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Efficacy and safety of insulin glargine added
to a fixed-dose combination of metformin
and a dipeptidyl peptidase-4 inhibitor: results
of the GOLD observational study
This article was published in the following Dove Press journal:
Vascular Health and Risk Management
12 November 2013
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Jochen Seufert 1 Background: For patients with type 2 diabetes who are uncontrolled on a combination of two
Katrin Pegelow 2 oral antidiabetic agents, addition of the long-acting basal insulin glargine is a well established
Peter Bramlage 3 treatment option. However, data on the efficacy and safety of a combination of metformin, a
dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin glargine are limited in real-world settings.
Division of Endocrinology and
Diabetology, Department of Internal Therefore, the aim of this study was to analyze blood glucose control, rates of hypoglycemia
Medicine II, University Hospital of and body weight in a large cohort of patients with type 2 diabetes treated with this combination
Freiburg, Freiburg, 2Sanofi Aventis
Deutschland GmbH, Berlin, 3Institut
therapy in real practice.
für Pharmakologie und Präventive Methods: This noninterventional, multicenter, prospective, observational trial with a follow-up
Medizin, Mahlow, Germany of 20 weeks enrolled insulin-naïve patients who had been on a stable fixed dose of metformin
and a DPP-4 inhibitor for at least 3 months, and had a glycosylated hemoglobin (HbA1c) between
7.5% and 10%. Patients were selected at the investigators’ discretion for initiation of insulin
glargine at baseline. A total of 1,483 patients were included, of whom 1,262 were considered
to be the efficacy set. Primary efficacy parameters were HbA1c and fasting plasma glucose.
Secondary outcome measures included achievement of glycemic targets, body weight, rates of
hypoglycemia, and other safety parameters, as well as resource consumption.
Results: Upon initiation of insulin glargine, mean HbA1c decreased from 8.51% to 7.36%
(−1.15%±0.91%; 95% confidence interval [CI] −1.20 to −1.10). An HbA1c level ,6.5% was
achieved in 8.2% of patients and a level ,7.0% in 31.5%. Mean fasting plasma glucose decreased
from 174±47 mg/dL to 127±31 mg/dL (−47.3±44.1 mg/dL; 95% CI −49.8 to −44.8). In 11.9%
of patients, a fasting plasma glucose level ,100 mg/dL was achieved. Bodyweight decreased
on average by 0.98±3.90 kg (95% CI 1.19–0.76). Hypoglycemia (blood glucose #70 mg/dL)
was observed in 29 patients (2.30%), of whom six (0.48%) had nocturnal hypoglycemia and
four (0.32%) had documented severe events (blood glucose ,56 mg/dL).
Conclusion: The results of this observational study show that insulin glargine, when added
to a fixed-dose combination of metformin and a DPP-4 inhibitor, resulted in a significant and
clinically relevant improvement of glycemic control. Importantly, this intervention did not
interfere with the action of the DPP-4 inhibitors, resulting in neutral effects on weight and low
rates of hypoglycemia. We conclude that this treatment intensification approach may be useful,
Correspondence: Jochen Seufert
efficient, and safe in daily clinical practice for patients with type 2 diabetes.
