRESENT study according to diabetes duration Total cohort
N Major hypoglycaemia (% patients with events) Minor hypoglycaemia (% patients with events) Nocturnal hypoglycaemia (% patients with events) Daytime hypoglycaemia (% patients with events) Overall rate of hypoglycaemia (events/patient/year)
33,639 5.3 26.5 16.8 23.1 6.7
Diabetes duration <5 years
5 to <10 years
10 to <20 years
10,646 5.9 25.4 16.4 22.6 6.4
10,099 5.3 28.6 18.3 24.8 7.1
8150 4.9 26.8 16.5 23.0 6.8
20 years 2149 5.5 30.3 18.8 26.5 8.0
Table 6 – BIAsp 30 injection regimen at baseline and dose per body weight Injection regimen
Once daily (%) Twice daily Three times daily Mean BIAsp 30 dose (U/kg, mean (S.D.))
Total cohort
11.0 85.5 3.4 0.46 (0.20)
Diabetes duration <5 years
5 to <10 years
10 to <20 years
9.80 87.4 2.7 0.43 (0.19)
11.0 85.8 3.2 0.46 (0.19)
12.7 83.9 3.4 0.49 (0.21)
20 years 14.2 81.9 4.0 0.54 (0.23)
BIAsp, biphasic insulin aspart.
4.
Discussion
The PRESENT study is a 6-month, multi-national observational study of patients with type 2 diabetes inadequately controlled on current therapy. The study assesses efficacy, safety and physicians’ satisfaction with BIAsp 30 treatment in clinical practice. Over 30,000 patients from 15 countries took part. The BIAsp 30 dosing and injection regimen were entirely at the discretion of the physicians. There were no inclusion or exclusion criteria. Each country contributed less than 10% of the sample, apart from China (35%), South Korea (17%) and India (11%). As the largest group, providing more than a third of the cohort, came from China (N = 11,662) this sub-sample will also be analysed and reported separately, to ensure that this fact is not a confounding factor in the overall analysis. Baseline characteristics were examined according to four predefined groups stratified by diabetes duration. Not surprisingly, mean age increased from 50 years to 64 years with increasing diabetes duration. Mean weight (71.5 14.3 kg) and BMI (26.1 4.6 kg/m2) were fairly high but similar across all four groups. However, a large proportion of this sample comprised patients from China (35%)—a fact which may have reduced the mean weight and BMI of the total cohort. Many patients reported macrovascular and microvascular complications and these did increase with increasing diabetes
duration. For example, the percentage of patients with hypertension increased from 41% to 72%, the percentage with stroke nearly tripled (3 to 9%), and the microvascular complications quadrupled from the shortest to the longest diabetes duration groups. The high incidence of complications such as hypertension indicates long-term inadequate glycaemic control that may cause further problems in diabetes management. Conversely, improving glycaemic control has been shown to improve the rate of diabetic complications [16]. Had the patients been treated more adequately earlier, complications might have been fewer and less severe [17]. Glycaemic control at baseline was fairly poor across all four groups (mean HbA1c 9.4%), and there was very little variation in HbA1c, FPG or PPG according to diabetes duration. The International Diabetes Foundation recommends a target for HbA1c of 6.5% or lower [8], and the treatment goal for PPG is 7.8 mmol/L or lower and for FPG 6.1 mmol/L or lower [18,19]. In this study, patients’ glycaemic control was well above the recommended targets and did not differ according to diabetes duration. However, patients were included in the study if their glycaemic control was poor; so all patients in the study had poor glycaemic control at baseline. Before enrolling in the PRESENT study, 50% of patients were receiving insulin with or without OADs, but almost 40% were receiving OAD therapy only, despite poor glycaemic control. With increasing diabetes duration, the proportion of
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patients using insulin with or without OADs increased (from 28% to 67%), and the proportion of patients not receiving any therapy decreased (from 32% to 3%). The percentage of patients using OADs only increased from 40% (<5 years’ diabetes duration) to 47% by 5–10 years, but subsequently decreased (to 37% and 28%) in the longer duration groups. In comparison, the proportion of patients using OADs only was higher in the 1-2-3 study (72%) with mean diabetes duration of 11 years than in the PRESENT study [11]. The opposite was the case for insulin use; only 28% of patients were using insulin prior to the 1-2-3 study, whereas in the PRESENT study this number increased from 28% to 67% with increasing diabetes duration. Furthermore, 5% of patients in the PRESENT study experienced major hypoglycaemia in the previous 3 months and this did not differ greatly between the groups. The proportion of patients with minor hypoglycaemia increased from 25% to 30%, and the overall rate of hypoglycaemia increased from 6.4 to 8.0 events/patient/year with increasing diabetes duration. However, this may be explained by the fact that as diabetes duration increased, more patients were receiving insulin, and therefore the rate of hypoglycaemia increased. Several conclusions can be made from these findings: physicians may not be setting appropriate treatment targets, as patients appear to be left with inadequate glycaemic control for too long; patients are not achieving better control with more experience in the management of their diabetes; patients and physicians postpone insulin initiation for too long and are reluctant to intensify therapy accordingly. This may be due to several barriers to insulin therapy including needle anxiety, fear of hypoglycaemia, and weight gain. Education of patients and physicians about the importance of glycaemic control is therefore essential in order to limit long-term diabetes complications. The relatively high mean HbA1c at baseline (9.4%), high percentage of patients with complications and the high percentage of patients on OADs only indicate that many patients may have benefited from an earlier start on insulin. Upon enrolling in the PRESENT study, BIAsp 30 was started twice daily in the majority of patients, and resulted in significant improvements in patients’ glycaemic control. These in turn will help patients and physicians achieve the long-term benefits of early insulin initiation, intensification and attainment of glycaemic targets.
Acknowledgements The PRESENT study was sponsored by Novo Nordisk International Operations. The authors would like to thank the patients and physicians for taking part in the study, and Dr. Eva Cyhlarova for assistance in the preparation of this manuscript.
Conflict of interest Marina Shestakova and Munther Momani have no conflict of interests to declare. Ole Molskov Bech is an employee of Novo Nordisk.
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