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Clinical Review Report: Semaglutide (Ozempic): (Novo Nordisk Canada Inc.): Indication: For the treatment of adult patients with type 2 diabetes mellitus to improve glycemic control, in combination with metformin (second-line treatment), and in combination with metformin and sulfonylurea (third-line treatment) [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Jun.

Cover of Clinical Review Report: Semaglutide (Ozempic)

Clinical Review Report: Semaglutide (Ozempic): (Novo Nordisk Canada Inc.): Indication: For the treatment of adult patients with type 2 diabetes mellitus to improve glycemic control, in combination with metformin (second-line treatment), and in combination with metformin and sulfonylurea (third-line treatment) [Internet].

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Results

Findings from the Literature

A total of eight studies were identified from the literature for inclusion in the systematic review (Figure 1). An overview of the included RCTs is provided in Table 5. Details of these trials are presented in Table 6 and Table 7. A list of excluded studies is presented in Appendix 3.

Figure 1. Flow Diagram for Inclusion and Exclusion of Studies.

Figure 1

Flow Diagram for Inclusion and Exclusion of Studies.

Table 5. Overview of Included Clinical Trials.

Table 5

Overview of Included Clinical Trials.

Table 6. Details of Included Studies (Placebo-Controlled RCTs).

Table 6

Details of Included Studies (Placebo-Controlled RCTs).

Table 7. Details of Included Studies (Active-Controlled RCTs).

Table 7

Details of Included Studies (Active-Controlled RCTs).

Included Studies

Description of Studies

A total of eight phase III RCTs met the inclusion criteria (SUSTAIN-1 to 7 and the Seino study).7–14

These trials evaluated the efficacy and safety of SEM 0.5 mg or 1 mg once weekly (alone or in combination with oral antidiabetic drug [OAD] such as MET or MET plus an SU, or insulin), compared with placebo or active comparators in adults with T2DM and inadequate glycemic control with background therapy. All three placebo-controlled trials (SUSTAIN-1, 5, and 6)7–9 and one active-controlled trial (SUSTAIN-2)10 included a randomized double-blind treatment period, and all other active-controlled trials had an open-label design (SUSTAIN-3, 4, 7, and the Seino study).11–14 In all trials, the patients who met the inclusion criteria and were assigned to the treatment with either dose of SEM underwent a dose escalation period. Randomization was conducted using an interactive voice or interactive Web response system (IV/WRS). Patients were stratified based on their background therapy (SUSTAIN-4, 5, and 6), baseline A1C level (SUSTAIN-5), their extent of cardiovascular (CV) disease (SUSTAIN-6) or renal function (SUSTAIN-6) in some trials (Table 5). There was no stratification for randomization in other trials. The primary objective of the included trials was to compare the effect of SEM once weekly treatment with the comparators on change in A1C from baseline, except for SUSTAIN-6 and the Seino study. “Time from randomization to first occurrence of major adverse cardiovascular event (MACE)” was the primary outcome in SUSTAIN-6. The occurrence of treatment-emergent adverse event (TEAE) was the primary outcome in the Seino study. The occurrence of diabetes-related comorbidities (macrovascular and microvascular) was also measured in the only cardiovascular outcomes trial (CVOT) SUSTAIN-6. Change in body weight, body mass index (BMI), blood pressure, and blood lipid profile were evaluated in all trials. Health-related quality of life (HRQoL) was evaluated in all trials but SUSTAIN-1 and the Seino study. Non-inferiority (NI) of treatment with SEM versus active comparators (SUSTAIN-2, 3, 4, and 7) on glycemic control was assessed in four SUSTAIN trials. NI of treatment with SEM compared with placebo on increase in CV events was assessed in patients who had prior or concomitant CV conditions in SUSTAIN-6. SUSTAIN-1 and 5 and the Seino study evaluated the superiority of two dose levels (0.5 mg and 1.0 mg) of SEM versus placebo on glycemic control or safety in patients with T2DM.

All the trials had a 2-week screening period. In the Seino study, patients were required to undergo an 8-week washout period if they received pre-trial OAD monotherapy. Patients on stable doses of background therapies who met the inclusion criteria were randomly assigned to treatment with SEM or the comparators. The treatment duration varied from 30 to 56 weeks in the majority of the trials, while the study participants in SUSTAIN-6 received 104 weeks of treatment with the study drugs. Patients had a 5-week follow-up period after the last dose of the study drug.

For all trials, an independent external Event Adjudication Committee (EAC) was established to perform ongoing adjudication, standardization, and assessment of selected outcomes, such as CV death, pancreatitis, and neoplasms, according to pre-defined diagnostic criteria. The purpose of the adjudication was to confirm events in a consistent manner according to standardized criteria using independent external medical experts.

