GLP-1 REceptor Agonists and Real World EvIdeNce

Type 2 Diabetes Clinical Trial

— GLP-1REWIN  

Official title:

Effectiveness and Persistence of Therapy With GLP-1 Receptor Agonists in Clinical Practice. A Multicenter Retrospective Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03959865
• Other study ID #: 4462/AO/18
• Status: Active, not recruiting
• Start date: December 19, 2018
• Est. completion date: May 31, 2019

Study information

• Verified date: May 2019
• Source: University of Padova
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are powerful second-line agents for the treatment of type 2 diabetes. GLP-1RA have bene marketed in 2010 in Italy and years of experience have accumulated for the treatment with this class of drugs. Cardiovascular outcome trials have shown that type 2 diabetic patients with established cardiovascular disease treated with GLP-1RA have a lower risk of future cardiovascular events.

In this real world study, we wish to evaluate retrospectively the effectiveness and persistence on treatment of GLP-1RA therapy in patients with type 2 diabetes from 2010 to 2018.

Effectiveness endpoints will be glycemic (fasting plasma glucose and HbA1c) and extra-glycemic (body weight and blood pressure). Data from diabetes outpatient clinics in North East Italy will be automatically extracted from electronic chart records and collected into a unique database.

Different groups of GLP-1RA therapies will be compared:

• Long-acting (e.g. dulaglutide and exenatide once weekly) versus short acting (exenatide, liraglutide and lixisenatide)

• Fixed versus flexible combinations of GLP-1RA and basal insulin.

• GLP-1RA with similarities to human GLP-1 (e.g. liraglutide) versus exendin-based GLP-1RA (e.g. exenatide).

Description:

Introduction. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are prioritized as a second-line therapy for the treatment of type 2 diabetes (T2D), especially in patients with a history of cardiovascular disease (CVD) or when there is a need to avoid weight gain and hypoglycemia. Randomized controlled trials (RCTs) have shown that addition of GLP-1RA is more effective in reducing HbA1c than addition of basal insulin (BI) in patients with uncontrolled T2D on oral therapy. GLP-1RA are associated with a low risk of hypoglycaemia and are provided with extra-glycemic effects, including reduction of body weight and blood pressure. Notably, GLP-1RA as a class improve cardiovascular outcomes in T2D patients with established CVD. These benefits justify the positioning of GLP-1RA as the first injectable therapy in most T2D patients and an alternative to insulin.

In the absence of data from RCTs, observational studies can provide medium-level evidence to inform clinical practice, if well-designed and carefully conducted. Real-world studies are hypothesis-generating and cannot substitute for RCTs, but they can guide the design of dedicated RCTs. Retrospective real-world studies are particularly attractive as they can rapidly gather data from large heterogeneous populations that are representative of those seen in routine clinical practice.

Design. The GLP-1REWIN study is a retrospective, multicenter, real-world study on T2D patients initiating GLP-1RA in the routine clinical practice of Italian diabetes outpatient clinics. The study will be conducted at 6 diabetes specialist outpatient clinics in the Veneto Region, North-East Italy.

Objective. The general objective of the study is to evaluate effectiveness of GLP-1RA on glycemic and extra-glycemic endpoints in the real world clinical practice from 2010 to 2018. The study will be conducted at diabetes Centers because only diabetologists were allowed to prescribe GLP-1RA in Italy during the study period.

Methods. Data will be collected retrospectively by automatically interrogating the same electronic chart at all Centers. A dedicated software was developed to extract all relevant anonymized patient information into a clinical research form without manual intervention. We will collect data on all patients aged 18-80 years, with a diagnosis of T2D since at least 1 year (as recorded in the chart), who initiated one GLP-1RA available on the market between 1st Jan 2010 to 31st Dec 2018. These included exenatide twice daily and once weekly, liraglutide, lixisenatide, dulaglutide and fixed ratio combinations of BI/GLP-1RA. The baseline visit date will be set as the date when the patients attended the outpatient clinic and received for the first time a new prescription of GLP-1RA. The following clinical characteristics and laboratory data will be collected from the electronic chart up to 90 days before baseline: age, sex, diabetes duration, body height and weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure (SBP and DBP), heart rate, fasting plasma glucose (FPG), HbA1c, total cholesterol, HDL cholesterol, triglycerides (LDL cholesterol was calculated using Friedwald's equation), liver enzymes, serum creatinine (eGFR was calculated using the chronic kidney diseae [CKD]-Epidemiology [EPI] equation), urinary albumin excretion rate (UAER, expressed as mg/g of urinary creatinine). Details on chronic complication, as reported by international classification of disease (ICD)-9 codes in the electronic charts wil be used to define the presence of micro- and macroangiopathy. Microangiopathy will be defined as any of the following: UAER >30 mg/g; eGFR<60 ml/min/1.73 m2; diabetic retinopathy (any stage) or diabetic macular edema; peripheral or autonomic neuropathy. Macroangiopathy will be defined as any of the following: peripheral arterial disease or peripheral revascularization; history of stroke/transient ischemic attack or carotid revascularization; ischemic heart disease, coronary artery disease, history of myocardial infarction, or coronary revascularization. Information on concomitant medications for the treatment of diabetes and of other cardiovascular risk factors will also be recorded. Detailed dose data will be collected for insulin and GLP-1RA. After having set the baseline date, we will identify the first available follow-up visit attended by the patients at the same Clinic at least 3 months after baseline. Updated values of HbA1c, FPG, SBP and body weight were recorded at the end of follow-up, along with updated information on medications and dosages of GLP-RA.