Division of Endocrinology and
Diabetology, Department of Internal Keywords: diabetes, dipeptidyl dipeptidase-4 inhibitors, metformin, insulin glargine
Medicine II, University Hospital of
Freiburg, Freiburg, Hugstetter Str 55,
79106 Freiburg, Germany Introduction
Tel +49 761 2703 6340
Fax +49 761 2703 4130
A fixed-dose combination of metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor has
Email been shown to be an effective and particularly safe and convenient treatment strategy.1,2

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mean change in numbers of daily insulin injections. had experienced episodes of severe group. The triple nation of metformin and any DPP-4 inhibitor (agents used not combination was safe. fasting plasma glucose. not allow stipulation of particular treatments or procedures. and consumption of pen needles per day study was carried out in accordance with §67(6) of the Ger. or a general inability to comply with results of these studies could be reproduced in a clinical the study requirements. patients with a contraindica- practice setting where patients do not necessarily match those tion to insulin glargine were excluded. and per month at endpoint.56 mg/dL or . the groups. DPP-4  inhibitor in basal supported oral therapy [BOT] in changes in timing of administration of insulin. AMG).3. The glucose test strips. we of randomized. and the head organizations of health insurance and incretin-based therapies on fasting and postprandial Vascular Health and Risk Management 2013:9 Dovepress . formin/sitagliptin compared with metformin/sitagliptin with Patients were excluded if they had received prior treatment or without sulfonylurea. Materials and methods mean change in insulin dose per day and number of adjust- GOLD (Blood glucose reGulatiOn with Lantus® and a ments. 712 submit your manuscript | www.9 with a low risk of hypoglycemia.001) were larger in the insulin detemir the previous 6 months.001) and fasting plasma glucose (−3. Secondary outcome measures were: achievement of individualized treatment goals for fasting plasma glucose. sulfonylureas. or had a history of alcohol or These reports prompted us to investigate whether the drug abuse. as DPP-4 inhibitors.7 For treatment escalation. 2010. hypoglycemia) were generally low and comparable between and were able to perform blood glucose self-measurements. On the other hand.5%–10%).5% and 10%. had taken a combi- hour with insulin glargine/metformin. Further. provided that they were at least 18 years with the triple combination versus 728±132  mg/dL per old.2 mmol/L. Hollander et al3 evaluated the efficacy and safety Patients were only considered for inclusion if the treating phy- of insulin detemir added to an existing treatment with met. The specific DPP-4 inhibitor and man Medicines Law (Arzneimittelgesetz.100 mg/dL and to investigate the safety and tolerability of initiating (5. thiazolidinediones (glitazones). −0. or dementia. insulin glargine in these patients.dovepress. prospective observational study. a long-acting insulin analog. and hypoglycemia rates (no major specified) for at least 3 months previously.Seufert et al Dovepress In patients who do not reach their individual target glycosy.10 We added insulin glargine to Outcome measures a treatment regimen of metformin and a DPP-4  inhibitor The principal outcome measures for the study were mean established for at least 3 months in patients with an HbA1c changes in HbA1c. and the proportion of patients reaching that remained elevated (7. It was announced to using this combination. with no differences in weight changes and no episodes hypoglycemia during the course of the disease (blood glucose of major hypoglycemia.0. mean change type 2 diabetes patients) was a noninterventional. were insulin-naïve.6. P=0. Patients had to provide written investigated whether addition of sitagliptin 100 mg/day to an informed consent prior to enrolment. use of blood trolled. . is an attractive option for treatment escalation because of the the German Medical Association (Kassenärztliche Bundesv- combination of complementary effects of long-acting insulin ereinigung). lated hemoglobin (HbA1c) or fasting plasma glucose levels but monitoring of treatment decisions.0. a proven flexible and efficient therapeutic option8. controlled trials. of patients achieving a fasting plasma glucose . P. This observational study an HbA1c . (HbA1c). sician had made a decision to use insulin glargine at baseline. multicenter.7. funds as necessary. mean change in body weight. had an HbA1c between 7.0008). in metformin dose.6 mmol/L) were analyzed.44% versus with insulin.0% from the start of treatment with had two principal objectives: to document glycemic efficacy insulin glargine to the end of the 20-week observation period.89%. noncon. and insulin glargine doses Further. changes in fasting plasma glucose and the proportion used between baseline and the end of 20 weeks of follow-up.5% or .7 versus glucagon-like peptide-1 receptor agonists or acarbose within −1. Reductions in HbA1c (−1. The protocol of the study was approved cose and consequently HbA1c. which does its dose were not recorded. P.3–5 by the ethics committee of the Berlin Chamber of Physi- A recent study by Arnolds et al6 performed in 48 subjects cians on November 3.1 mmol/L). existing treatment of insulin glargine titrated to achieve fast- ing plasma glucose #100 mg/dL and/or metformin results in Patients improved blood glucose control. did not stipulate specific contraindications for metformin or we used insulin glargine. adding a long-acting insulin (analog) the Federal Institute of Drugs and Medical Devices (BfArM). Reduced 6-hour postprandial Patients with type 2 diabetes mellitus were included in this glucose excursions were found (612±133 mg/dL per hour observational trial.