Details of the trial characteristics are presented in Table 6 and Table 7.

Populations

Inclusion and Exclusion Criteria

Patients enrolled in the SUSTAIN trials were adults (greater than and equal to 18 years of age) with T2DM, while patients enrolled from Japan (Seino study) were greater than and equal to 20 years of age. They were required to have inadequate glycemic control with previous antihyperglycemic treatments, such as diet or exercise, or stable diabetes drug treatment (e.g., MET, SU, TZD, or insulin). Stable diabetes treatment was defined as “unchanged medication and unchanged dose” in SUSTAIN-2, 3, 4, and “+/− 20% change in total daily dose with basal insulin alone or in combination with metformin” in SUSTAIN-5. In the Seino study, stable OAD monotherapy was defined as “receiving half-maximum or below dose according to Japanese labelling for 30 days prior to screening.” Each trial had specific inclusion criteria related to A1C levels and background medications at screening (Table 6 and Table 7). The required A1C levels at baseline ranged from 7% to 10% in the majority of the trials. MET monotherapy or combination of MET plus SU or MET plus insulin were common background medications in the included trials. In SUSTAIN-1, all study participants were drug naive at baseline. Some patients in SUSTAIN-6 (1.6%) and the Seino study (70%) did not receive prior antihyperglycemic treatment (Table 5).

Eligible patients in SUSTAIN-6 were required to have clinical or subclinical evidence of CV disease, defined as meeting at least one of the following criteria presented in the table below.

Clinical Evidence of CV DiseaseSubclinical Evidence of CV Disease
  • Persistent microalbuminuria (30 mg/g to 299 mg/g) or proteinuria
  • Prior stroke or TIA
  • Hypertension and left ventricular hypertrophy by ECG or imaging
  • Prior coronary, carotid, or peripheral arterial revascularization
  • Left ventricular systolic or diastolic dysfunction by imaging
  • > 50% stenosis on angiography or imaging of coronary, carotid, or lower extremity arteries
  • Ankle/brachial index < 0.9
  • History of symptomatic coronary heart disease documented by e.g., positive exercise stress test or any cardiac imaging, or unstable angina with ECG changes
  • Asymptomatic cardiac ischemia documented by positive nuclear imaging test or exercise test or stress echocardiogram or any cardiac imaging
  • Chronic heart failure (NYHA class II to III)
  • Chronic renal impairment, documented (prior to screening) by eGFR < 60 mL/min/1.73m2

CV = cardiovascular; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; MI = myocardial infarction; NYHA = New York Heart Association; TIA = transient ischemic attack.

Exclusion criteria were similar across trials and those with recent cardiovascular events or heart failure (NYHA class IV), history of acute or chronic pancreatitis, impaired renal function, or any chronic disorder or severe disease that might jeopardize patient’s safety or compliance with the protocol, were not eligible for enrolment. In SUSTAIN-4 and SUSTAIN-5, patients were excluded if they experienced more than three episodes of severe hypoglycemia within six months prior to screening, or if they experienced hypoglycemia unawareness (Table 6 and Table 7).

Baseline Characteristics

The proportion of patients who were male ranged from 43% to 79% per treatment group and the mean age per treatment group was from 53 years to 65 years (Table 8, Table 9, and Table 10). In the SUSTAIN trials, the patients enrolled were predominantly white (61% to 84%) with a mean BMI per group ranging from 32 kg/m2 to 34 kg/m2, and with body weight ranging from 89 kg to 97 kg. The patient’s baseline characteristics in the Japanese study (Seino) differed from the SUSTAIN trials, in that the average BMI was 25 kg/m2 to 26 kg/m2 and the average body weight was 68 kg to 71 kg. The baseline A1C in all trials ranged from 8.0% to 8.7%. The mean duration of diabetes varied across trials and was lowest for SUSTAIN-1 (6.4 years to 6.7 years), and highest for SUSTAIN-6 (13.2 years to 14.3 years). The mean eGFR at baseline was above 90 mL/min/1.73 m2 for all trials except for SUSTAIN-6, where the average eGFR ranged from 75.6 mL/min/1.73 m2 to 77.2 mL/min/1.73 m2.

Table 8. Summary of Baseline Characteristics (Placebo-Controlled RCTs; FAS).

Table 8

Summary of Baseline Characteristics (Placebo-Controlled RCTs; FAS).

Table 9. Summary of Baseline Characteristics (Active-Controlled RCTs; FAS).

Table 9

Summary of Baseline Characteristics (Active-Controlled RCTs; FAS).

Table 10. Summary of Baseline Characteristics (Cv Outcome RCT).

Table 10

Summary of Baseline Characteristics (Cv Outcome RCT).

