Real-world use of once-weekly semaglutide in patients with type 2 diabetes: Results from the SURE Denmark/Sweden multicentre, prospective, observational study

Open AccessPublished:June 25, 2021DOI:https://doi.org/10.1016/j.pcd.2021.06.008

      Highlights

      • Real-world SURE programme data complement those from the SUSTAIN clinical trials.
      • SURE Denmark/Sweden studied local use of once-weekly semaglutide in adults with T2D.
      • Semaglutide was associated with significant HbA1c and body weight reductions.
      • No new safety concerns were reported.
      • These data support the clinical use of once-weekly semaglutide in Denmark/Sweden.

      Abstract

      Aims

      As part of the SURE programme, SURE Denmark/Sweden aimed to study the real-world use of once-weekly (OW) semaglutide in adults with type 2 diabetes (T2D) in Denmark/Sweden.

      Methods

      SURE Denmark/Sweden was an ∼30-week, prospective, multicentre, open-label, observational study, enrolling adults with T2D and ≥1 documented HbA1c value ≤12 weeks before initiating semaglutide at their physician’s discretion. Primary (change in HbA1c) and secondary (including change in body weight, glycaemic and weight-loss target achievement) endpoints were assessed between baseline and end of study (EOS).

      Results

      Of the 331 patients initiating semaglutide, 282 (85%) completed the study on treatment. For the latter, estimated mean changes [95% confidence interval] in HbA1c and body weight between baseline and EOS were –1.2 [–1.3; –1.1]%-points (–13 [–14; –12] mmol/mol) and –5.4 [–6.0; –4.7] kg (both p < 0.0001), respectively, with similar results in Denmark and Sweden. At EOS, 67.5% of patients achieved HbA1c <7%; 49.4% achieved a weight reduction of ≥5%. Reported adverse events were consistent with the known safety profile of semaglutide.

      Conclusions

      In routine clinical practice in Denmark/Sweden, use of OW semaglutide was associated with glycaemic and weight-loss benefits in a wide range of adults with T2D, supporting real-world use.

      ClinicalTrials.gov Identifier

      NCT03648281.

      Graphical abstract

      Abbreviations:

      AE (adverse event), ANCOVA (analysis of covariance), BMI (body mass index), BW (body weight), CI (confidence interval), DPP-4i (dipeptidyl peptidase-4 inhibitor), DTSQc (Diabetes Treatment Satisfaction Questionnaire change version), DTSQs (Diabetes Treatment Satisfaction Questionnaire status version), EAS (effectiveness analysis set), EOS (end of study), FAS (full analysis set), GLP-1RA (glucagon-like peptide-1 receptor agonist), GP (general practitioner), MMAS-8 (8-item Morisky Medication Adherence Scale), OW (once-weekly), PRO (patient-reported outcome), QoL (quality of life), SD (standard deviation), SF-36®v2 (Short-Form 36 Health Survey version 2), SGLT-2 (sodium–glucose cotransporter-2), T2D (type 2 diabetes), WC (waist circumference)