who comprised a such as dizziness.   Microalbuminuria 1.35±7.341% to 0. with a HbA1c and fasting plasma glucose 95% confidence interval (CI) ranging from 0.3±44.5±14.222 96 (7. glycosylated hemoglobin.1) using absolute and relative frequencies.2% between 100 and . needed to be able to answer the predefined primary research questions. correspond- A normally distributed fasting plasma glucose decrease of ing to a mean change of −1.3)   Retinopathy 1. 50%.7) 15 software (SPSS Inc. these.0) based physicians (66. Categorical data were described Diabetes duration $5 years 1.217 175 (14.247 8.262) with available data. Chicago. Adverse events occurring in 174±47 mg/dL to 127±31 mg/dL. probability of 95% and those occurring in one of 1. criteria as the efficacy set. 33.222 175 (14.6.9%.5%.56 mg/dL (3. typical patient population with type 2 diabetes mellitus with and convulsions.5% general practitioners. An HbA1c level .255 436 (34. and for other estimated parameters. Table  2).91% (95% CI −1.9%–77.221 122 (10. characteristics for these 1.8 Body mass index (kg/m2) 1.0% in 31. fasting plasma   HbA1c (%) 1.7) Results   Nephropathy 1. in 11. incidence of confirmed severe hypoglycemia other selection criteria. standard deviation.   Fasting blood glucose (mg/dL) 1.0 mg/dL.1%–51. IL.05 mean ± standard deviation.459%. erysipelas.1 mmol/L). FL.262 patients.600 patients were mean dose of 13.230 381 (31.2±10.9%–27.8)   Macroalbuminuria 1. USA).1 goals were achieved in 35.242 174.225 402 (32. respectively.9%. and in 8.23% of all sites).262 patients being with blood glucose levels .4%±1. presence of comorbidities. This was because actual (Sigmasoft International.215 57 (4. 1.   Diabetic foot syndrome 1.5% of both professions.1±11.9)   Stroke/transient ischemic attack 1.7. Table 1 shows the baseline incidence of other spontaneously reported adverse events. Vascular Health and Risk Management 2013:9 submit your manuscript | www.130 mg/dL.3) per center) across Germany on the basis of a representative   Myocardial infarction 1.230 336 (27. All patients documented were regarded 117.10. A comparison treatment goals for fasting plasma glucose were slightly with the source documentation was performed at 21  sites higher than 100 mg/dL (mean fasting plasma glucose goal (3.258 562 (44.483 patients were documented by 650 office-   Neuropathy 1. as indicated in the tables for calculating n available Mean ± SD or n (%) proportions. mean fasting plasma glucose (n=1. Insulin glargine was initiated. Because selected variables were missing in some patients.8) nists.1%. we considered only the subsets Table 1 Patient demographics (n=1. USA).9% of patients. This number was calculated based on the assumption Mean changes and achievement of target of a normally distributed HbA1c decrease of 0. The 95% CIs were Blood glucose values reported for the mean changes in HbA1c.   Peripheral arterial disease 1. 48.255 905 (72. Naples.0% inter. and blood glucose control.6 ated using Statistical Package for the Social ­Sciences version Diabetes-related comorbidity*  None 1.2% of patients and a level . The 75% would result in 95% CIs of 22. on Statistics average. and a further 51 patients were tomatic hypoglycemia with blood glucose levels #70 mg/dL treated with insulin despite not complying with some of the (3. These patients were considered the safety set. Continuous data were described by the Body weight (kg) 1.15%±0.50±0.5 patients   Coronary artery disease 1.04 units per day.51% to 7.7) statistical analysis plan.214 64 (5.36%. and 0.197) decreased from and 72. Among Note: *Overlap because of multiple comorbidities.262 64.5% was achieved to 22. recorded in 170 patients.7 formed using descriptive measures according to a predefined Female sex 1. classified by severity.dovepress. and the