We will compare the changes in glycemic (HbA1c and fasting plasma glucose) and extra-glycemic (body weight and systolic blood pressure) effectiveness parameters between patients in two groups.

Different groups of GLP-1RA therapies will be compared:

• Long-acting (e.g. dulaglutide and exenatide once weekly) versus short acting (exenatide, liraglutide and lixisenatide)

• Fixed versus flexible combinations of GLP-1RA and basal insulin.

• GLP-1RA with similarities to human GLP-1 (e.g. liraglutide) versus exendin-based GLP-1RA (e.g. exenatide).

Statistics. Continuous variables will be expressed as mean ± standard deviation (SD) if normally distributed or as median (interquartile range) if non-normally distributed. Non-normal variables will be log-transformed before being analyzed with parametric tests. Categorical variables will be expressed as percentage. The comparison of baseline characteristics between two groups will be performed using unpaired 2-tail Student's t test for continuous variables and with chi square for categorical variables. To evaluate the balance between two groups, in addition to p-values, we will calculate the standardized mean difference (SMD). The intra-group change in effectiveness endpoint variables from baseline to end of follow-up will be analyzed using paired 2-tail Student's t test. We will then calculate the change in endpoint variables within each group, which will be compared using unpaired 2-tail Student's t test.

To address the issue of channeling bias (differences in baseline characteristics between the two groups that drive differential outcomes), we will use two different approaches. In the primary analysis, we will perform a propensity score matching (PSM), whereas multivariable adjustment (MVA) with linear regressions will be used as a second approach.

Statistical analyses will be performed using SAS version 9.4 (TS1M4) or higher and a 2-tail p-value <0.05 considered statistically significant.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 6000
• Est. completion date: May 31, 2019
• Est. primary completion date: February 11, 2019
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Type 2 diabetes

• Diabetes duration of at least 1 year

• Initiated on a GLP-1RA during the data collection period

Exclusion Criteria:

• Type 1 diabetes

• Previous therapy with a GLP-1RA before the data collection period

Related Conditions & MeSH terms

• Type 2 Diabetes

Intervention

Drug:
• Long-acting GLP-1RA
Dulaglutide 0.75 or 1.5 mg /week or Exenatide once weekly 2 mg
• Short-acting GLP-1RA
Liraglutide 0.6 mg or 1.2 mg or 1.8 mg / day or exenatide 10 mcg or 20 mcg bid or lixisenatide 10 mcg or 20 mcg / day.
• Human-based GLP-1RA
Liraglutide 0.6 mg or 1.2 mg or 1.8 mg / day or dulaglutide 0.75 or 1.5 mg / week
• Exendin-based GLP-1RA
Exenatide 10 mcg or 20 mcg day or 2 mg / week or lixisenatide 10 mcg or 20 mcg / day.
• Fixed ratio BI/GLP-1RA combination
Insulin degludec / liraglutide (0.036/U) or insulin glargine / lixisenatide (0.5 mcg/U)
• Flexible BI/GLP-1RA combination
GLP-1RA (Liraglutide or dulaglutide or exenatide or lixisenatide) and basal insulin (BI, glargine, degludec, detemir, NPH insulin)

Locations

Country	Name	City	State
Italy	Servizio di Diabetologia UOC Medicina Generale	Cittadella	Padova
Italy	U.O.S Diabetologia, Ospedale di Schiavonia	Monselice	Padova
Italy	Azienda Ospedaliera di Padova	Padova
Italy	U.O. Diabetologia e Dietetica ULSS6	Padova
Italy	U.O. Diabetologia ULSS2	Pieve di Soligo	Treviso
Italy	Diabetologia ULSS2	Treviso

Sponsors (2)

Lead Sponsor	Collaborator
University of Padova	Azienda Ospedaliera di Padova

Country where clinical trial is conducted

Italy, 

References & Publications (5)

Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes Obes Metab. 2017 Feb;19(2):216-227. doi: 10.1111/dom.12804. Epub 2016 Nov 29. — View Citation

Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, Pagidipati NJ, Chan JC, Gustavson SM, Iqbal N, Maggioni AP, Öhman P, Poulter NR, Ramachandran A, Zinman B, Hernandez AF, Holman RR; EXSCEL Study Group. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018 Feb;6(2):105-113. doi: 10.1016/S2213-8587(17)30412-6. Epub 2017 Dec 6. — View Citation

Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-2701. doi: 10.2337/dci18-0033. Epub 2018 Oct 4. — View Citation

Lovshin JA, Drucker DJ. Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol. 2009 May;5(5):262-9. doi: 10.1038/nrendo.2009.48. Review. — View Citation

Singh S, Wright EE Jr, Kwan AY, Thompson JC, Syed IA, Korol EE, Waser NA, Yu MB, Juneja R. Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2017 Feb;19(2):228-238. doi: 10.1111/dom.12805. Epub 2016 Dec 5. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HbA1c	Change in HbA1c from baseline to end of follow-up	3-12 months
Secondary	Weight	Change in body weight from baseline to end of follow-up	3-12 months
Secondary	Blood pressure	Change in systolic blood pressure from baseline to end of follow-up	3-12 months
Secondary	Persistence	Percentage of patients who persist on treatment at the end of follow-up	3-12 months