      Keywords

      1. Introduction

      Approximately 7‒9% of adults in Denmark and Sweden have diabetes [
      • International Diabetes Federation
      Diabetes Atlas.
      ], with type 2 diabetes (T2D) accounting for 85–91% of cases [
      • Andersson T.
      • Ahlbom A.
      • Carlsson S.
      Diabetes prevalence in Sweden at present and projections for year 2050.
      ,
      • Carstensen B.
      • Rønn P.F.
      • Jørgensen M.E.
      Prevalence, incidence and mortality of type 1 and type 2 diabetes in Denmark 1996–2016.
      ]. T2D is a substantial healthcare challenge, profoundly impacting affected individuals and placing a heavy burden on society [
      • American Diabetes Association
      Economic costs of diabetes in the U.S. in 2017.
      ,
      • Campbell R.K.
      • Martin T.M.
      The chronic burden of diabetes.
      ]. Diabetes and primary care guidelines recommend a patient-centred approach to T2D treatment, considering factors including patient preference, impact on body weight (BW), cardiovascular and hypoglycaemia risk, and drug efficacy [
      • Davies M.J.
      • D’Alessio D.A.
      • Fradkin J.
      • et al.
      Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      ,
      • Seidu S.
      • Cos X.
      • Brunton S.
      • et al.
      A disease state approach to the pharmacological management of type 2 diabetes in primary care: a position statement by Primary Care Diabetes Europe.
      ].
      The once-weekly (OW), subcutaneous formulation of the glucagon-like peptide-1 receptor agonist (GLP-1RA), semaglutide, is approved as an adjunct to diet and exercise for improving glycaemic control (multiple countries) and reducing the risk of major adverse cardiovascular events (USA) in adults with T2D [
      • Novo Nordisk
      OZEMPIC® Summary of Product Characteristics.
      ,
      • Novo Nordisk
      OZEMPIC® Highlights of Prescribing Information.
      ,
      • Novo Nordisk Canada Inc
      OZEMPIC® Product Monograph.
      ,
      • Novo Nordisk A/S
      OZEMPIC® Approved in Japan for the Treatment of Type 2 Diabetes.
      ]. In the SUSTAIN clinical trial programme, which included subjects across the T2D spectrum, OW semaglutide 0.5 and 1.0 mg demonstrated superior, clinically relevant glycaemic and weight-loss benefits vs placebo and a range of active comparators (canagliflozin 300 mg, dulaglutide 0.75 and 1.5 mg, exenatide extended-release 2.0 mg, insulin glargine, liraglutide 1.2 mg and sitagliptin 100 mg) and as add-on to insulin and oral antidiabetic drugs (OADs; including metformin and sodium–glucose cotransporter-2 inhibitors [SGLT-2is]) [
      • Pratley R.E.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial.
      ,
      • Capehorn M.S.
      • Catarig A.M.
      • Furberg J.K.
      • et al.
      Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10).
      ,
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial.
      ,
      • Lingvay I.
      • Catarig A.M.
      • Frias J.P.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial.
      ,
      • Zinman B.
      • Bhosekar V.
      • Busch R.
      • et al.
      Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo controlled trial.
      ]. Semaglutide has also demonstrated superiority vs placebo for cardiovascular protection [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ], with a low risk of hypoglycaemia [
      • Pratley R.E.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial.
      ,
      • Capehorn M.S.
      • Catarig A.M.
      • Furberg J.K.
      • et al.
      Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10).
      ,
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial.
      ,
      • Lingvay I.
      • Catarig A.M.
      • Frias J.P.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial.
      ,
      • Zinman B.
      • Bhosekar V.
      • Busch R.
      • et al.
      Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo controlled trial.
      ] and evidence indicating a potential kidney-protective effect [
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ]. However, there is a need for complementary real-world evidence to validate clinical trial results in a wider pool of patient types and for specific countries or regions [
      • de Lusignan S.
      • Crawford L.
      • Munro N.
      Creating and using real-world evidence to answer questions about clinical effectiveness.
      ].
      The aim of the SURE programme, consisting of nine observational studies across 10 countries (Canada, Denmark, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the UK), is to gather real-world evidence on the use of OW semaglutide in clinical practice. Denmark and Sweden are neighbouring countries with comparable populations and lifestyles, despite some differences in T2D management and prescribing patterns for glucose-lowering drugs (including insulin) [
      • Dansk Endokrinologisk Selskab
      Type 2 Diabetes.
      ,
      • Knudsen S.T.
      • Bodegård J.
      • Birkeland K.I.
      • et al.
      Risk factor management of type 2 diabetic patients in primary care in the Scandinavian countries between 2003 and 2015.
      ,
      • Region Stockholm
      KLOKA LISTAN 2020: Expertgruppen för Endokrina sjukdomar.
      ] due to clinical practice and regulatory conditions. As part of the SURE programme, the SURE Denmark/Sweden study evaluated the use of OW semaglutide in routine clinical practice within these two countries.

      2. Methods

      2.1 Study design

      This was an ∼30-week, prospective, multicentre, open-label, observational study, including adults with T2D in Denmark and Sweden. The decision to initiate treatment with OW semaglutide (administered via standard pen injector) was at the treating physician’s discretion, separately from the decision to include the patient in the study. The physician determined the semaglutide initiation dose, dose escalation schedule, intended maintenance dose and any changes thereafter. Diet and physical activity counselling and additional antihyperglycaemic treatments were permitted as part of routine clinical practice. The initiation visit (hereafter referred to as ‘baseline’; week 0) was the visit during which consent was obtained and the study initiated, with treatment initiation recommended within 7 days. The end of study (EOS) visit was the first visit between weeks 28 and 38. The total number of visits (maximum six) depended upon local clinical practice.
      This study was conducted in accordance with the Declaration of Helsinki [
      • World Medical Association
      WMA Declaration of Helsinki — Ethical Principles for Medical Research Involving Human Subjects.
      ] and the Guidelines for Good Pharmacoepidemiology Practices [
      • Public Policy Committee
      • International Society of Pharmacoepidemiology
      Guidelines for good pharmacoepidemiology practice (GPP).
      ]. Study materials were reviewed and approved by the independent ethics committee or institutional review board at each participating site. SURE Denmark/Sweden is registered with ClinicalTrials.gov, NCT03648281.

      2.2 Study population

      Patients were included from 15 general practitioner (GP) and two specialist sites across Denmark, and 21 GP and six specialist sites across Sweden, with the first patient visit on 24 August 2018 and the last patient visit on 10 January 2020. Inclusion criteria were age ≥18 years at informed consent; T2D diagnosis ≥12 weeks before inclusion; and ≥1 documented HbA1c value within 12 weeks prior to informed consent and treatment initiation. Exclusion criteria included mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation; treatment with any investigational drug within 90 days prior to enrolment; hypersensitivity to semaglutide or any of the excipients; and previously having given informed consent in one of the SURE studies.
      The study duration for each patient was ∼30 weeks, which was considered sufficient to initiate and optimise the study treatment regimen and obtain real-world data for the evaluation of the primary endpoint.