available for the efficacy analysis. Individualized fasting plasma glucose Double data entry was done using DMSys® version 5.1%.260 30. Mean HbA1c decreased from 8.8 to −44. corresponding to a mean one of 534 patients were determined to be observable with a change of −47. hypoglycemia) with a probability of 80%.0±46.100 mg/dL was achieved (eg. This resulted in 1.2%.94 mg/dL.Dovepress Insulin glargine added to metformin and a DDP-4 inhibitor Safety parameters were: incidence of confirmed symp. no prior metformin/DPP-4  inhibitor treatment was Abbreviations: HbA1c. as the safety set.3) demographic pattern between January 1. Age (years) 1.9 mmol/L).1  mg/dL (95% CI −49.227 89.8). and all patients complying with the selection Table 3). SD.0) 2012. hyperhidrosis.6±16. weight gain. 2010 and ­January 9.000 patients A fasting plasma glucose level .76±5.06 mg/dL to − 713 Dovepress .98 glucose.20 20±60 mg/dL would have a 95% CI ranging from 17. Statistical analysis of all collected data was per. with 2. An observed response rate of 25%. respect to age and sex distribution.3) A total of 1. 78.3±1..225 108 (8.2 days prior to the baseline evaluation at a Power calculations showed that about 1. Data were evalu.

In two patients ments decreased during the observation period.0%. kg (n=1.262)   Once daily insulin injection.93) 189 (14. hyperhidrosis.70 6.888.82) 37 (2.262) – 150 (11.81 7. 5. the dose A total of 29 adverse events occurred in 13 patients of insulin glargine was initiated at 13.9%.88%. Only 1. CI.90 -1.33%). of whom six (0.2) 6.13% each).140 (90. sidered to be severe (blood glucose .13%).56 1.8 88.262) – 397 (31.1 -49.197) 174±47 127±31 -47.9%.241) 1. n (%) 20 (1. 6.3±44.30%).8% Abbreviations: HbA1c. during the study for reasons unrelated to insulin glargine respectively.70 units/day and weight increase (0.72±0.180) 13.Seufert et al Dovepress Table 2 Primary efficacy measures of HbA1c and FPG Post-baseline End of follow-up Difference 95% CI Mean HbA1c. 3 (0.8%. up.10   HbA1c level . -0. 0.20%) and dizziness.41 -7. hyperhidrosis. 714 submit your manuscript | www.2) – 75.6. n (%) 463 (36. The Table 3 Secondary outcome measures Post-baseline End of follow-up Difference 95% CI Individual FPG treatment goals (n=1.100 mg/dL n (%) (n=1. and 5 (0.5%. n (%) 201 (15.52±0.15±0.11 units/day and (0.1% Mean FPG.56  mg/dL). 4 (0.98±3.07% each).210) 8.39 +6.47±36.06±36.98) – – Vascular Health and Risk Management 2013:9 Dovepress . n (%) – 61 (5. n (%) (n=1.04±0.79).35±1. erysipelas.96±7.183) Abbreviations: CI.66 strips per month at 20 weeks (n=1. Preferred treatment. Secondary outcomes Safety During the approximately 20 weeks of treatment. FPG.75 – 23.208)   .95) – –    Evening. Relevant adverse events were hypogly- then increased to 20.43±7.59±37.58±16.9% Mean insulin dose per day (n=1. The frequency of insulin dose adjust.58±14. respectively. One patient died observation (90.75).19.130 mg/dL. and weight increase (0.8   .881. 13.46 1. 25. n (%) 23 (1.69) 433 (34. n (%) – 202 (16. Seri- Insulin glargine was injected in the majority of patients ous adverse drug reactions were observed in one patient once a day post baseline (96.91 -1. 80.dovepress. confidence interval.20.53 45.262) – 104 (8. n (%) 538 (42.9) 10.9%   HbA1c level .2%.59) 1. Table 3).8%.76 Mean consumption of blood glucose test 41. mg/dL (n=1.4%   100 to .07%). Reported adverse with a decrease in months 2 (1.7%.15±145.40% (n=6) of patients. a mean of 1.93) – –    No data.74) – –   Mean metformin dose.54 units/day at the end of follow. convulsions. n (%) 1.227) 89.58) 85 (6.52.36±0.39±9.39±0. n (%) (n=1.63) 506 (40. injected insulin glargine twice daily. drug reactions were hypoglycemia (0. 34.94   Mean body weight.51±0.5%   $130 mg/dL. 7.30 +3.48%) and 40.0) – 3.7) – 14. insulin glargine could not be excluded.219 (96.067) Mean consumption of pen needles per – 24.24. mg (n=1.10% after 20 weeks) and in the evening (36.42 month at 20 weeks (n=1.7.31) – –    Bedtime.10) – –    Twice daily. -1.82% and 2.19 -15.31%. corresponding to a mean change of 6.59%) and after 20 weeks of (hypoglycemia and convulsions.5) 28.74.33) – –  Administration time point    Morning. ­Hypoglycemia (blood glucose #70 mg/dL) was administration times were at bedtime (42. % (n=1.87).93).28. In the first with a total of five events. fasting plasma glucose.3 -0. n (%) – 945 (78. glycosylated hemoglobin. 9.69% and occurred during the night and four (0. Table 4).35) 12 (0.96±7. fasting plasma glucose. were observed for 0.88 -1.40 Insulin injection (n=1.24 insulin adjustments took place.32%) were con- 34. cemia (0. a causal relationship with month.93% of the patients. Serious adverse events on treatment (Table 3). confidence interval.8.63% post baseline observed in 29 patients (2. n (%) 17 (1. FPG.43 20.56±16. 0. -44.100 mg/dL. 18.

0% despite multiple combinations of oral discontinued because of adverse events. the use of basal used at any stage of the disease.03 Nocturnal hypoglycemia 1.13) found an HbA1c reduction of 1. n (%) was high.07) treatment duration of 20 weeks.240 6 (0.15% and a decrease in fasting   Dizziness 1. with a low frequency of   Erysipelas 1.dovepress. We [29 events] [5 events]   Hypoglycemia 1. in whom the early use of basal Discussion insulin was associated with a significant improvement in The role of insulin in the treatment of patients with type 2 residual pancreatic beta-cell function.241 1. Treatment satisfaction n available Hypoglycemia.5% or 8.88) 2 (0. with long-term exposure to hyperglycemia.483 6 (0.6% of patients continuing their or mean ± SD treatment beyond the observation period. and a 1.48) controlled trial results suggesting that the complementary  Mean number of episodes 1. metformin. it was reduced by about 1 kg.241 4 (0. main reason for discontinuation of insulin glargine was Insulin is frequently used when HbA1c values rise insufficient blood glucose control (n=17.88±1. ­sulfonylurea.13–16 In real-world clinical practice however.12 is with a shorter history of diabetes and a higher HbA1c at powerful in improving long-term glycemic control. no reason for discontinuation was recorded.3 episodes per (no data available for 4. Body weight did not increase.07)  Convulsion 1.13) 0 plasma glucose of 47. 18 In the EARLY diabetes has evolved considerably within the last decade from (Early Basal Insulin Therapy under Real-Life Conditions being a last resort treatment to a first-line drug that may be in Type 2 Diabetics)19 observational trial. a mean HbA1c decrease of 1.483 3 (0.07) on the contrary.20 Fonseca et  al confirmed these results in a prevent or delay chronic complications in patients with type 2 recent meta-­analysis demonstrating the benefits of early diabetes.30% any and 0.25  mg/dL. ADR.17 Patients on metformin monotherapy and add-on insulin Vascular Health and Risk Management 2013:9 submit your manuscript | www. At the end of the 20-week observation period. timely addition of basal insulin to metformin compared with initiation of insulin is often hampered by concerns about weight a prior combination of metformin and a sulfonylurea.32) strategies on a background metformin therapy is both effec-  Mean number of episodes 715 Dovepress .20) 2 (0.4% within 24 weeks.67±0. in that it is associated with a low Abbreviations: AE.0 tive and well tolerated.35%).3 when insulin detemir was added to a combination of sitagliptin and met- mean number of confirmed hypoglycemic episodes was formin versus a combination of sitagliptin. 