      2.3 Endpoints

      The primary endpoint was the change in HbA1c (%-point and mmol/mol) from baseline to EOS. Secondary endpoints included changes from baseline to EOS in BW (kg and %) and waist circumference (WC; cm); proportion of patients achieving HbA1c target of <7.0% (53 mmol/mol) [
      • American Diabetes Association
      6. Glycemic targets: standards of medical care in diabetes–2018.
      ], weight loss ≥5% or ≥10% (latter not prespecified), the composite endpoint of HbA1c reduction ≥1% and weight loss ≥3%; patient-reported severe or documented hypoglycaemia; and scores for patient-reported outcomes (PROs). PRO instruments included the Diabetes Treatment Satisfaction Questionnaire status (DTSQs) and change (DTSQc) versions for assessing absolute and relative treatment satisfaction, respectively [
      • Bradley C.
      • Lewis K.S.
      Measures of psychological well-being and treatment satisfaction developed from the responses of people with tablet-treated diabetes.
      ,
      • Bradley C.
      • Plowright R.
      • Stewart J.
      • et al.
      The Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) evaluated in insulin glargine trials shows greater responsiveness to improvements than the original DTSQ.
      ] and the Short-Form 36 Health Survey version 2 (SF-36®v2) [
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
      ] for assessing overall health-related quality of life (QoL). The DTSQs contains six items relating to treatment satisfaction (in addition to two items relating to perceived hypoglycaemia and hyperglycaemia that are not presented herein); each item is scored on a 7-point scale ranging from very dissatisfied (0) to very satisfied (6), with overall possible scores ranging from 0 to 36 [
      • Bradley C.
      • Lewis K.S.
      Measures of psychological well-being and treatment satisfaction developed from the responses of people with tablet-treated diabetes.
      ]. The DTSQc contains the same questions as the DTSQs, but each of the six treatment satisfaction items is scored on a scale from –3 (much less satisfied vs previous treatment) to +3 (much more satisfied vs previous treatment), with overall possible scores ranging from –18 to +18 [
      • Bradley C.
      • Plowright R.
      • Stewart J.
      • et al.
      The Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) evaluated in insulin glargine trials shows greater responsiveness to improvements than the original DTSQ.
      ]. The SF-36®v2 contains 36 questions grouped into eight domains, which are further combined into two component scores: the physical component summary and the mental component summary [
      • Ware Jr., J.E.
      • Sherbourne C.D.
      The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection.
      ].
      Exploratory endpoints evaluated at EOS included physician-assessed achievement of clinical success in relation to the reason to initiate semaglutide (multiple answers possible); weekly semaglutide dose; insulin dose and other antihyperglycaemic medication use; and level of medication adherence (low, medium or high) based on the 8-item Morisky Medication Adherence Scale (MMAS-8; a structured, self-reported medication adherence measure) [
      • Morisky D.E.
      • Ang A.
      • Krousel-Wood M.
      • Ward H.J.
      Predictive validity of a medication adherence measure in an outpatient setting.
      ,
      • Krousel-Wood M.A.
      • Islam T.
      • Webber L.S.
      • Re R.S.
      • Morisky D.E.
      • Muntner P.
      New medication adherence scale versus pharmacy fill rates in seniors with hypertension.
      ,
      • Morisky D.E.
      • DiMatteo M.R.
      Improving the measurement of self-reported medication nonadherence: final response.
      ].
      Only serious adverse drug reactions (SADRs), fatal events, pregnancies and AEs in foetuses or newborn infants were systematically collected at each visit. Other AE data were not systematically collected but were voluntarily reported by site physicians.

      2.4 Statistical analysis

      To ensure sufficient statistical power to estimate mean change in HbA1c with a precision corresponding to a halfwidth of the 95% confidence interval (CI) equal to 0.3, 130 patients completing the study on treatment were needed. From previous observational study results, it was assumed that 60% of patients would be on semaglutide and have an HbA1c measurement at EOS [
      • Divino V.
      • DeKoven M.
      • Hallinan S.
      • et al.
      Glucagon-like peptide-1 receptor agonist treatment patterns among type 2 diabetes patients in six European countries.
      ,
      • Wilke T.
      • Mueller S.
      • Groth A.
      • et al.
      Non-persistence and non-adherence of patients with type 2 diabetes mellitus in therapy with GLP-1 receptor agonists: a retrospective analysis.
      ]. Therefore, to ensure 130 patients at EOS in the Swedish population (prespecified), 217 (130/0.6) patients initiating semaglutide in Sweden were needed, with 108 patients planned for enrolment in Denmark (325 patients overall).
      Baseline characteristics were analysed using the full analysis set (FAS; all eligible patients who gave informed consent and initiated treatment with semaglutide) and presented using descriptive statistics (mean ± standard deviation for continuous variables and number and proportion for categorical variables). Primary analyses of the primary, secondary and exploratory endpoints used the effectiveness analysis set (EAS; all patients who attended the EOS visit and were receiving semaglutide treatment at EOS) and considered all patients with the relevant endpoint information at EOS. AE analyses were based on the FAS, with severe or documented hypoglycaemia also assessed in the EAS.
      Primary analyses (primary and secondary outcomes) used an adjusted analysis of covariance (ANCOVA) model to generate least-square mean estimates with 95% CIs and p-values for the change in continuous variables between baseline and EOS; covariates were baseline values for the analysed outcome, T2D duration, age, body mass index (BMI), pre-initiation use of GLP-1RA (yes/no), pre-initiation use of dipeptidyl peptidase-4 inhibitor (DPP-4i; yes/no), pre-initiation use of insulin (yes/no), number of OADs used pre-initiation (0–1/2+), and sex. Statistical tests for primary and secondary endpoints were two-sided (0.05 significance level).
      Sensitivity analyses of the primary endpoint were based on FAS data for ‘in-study’ (period between semaglutide initiation and EOS visit, withdrawal of informed consent, last patient-physician contact [if lost to follow-up], or death, regardless of semaglutide treatment status) and ‘on-treatment’ (period between treatment initiation and final study dose of semaglutide) observation periods. These analyses used a mixed model for repeated measurements, with baseline HbA1c, T2D duration, age, BMI, time and time-squared as covariates and pre-initiation use of GLP-1RA (yes/no), pre-initiation use of DPP-4i (yes/no), pre-initiation use of insulin (yes/no), number of OADs use pre-initiation (0–1/2+) and sex as fixed factors with random intercept and random time coefficient for time (slope). Sensitivity analyses for continuous secondary endpoints were based on patients in the FAS with available endpoint information at EOS and used an ANCOVA model analogous to that for the primary analyses.