1. and fasting plasma glucose decreased by Treatment satisfaction 66.11 Early initiation.13) 1 (0.03 (n=24).2%). This is in contrast with a recent study (n=15). standard deviation.483 2 (0. tice was to observe and analyze the use of insulin glargine n (%) n (%) added to a baseline combination treatment of metformin and a Any event 1.33)  Mean number of episodes 1.240 1.13) 1 (0.483 2 (0.7  mmol/L) when basal insulin was added.483 1 (0.13%) and serious Death 1. One patient above 7.3–6 In a previous randomized controlled trial.483 13 (0. rate of hypoglycemia and comes without weight gain.82 action of long-acting insulin and incretin-based treatment Severe hypoglycemia 1. SD.32% severe) over a   Hyperhidrosis 1. and may ­baseline. Physicians indicated that the year).238 These results are in agreement with previous randomized 1. and the patient’s fear of injections. ADR rate. Rates of hypoglycemia were low (1. as a low risk of hypoglycemia and slightly decreased weight. Adverse drug Serious events 1. 92. For the other patients antidiabetic drugs.483 0 1 (0. adverse event.88±1.13) 0 hypoglycemic episodes (2. suggested by the recent results of the ORIGIN (Outcome ­Multivariate analysis demonstrated better results in patients Reduction with an Initial Glargine Intervention) trial.13) DPP-4 inhibitor in patients with type 2 diabetes mellitus.0±0. with no severe episodes recorded.483 2 (0. hypoglycemia. Early treatment with insulin insulin glargine in patients on maximal doses of metformin is thought to protect the beta-cell from the consequences of reduced HbA1c from 8.40) 1 (0.   Weight gain 1. in patients with type 2 diabetes who were inadequately controlled by metformin. adverse drug reaction.7% to 7. with at least 92.6% of Small decreases were seen in body weight and body mass patients were continuing their insulin glargine treatment index.19. Confirmed hypoglycemia 1.243 29 (2.21 gain.3  mg/dL (3.483 2 (0.07) reactions were recorded in two patients (0.Dovepress Insulin glargine added to metformin and a DDP-4 inhibitor Table 4 Safety and rates of hypoglycemia The aim of this noninterventional study in clinical prac- n available AE rate.07) 0 adverse drug reactions in one patient.44% was observed within 26 weeks.

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Horne PJ. lower rates of severe hypoglycemia and less weight gain Novartis. Do infants show generalized imitation of gestures? Takeda.33(7):1509–1515. Intensive blood- All authors approved the final version for publication. Wenying Y. 2012. been on speaker’s bureaus for AstraZeneca. GlaxoSmithKline. The results of this observational study showed that insulin 2007. Yki-Jarvinen H. et al. 12. Diabetes Obes Metab. 4 inhibitors and HbA1c target of . This intervention did not 9. This may have led to a selection bias of randomized controlled trials. Mannucci E.87(1):63–87. the relative contribution of fasting plasma Diabetes Obes Metab. Bethel MA. Clin Ther. Gross JL. 2007. Valensi P. establishing insulin therapy in these patients. Sanofi.1(2):67–74. and safe in binomial meta-regression analysis of combined glycosylated hemoglobin daily clinical practice when treatment has to be intensified in and hypoglycemia outcomes across eleven Phase III and IV studies of insulin glargine compared with neutral protamine Hagedorn insulin in patients who are not well controlled on oral antidiabetic drugs. Haring HU. 2009. Because of the lack of a control group taking 3.10(5):333–349. Merck Sharp and betes mellitus: a meta-analysis of randomised controlled trials. and 17.13(7): 594–603. 1999. PB has received research funding and honoraria J Exp Anal Behav. type 1 and type 2 diabetes mellitus. Effect of intensive control Squibb. Fleck PR. Cerasi E.7  mmol/L). when added to a combination of metformin and a 8. Lancet. Berlin.12(2):167–177. 