      3. Results

      3.1 Patient population and baseline characteristics

      The FAS comprised 331 patients (Denmark: 107; Sweden: 224) (Fig. S1), 23 of whom did not complete the study due to no final visit, loss to follow-up, withdrawal, or death (10, 9, 3 and 1 patients, respectively). In total, 31 patients (9.4%) discontinued study treatment, including 5 patients who did not complete the study. The EAS comprised 282 patients (Denmark: 84; Sweden: 198) completing the study on treatment with semaglutide (median follow-up: 34.1 weeks).
      At baseline in the FAS, female sex and mean age, HbA1c level, diabetes duration, BW and WC were similar in Denmark and Sweden (Table 1). The most prevalent cardiovascular comorbidities were hypertension (Denmark: 57.9%; Sweden: 78.6%) and dyslipidaemia (Denmark: 38.3%; Sweden: 73.7%) (Table S1). The majority of patients were initiated on a 0.25 mg dose of semaglutide (Denmark: 59.8%; Sweden: 91.5%) (Table 1). Baseline characteristics for the EAS are given in Table S2.
      Table 1Baseline characteristics of patients overall and by country (FAS).
      CountryTotal
      DenmarkSweden
      N107224331
      Age, years61.3 (11.1)61.1 (11.4)61.1 (11.3)
      Female, n (%)35 (32.7)82 (36.6)117 (35.3)
      Baseline HbA1c, %7.6 (1.3)8.0 (1.4)7.9 (1.4)
      Baseline HbA1c, mmol/mol60 (14)64 (15)63 (15)
      Fasting plasma glucose, mmol/L
      N-numbers contributing to analysis: n = 40 in Denmark and n = 133 in Sweden.
      8.7 (2.1)9.0 (2.5)8.9 (2.4)
      Body weight, kg
      N-numbers contributing to analysis: n = 103 in Denmark and n = 221 in Sweden.
      100.7 (22.8)101.9 (20.2)101.5 (21.1)
      Body mass index, kg/m2
      N-numbers contributing to analysis: n = 103 in Denmark and n = 219 in Sweden.
      33.1 (6.9)34.4 (6.1)34.0 (6.4)
      Waist circumference, cm
      N-numbers contributing to analysis: n = 79 in Denmark, n = 153 in Sweden, and n = 232 in total.
      113.5 (16.8)116.8 (14.5)115.7 (15.4)
      Diabetes duration, years10.8 (6.5)10.3 (7.6)10.5 (7.3)
      eGFR, mL/min/1.73 m2
      N-numbers contributing to analysis: n = 91 in Denmark, n = 170 in Sweden, and n = 261 in total.
      83.5 (21.9)87.8 (22.0)86.3 (22.0)
      Starting dose of semaglutide, n (%)
       0.25 mg64 (59.8)205 (91.5)269 (81.3)
       0.5 mg41 (38.3)11 (4.9)52 (15.7)
       1.0 mg2 (1.9)8 (3.6)10 (3.0)
      Reasons to initiate semaglutide, n (%)
      In addition to improving glycaemic control (multiple answers possible).
       Improve glycaemic control77 (72.0)199 (88.8)276 (83.4)
       Weight reduction62 (57.9)156 (69.6)218 (65.9)
       Issues with hypoglycaemia05 (2.2)5 (1.5)
       Address cardiovascular risk factors11 (10.3)43 (19.2)54 (16.3)
       Simplify current treatment regimen30 (28.0)27 (12.1)57 (17.2)
       Convenience9 (8.4)9 (4.0)18 (5.4)
       Other4 (3.7)7 (3.1)11 (3.3)
      Values are mean (SD) unless otherwise specified. Data are from the FAS. eGFR, estimated glomerular filtration rate; FAS, full analysis set; SD, standard deviation.
      a N-numbers contributing to analysis: n = 40 in Denmark and n = 133 in Sweden.
      b N-numbers contributing to analysis: n = 103 in Denmark and n = 221 in Sweden.
      c N-numbers contributing to analysis: n = 103 in Denmark and n = 219 in Sweden.
      d N-numbers contributing to analysis: n = 79 in Denmark, n = 153 in Sweden, and n = 232 in total.
      e N-numbers contributing to analysis: n = 91 in Denmark, n = 170 in Sweden, and n = 261 in total.
      f In addition to improving glycaemic control (multiple answers possible).
      Among physicians, frequent reasons for initiating semaglutide were to improve glycaemic control (Denmark: 72.0%; Sweden: 88.8%) and to address cardiovascular risk factors (Denmark: 10.2%; Sweden: 19.2%) (Table 1). Other common motives for semaglutide initiation (in addition to glycaemic control) were weight reduction and treatment regimen simplification. Overall, 87.2% of patients in the EAS (Denmark: 92.9%; Sweden; 84.8%) achieved clinical success at EOS in relation to the reason for semaglutide initiation, as assessed by the physician.

      3.2 HbA1c

      In the EAS, mean HbA1c at EOS was 6.7% (50 mmol/mol), and overall estimated mean change from baseline [95% CI] was –1.2 [–1.30; –1.11]%-points (–13 [–14; –12] mmol/mol) (p < 0.0001) (Fig. 1A). The estimated mean changes [95% CI] in HbA1c between baseline and EOS were –1.0 [–1.20; –0.86]%-points (–11 [–13; –9] mmol/mol) in Denmark and –1.3 [–1.39; –1.16]%-points (–14 [–15; –13] mmol/mol) in Sweden (both p < 0.0001). Sensitivity analyses supported findings from the primary analysis (Fig. 1A; Fig. S2). At EOS, 67.5% of patients had an HbA1c of <7.0% (53 mmol/mol) (Fig. 2A).
      Fig. 1
      Fig. 1Primary and sensitivity analyses for: (A) change in HbA1c from baseline to EOS; (B) change in body weight from baseline to EOS.
      *p < 0.0001 for change vs baseline. Data from the EAS. Data from the FAS. Primary analyses of change in HbA1c and primary and sensitivity analyses of change in body weight analysed using an adjusted ANCOVA model with baseline HbA1c (A only), body weight (B only), T2D duration, age, BMI, pre-initiation use of GLP-1RA (yes/no), pre-initiation use of DPP-4i (yes/no), pre-initiation use of insulin (yes/no), number of OADs use pre-initiation (0–1/2+) and sex as covariates. Sensitivity analyses of change in HbA1c used a mixed model for repeated measurements with baseline HbA1c, T2D duration, age, BMI, time and time-squared as covariates and pre-initiation use of GLP-1RA (yes/no), pre-initiation use of DPP-4i (yes/no), pre-initiation use of insulin (yes/no), number of OADs use pre-initiation (0–1/2+) and sex as fixed factors with random intercept and random coefficient for time (slope). On-treatment period represents the time period in which patients were considered treated with semaglutide. In-study period represents the time period during which patients were considered to be participating in the study, regardless of semaglutide treatment status. Mean (±SD) baseline values for HbA1c and body weight were 7.9 ± 1.3% (62.9 ± 14.2 mmol/mol) and 102.0 ± 21.2 kg, respectively, in the EAS and 7.9 ± 1.4% (62.9 ± 14.9 mmol/mol) and 101.5 ± 21.1 kg, respectively, in the FAS. Error bars represent upper and lower 95% CIs. n-Values indicate patients contributing to the analysis. ANCOVA, analysis of covariance; BMI, body mass index; CI, confidence interval; DPP-4i, dipeptidyl peptidase-4 inhibitor; EAS, effectiveness analysis set; EOS, end of study; FAS, full analysis set; GLP-1RA, glucagon-like peptide-1 receptor agonist; OAD, oral antidiabetic drug; T2D, type 2 diabetes.
      Fig. 2
      Fig. 2Proportions of patients achieving (A) HbA1c <7.0% (53 mmol/mol); (B) weight loss of ≥5%; (C) weight loss of ≥10%; and (D) composite endpoint of HbA1c reduction of ≥1.0% (11 mmol/mol) and weight loss of ≥3%.
      *Data are from the EAS. Data are from the FAS. Primary and sensitivity response at EOS reported as number and proportion of patients. n-Values represent the proportions of patients who met the target/total number of patients with a recorded value at EOS. The proportion of patients with HbA1c <7.0% (53 mmol/mol) at baseline was 18.8% in the EAS and 19.9% in the FAS. EAS, effectiveness analysis set; EOS, end of study; FAS, full analysis set.