2009. et al. comparative pharmacology. Intensive glucose control and The analysis was funded by Sanofi. Erjavec M. N Engl J Med. 2008. treatment effects and complications like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as such as hypoglycemia cannot be linked to a particular add-on therapy to metformin in subjects with type 2 diabetes – a review and meta analysis.3 Because of the high 5. et al.52(11): 2288–2298. Rastam J.373(9677):1765–1772. Negative This approach was shown to be useful. Early intensive insulin treatment for induction of long-term glycaemic control in type 2 diabetes. KP baseline. Gerstein HC. Glycaemic efficacy of glucagon- be expected. Bristol-Myers 16. Owens DR. et al. 2008. Novartis. glucose versus postprandial plasma glucose to HbA1c may 6. Conclusion 7. Acta Diabetol. Pfizer Inc. Importance of observational studies in clinical practice. Clin Ther. is an employee of Sanofi. An important References 1. 716 submit your manuscript | www.5% and fasting plasma Alogliptin added to insulin therapy in patients with type 2 ­diabetes reduces HbA(1C) without causing weight gain or increased glucose of 174  mg/dL (9. 2010. glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. 2012.22 favoring the action of insulin. The design of this study.29(6 Pt 1):1284–1292. Rendell MS. Dohme. et al. 2008. Wijesuriya S. ­treatment. 1998. Another aspect is the rather poor control 4. Neil HA. Diabetes Obes Metab. the study reported by Hollander et al. and PB were involved in the analysis and interpreta. Dipeptidyl peptidase- aspect to be considered is its nonrandomized and non. Ahren B. Clair J. Raslova K. JS has macrovascular outcomes in type 2 diabetes.Seufert et al Dovepress glargine achieved a greater reduction in HbA1c. Further improvement in postprandial be increased.

20. Vascular Health and Risk Management Dovepress Publish your work in this journal Vascular Health and Risk Management is an international. Pistrosch F. mic control and Vascular Health and Risk Management 2013:9 submit your manuscript | www. Monnier L. Fonseca V. Lapinski H. The manuscript management system concise rapid reporting of clinical studies on the processes involved is completely online and includes a very quick and fair peer-review in the maintenance of vascular health. Diabetes. prevention and system. Leahy treatment of vascular disease and its sequelae. 814–822.dovepress.dovepress. Contributions of fasting and post- Early Basal Insulin Therapy under Real-Life conditions in type 2 prandial plasma glucose increments to the overall diurnal hyperglycemia ­Diabetics.php to read real quotes from published authors. 19.Dovepress Insulin glargine added to metformin and a DDP-4 inhibitor 18. Schiffhorst G. Fleischmann H. metabolic disorders. This journal is indexed on reviewed journal of therapeutics and risk management. Diabetes Obes Metab.26(3):881–885. Menge BA.dovepress. Meier JJ. EARLY Study: 22. Landgraf W.21(2):91–97. Submit your manuscript here: http://www. Bramlage P. particularly diabetes. 21. focusing on PubMed Central and MedLine.34(9):2048–2053. Nauck MA. Stoffwechsel und Herz. Pennartz 717 Dovepress . and the involvement of testimonials. 2003. Hanefeld M. Predictors Diabetes Care. Schenker N. 2011.and second-phase insulin secretion in patients with type 2 diabetes. 2012. Colette C. which is all easy to use.13(9): Diabetes Care. 2013. of type 2 diabetic patients: variations with increasing levels of HbA(1c). Fleischmann H. Hanefeld M. peer. Zhou R. Gill J. An analysis of early insulin glargine Chronic reduction of fasting glycemia with insulin glargine improves added to metformin with or without sulfonylurea: impact on glycae- first. Schmidt WE. 2011. Visit http://www. the monitoring. of response to early basal insulin treatment in patients with type-2 diabetes—the EARLY experience. Diab Technol Ther.