      3.3 Body weight and waist circumference

      At EOS in the EAS, mean BW was 96.5 kg and mean WC was 111.4 cm. Overall, the estimated mean absolute change in BW [95% CI] between baseline and EOS was –5.4 [–6.0; –4.7] kg (Denmark: –4.6 [–5.8; –3.4] kg; Sweden: –5.7 [–6.4; –5.0] kg; all p < 0.0001) (Fig. 1B), representing a proportional change of –5.3% [–6.0%; –4.7%] (Denmark: –4.3% [–5.4%; –3.1%]; Sweden: –5.7% [–6.5%; –5.0%]; all p < 0.0001). At EOS, 49.4% of patients had a weight reduction ≥5% (Denmark: 42.9%; Sweden: 52.1%) (Fig. 2B) and 14.4% had a weight loss ≥10% (Denmark: 9.1%; Sweden: 16.5%) (Fig. 2C). The overall estimated mean change from baseline in WC [95% CI] was –4.7 [–5.7; –3.8] cm (Denmark: –3.0 [–4.6; –1.4] cm; Sweden: –5.5 [–6.6; –4.3] cm; all p < 0.0001).

      3.4 Composite endpoints

      Overall, 34.8% of patients in the EAS had an HbA1c reduction of ≥1%-point and a weight reduction of ≥3% (Denmark: 33.3%; Sweden: 35.4%) (Fig. 2D).

      3.5 Semaglutide dose

      At EOS, 60.6%, 31.2% and 7.1% of patients in the EAS (Denmark: 72.6%, 20.2% and 3.6%; Sweden: 55.6%, 35.9% and 8.6%) were on semaglutide doses of 1.0, 0.5 and 0.25 mg, respectively; the mean weekly semaglutide dose was 0.79 ± 0.27 mg (Denmark: 0.86 ± 0.23 mg; Sweden: 0.76 ± 0.28 mg).

      3.6 Use of antihyperglycaemic medications

      Overall, 17.4% of patients in the EAS were switched to semaglutide from another GLP-1RA at baseline. The proportions of patients taking a biguanide, basal insulin and/or SGLT-2i at baseline were 81.6%, 29.4% and 27.7%, respectively; these proportions remained similar at EOS (Table S3). The mean total insulin dose (bolus, basal or premixed) for patients treated with insulin decreased from baseline to EOS (61.6–56.9 IU; 7.6% relative reduction). In Denmark, the proportions of patients using other antihyperglycaemic medications were similar at baseline and EOS, except for a reduction in the proportion using DPP-4is. In Sweden, a lower proportion of patients were using a sulphonylurea, DPP-4i, or basal–bolus/bolus insulin at EOS vs baseline.

      3.7 Patient-reported outcomes

      In the EAS, DTSQs scores and SF-36®v2 physical and mental health-related QoL scores increased from baseline to EOS by a mean [95% CI] of 4.9 [4.4; 5.4; p < 0.0001], 1.7 [1.0; 2.4; p < 0.0001] and 0.9 [0.0; 1.9; p = 0.0489], respectively (Fig. 3A‒C). The mean DTSQc score at EOS was 14.3 [13.8; 14.9]. The mean MMAS-8 score was 7.0 at baseline and 7.5 at EOS; high adherence was reported by 47.3% of patients at baseline and 63.1% at EOS (Table 2). PRO scores were generally similar between countries.
      Fig. 3
      Fig. 3Change from baseline in: (A) DTSQs (total treatment satisfaction); (B) SF–36®v2 physical component summary; and (C) SF–36®v2 mental component summary.
      Data are from the EAS. Change from baseline to EOS analysed using adjusted analysis of covariance model with baseline score, T2D duration, age, BMI, pre-initiation use of GLP-1RA (yes/no), pre-initiation use of DPP-4i (yes/no), pre-initiation use of insulin (yes/no), number of OADs use pre-initiation (0–1/2+) and sex as covariates. DTSQs scores were measured at the informed consent and initiation visit, and the EOS visit; responses ranged from 0 (very dissatisfied) to 6 (very satisfied) for each of the 8 items of the questionnaire. The maximum total score was 36. The SF-36®v2 questionnaire has 36 questions grouped into eight domains, which can be combined into two summary component scores (overall mental and physical health); a higher SF-36®v2 score indicates lower disability. BMI, body mass index; CI, confidence interval; DPP-4i, dipeptidyl peptidase-4 inhibitor; DTSQs, Diabetes Treatment Satisfaction Questionnaire status version; EAS, effectiveness analysis set; EOS, end of study; GLP-1RA, glucagon-like peptide-1 receptor agonist; MCS, mental component summary; OAD, oral antidiabetic drug; PCS, physical component summary; SF–36®v2, 36-Item Short-Form Health Survey version 2; T2D, type 2 diabetes.
      Table 2MMAS-8 scores at baseline and EOS.
      MMAS-8 scoreBaseline (n = 275)EOS (n = 263)
      Estimated mean (SD)7.0 (1.3)7.5 (0.9)
      Level of adherence, n (%)
       High adherence (score of 8)130 (47.3)166 (63.1)
       Medium adherence (6 to <8)98 (35.6)78 (29.7)
       Low adherence (<6)47 (17.1)19 (7.2)
      MMAS-8 is an 8-item structured, self-reported medication adherence measure with scores ranging from 0 (no adherence) to 8 (high adherence) [
      • Morisky D.E.
      • Ang A.
      • Krousel-Wood M.
      • Ward H.J.
      Predictive validity of a medication adherence measure in an outpatient setting.
      ,
      • Krousel-Wood M.A.
      • Islam T.
      • Webber L.S.
      • Re R.S.
      • Morisky D.E.
      • Muntner P.
      New medication adherence scale versus pharmacy fill rates in seniors with hypertension.
      ,
      • Morisky D.E.
      • DiMatteo M.R.
      Improving the measurement of self-reported medication nonadherence: final response.
      ]. Data are from the EAS. Use of the ©MMAS is protected by US Copyright laws. Permission for use is required. A license agreement is available from Donald E. Morisky, MMAS Research LLC 14725 NE 20th St. Bellevue WA 98007 or from [email protected]. EAS, effectiveness analysis set; EOS, end of study; MMAS-8, 8-item Morisky Medication Adherence Scale; SD, standard deviation.

      3.8 Adverse events and hypoglycaemia

      Two patients (0.6%) in the FAS reported SADRs (Table S4) — one gastrointestinal haemorrhage (considered possibly semaglutide-related) and one severe hypoglycaemia episode in a patient on concomitant insulin (considered probably semaglutide-related): both had fully resolved by EOS. There were no pregnancies or adverse events in foetuses or newborn infants. One fatal event (pancreatic carcinoma; considered unlikely semaglutide-related) was reported.
      Overall, 32 AEs in 21 patients were reported in the FAS (Table S4); 25 AEs were non-serious, of which 17 were gastrointestinal and 23 were possibly or probably semaglutide-related. Nine AEs in seven patients (2.1%) led to permanent semaglutide discontinuation: one serious AE (B-cell lymphoma stage III) in one patient, considered unlikely semaglutide-related and eight non-serious AEs (seven of which were gastrointestinal) in six patients, considered possibly/probably semaglutide-related.
      Five patients (1.8%) in the EAS experienced severe (one patient) or documented (four patients) hypoglycaemia; all were in Sweden and using concomitant insulin. Following the severe hypoglycaemia episode, insulin dose was reduced by 20% and the patient completed the study on treatment. No dose adjustments were recorded in patients with documented hypoglycaemia.

      4. Discussion

      As part of the global, prospective, real-world SURE programme investigating OW semaglutide use in routine clinical practice, SURE Denmark/Sweden is one of the first studies to report findings. OW semaglutide treatment was associated with statistically significant, clinically relevant reductions in HbA1c, BW and WC, with an apparent increase from baseline in treatment satisfaction and overall health-related QoL. Also, a higher proportion of patients reported high adherence at EOS vs baseline, corresponding to an increase of nearly 16%-points (change not formally assessed).
      OW semaglutide has been extensively studied in the phase 3 SUSTAIN clinical trial programme. While the SUSTAIN trials included subjects across the continuum of care, eligibility criteria in SURE Denmark/Sweden were even less restrictive, capturing a broad spectrum of adults initiating semaglutide in real-world clinical practice. The glycaemic and weight-loss results in SURE Denmark/Sweden were consistent with those observed with semaglutide in the SUSTAIN trials (mean reduction in HbA1c: –1.1 to –1.8%-point; mean reduction in BW; –3.5 to –6.5 kg) [
      • Pratley R.E.
      • Aroda V.R.
      • Lingvay I.
      • et al.
      Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial.
      ,
      • Capehorn M.S.
      • Catarig A.M.
      • Furberg J.K.
      • et al.
      Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1-3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10).
      ,
      • Sorli C.
      • Harashima S.I.
      • Tsoukas G.M.
      • et al.
      Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial.
      ,
      • Ahmann A.J.
      • Capehorn M.
      • Charpentier G.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial.
      ,
      • Ahrén B.
      • Masmiquel L.
      • Kumar H.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial.
      ,
      • Aroda V.R.
      • Bain S.C.
      • Cariou B.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.
      ,
      • Rodbard H.W.
      • Lingvay I.
      • Reed J.
      • et al.
      Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomized, controlled trial.
      ,
      • Lingvay I.
      • Catarig A.M.
      • Frias J.P.
      • et al.
      Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial.
      ,
      • Zinman B.
      • Bhosekar V.
      • Busch R.
      • et al.
      Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo controlled trial.
      ,
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      ], supporting the use of OW semaglutide in patients with a wide range of characteristics and background medications.
      Despite differences in clinical setting, region and regulatory conditions, reductions in HbA1c and BW in SURE Denmark/Sweden largely reiterated those observed during the real-world, retrospective SPARE study in adults with T2D initiating semaglutide at a Canadian specialist endocrinology practice [
      • Brown R.E.
      • Bech P.G.
      • Aronson R.
      Semaglutide once weekly in people with type 2 diabetes: real-world analysis of the Canadian LMC diabetes registry (SPARE study).
      ]. Additionally, HbA1c and BW data followed a similar trend to those from the US-based EXPERT and Canada-based REALISE-DM studies, evaluating the real-world effect of switching GLP-1-experienced patients to semaglutide [
      • Lingvay I.
      • Kirk A.
      • Lophaven S.
      • et al.
      GLP-1–experienced patients switching to once-weekly semaglutide in a real-world setting (EXPERT study).
      ,
      • Jain A.B.
      • Kanters S.
      • Khurana R.
      • et al.
      Real-world effectiveness analysis of switching from liraglutide or dulaglutide to semaglutide in patients with type 2 diabetes mellitus: the retrospective REALISE-DM study.
      ]. Almost 20% of the SURE Denmark/Sweden study population comprised GLP-1RA-experienced patients switching to semaglutide.
      While many outcomes were similar in patients from Denmark and Sweden, several parameters differed slightly. Patients in Sweden experienced a numerically greater reduction in BW and WC than those in Denmark, with a slightly higher proportion achieving weight-loss targets. This may be partly related to population differences and a reduction in sulphonylurea and basal–bolus/bolus insulin use (both of which have been associated with weight gain) in Sweden but not in Denmark [
      • Apovian C.M.
      • Okemah J.
      • O’Neil P.M.
      Body weight considerations in the management of type 2 diabetes.
      ]. Another difference was the higher proportion of patients initially prescribed a 0.5 mg dose of OW semaglutide in Denmark vs Sweden (almost all of which were started on a 0.25 mg dose); this was despite identical protocols referring to the same semaglutide label in the two countries. This finding suggests that further exploration of dosing behaviours and their effects on semaglutide efficacy and safety may be merited in future analyses. Differing prevalences of baseline cardiovascular comorbidity and concomitant antihyperglycaemic medication use, differing practical experiences, and distinct treatment pathways and prescribing patterns adopted in the two countries may have played a role in the differences observed [
      • Dansk Endokrinologisk Selskab
      Type 2 Diabetes.
      ,
      • Knudsen S.T.
      • Bodegård J.
      • Birkeland K.I.
      • et al.
      Risk factor management of type 2 diabetic patients in primary care in the Scandinavian countries between 2003 and 2015.
      ,
      • Region Stockholm
      KLOKA LISTAN 2020: Expertgruppen för Endokrina sjukdomar.
      ]. For example, GLP-1RAs are typically introduced earlier in the treatment cascade in Denmark vs Sweden; this may result in frequent prescription of semaglutide in patients with less severe T2D and fewer additional risk factors in Denmark but similar prescription frequencies in patients with more progressed T2D in the two countries. In this context, it may be unsurprising that patients in Sweden were more frequently on medications associated with hypoglycaemia, such as sulphonylureas and insulins [
      • Chaudhury A.
      • Duvoor C.
      • Reddy Dendi V.S.
      • et al.
      Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management.
      ], and that hypoglycaemia was more common in Sweden, both before and after semaglutide initiation. Indeed, hypoglycaemia rates were low in SURE DK/SE, with all five patients that experienced hypoglycaemia on concomitant insulin. When initiating semaglutide, it is recommended to consider lowering the dose of any concomitant secretagogues or insulin to reduce the risk of hypoglycaemia [
      • Novo Nordisk
      OZEMPIC® Highlights of Prescribing Information.
      ].
      There are limitations related to the observational nature of this study. For example, data were not collected through mandatory assessments at prespecified timepoints, which may affect data robustness and completeness. Furthermore, the study was single-arm and nonrandomised, so the effects of uncontrolled factors such as changes in lifestyle, concomitant medication, and regression to the mean cannot be separated from the effects of semaglutide. A strength of the study was the broad eligibility criteria, allowing a more representative, real-world patient population, though care should be taken when comparing SURE results to those from studies with different populations.

      5. Conclusion

      In SURE Denmark/Sweden, OW semaglutide was associated with glycaemic and weight-loss benefits in a wide range of adults with T2D across specialist and GP settings. Semaglutide was well tolerated in real-world clinical practice, with low rates of discontinuation and no new safety concerns arising from the reported AEs. Despite minor country-specific differences, semaglutide responses in Denmark and Sweden largely reflected findings from previous randomised controlled trials, supporting the use of OW semaglutide in routine clinical practice. Future RWE from other countries, regions and healthcare service models will provide additional information regarding the clinical use of semaglutide.

      Data availability

      The data sets analysed during the current study are available on reasonable request.

      Funding source

      This work was funded by Novo Nordisk A/S.

      Declaration of interest

      NRE reports payment for lecturing and reimbursement for participation in scientific advisory boards from Novo Nordisk (paid to her employer), outside the submitted work. UB reports personal fees for participation in a scientific advisory board from Novo Nordisk, outside the submitted work. AMC, KG and CNH are employees of Novo Nordisk and own stock in the company. SBC reports personal fees paid to his institution for national coordination of SURE Denmark/Sweden. STK reports grants from AstraZeneca and personal fees for lectures and/or consultancy from Boehringer Ingelheim, MSD, Novo Nordisk, Mundipharma and Sanofi, outside of the submitted work. BK has nothing to disclose.

      Acknowledgements

      We thank all the participants, investigators, and trial-site staff, as well as Umut Erhan, Michael Lyng Wolden, Jens Christian Øllgaard, and Trine Stougaard from Novo Nordisk for their review and input to the manuscript, and Helen Sims (AXON Communications) for medical writing and editorial assistance (funded by Novo Nordisk A/S). Use of the ©MMAS is protected by US Copyright laws. Permission for use is required. A license agreement is available from Donald E. Morisky, MMAS Research LLC 14725 NE 20th St. Bellevue WA 98007 or from [email protected].

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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