Baseline characteristics were generally similar between groups within trials although some differences in the average body weight were noted in SUSTAIN-1, as well as differences in the duration of diabetes in SUSTAIN-1 and SUSTAIN-4.

Compared with other trials, patients in SUSTAIN-6 were older, had longer history of diabetes, and poorer renal function. Among the patients enrolled in the trial, approximately 60% had ischemic heart disease, more than 40% had prior arterial revascularization, more than 30% had prior myocardial infarction or >50% artery stenosis, and more than 90% had hypertension. Neuropathy (41%) and nephropathy (44%) were common microvascular comorbidities in the study population. In SUSTAIN-6, the most commonly used antidiabetic medication at baseline was MET (approximately 73%) followed by insulin treatment (58% of patients were treated with basal insulin or pre-mix insulin; 42% were insulin-naive at baseline) and SUs (42.8%: 26.8% without insulin and 15.9% in combination with insulin). Less than 2% of patients did not use any diabetes medication at baseline (Table 10).

Interventions

All placebo-controlled trials and one active-controlled trial (SUSTAIN-2) had double-blind design. The manufacturer, investigators, and patients were blinded to treatment allocation. SUSTAIN-3, 4, 7, and the Seino study were open-label RCTs.

The treatment period included a dose escalation period followed by a maintenance period. SEM was initiated at 0.25 mg subcutaneously once weekly. The maintenance dose of SEM 0.5 mg subcutaneously once weekly was started after four doses (4 weeks) of 0.25 mg. The maintenance dose of SEM 1.0 mg subcutaneously once weekly was started after four doses (4 weeks) of 0.25 mg, followed by four doses (four weeks) of 0.5 mg. In SUSTAIN-1, 2, 5, and 6, SEM placebo was administered using the same strategy as SEM. After the maintenance dose was reached, the dose was not to be changed during the remainder of the trial. If the maintenance dose was not tolerated, treatment could be discontinued and in such cases, treatment was not re-initiated, except in cases where suspicion of acute pancreatitis led to discontinuation of treatment, but later acute pancreatitis was ruled out.

In SUSTAIN-1 to 5 and SUSTAIN-7, rescue medications were offered to patients with unacceptable hyperglycemia during the treatment with study drugs. Unacceptable hyperglycemia was determined when any of the fasting plasma glucose (FPG) levels measured at scheduled visits and a confirmatory FPG obtained by the local or central laboratory exceeded the following limits and no inter-current cause of the hyperglycemia could be identified:

  • 15 mmol/L from baseline to week 6 (or to week 7 in SUSTAIN-7)
  • 13.3 mmol/L from week 6 to week 12 (or from week 8 to week 13 in SUSTAIN-7)
  • 11.1 mmol/L from week 12 (or from week 14 in SUSTAIN-7) to end-of-trial

Rescue medication referred to intensification of the existing background medication or initiation of new medication, and it was prescribed as add-on to randomized treatment. In SUSTAIN-1, MET was the first choice of rescue medication unless contraindicated. In SUSTAIN-5, increasing the basal insulin dose was the first choice. In these six trials, GLP receptor agonists, DPP-4 inhibitors, and pramlintide or amylin analogues were not allowed or preferred not to be used as rescue medications. There was no description on the use of rescue medication in the study populations in SUSTAIN-6 and the Seino study.

In SUSTAIN-6, approximately 58% of the patients received concomitant insulin therapy. If their A1C was > 8% at screening, reductions in insulin doses were allowed in case of increased episodes of hypoglycemia. Patients treated with insulin and who had A1C ≤ 8.0% at screening were to have the insulin dose reduced by 20% at start of study drug to limit the potential risk of episodes of hypoglycemia induced by the combined therapy of insulin and SEM.

Outcomes

Glycemic Control

Change from baseline to end of study (week 30 to week 56 across studies) in A1C was a primary outcome in all included trials, except for SUSTAIN-6 and the Seino study. In SUSTAIN-6 and the Seino study, change from baseline to week 30 in A1C was a secondary end point. Note that in SUSTAIN-6, change in A1C was assessed at week 30, instead of end of study.

Mortality (all-cause, cardiovascular related)

This outcome was assessed in all included trials, and the cases of death required to be confirmed by EAC.

Diabetes-Related Morbidity and Mortality

This outcome was assessed in the only CVOT (SUSTAIN-6). In this trial, the primary end point was time from randomization to the first EAC-confirmed MACE, defined as CV death, non-fatal MI, or non-fatal stroke. In addition, the secondary end points in SUSTAIN-6 included:

  1. Time from randomization to first occurrence of an expanded composite CV outcome (defined as either EAC-confirmed MACE, revascularization (coronary and peripheral), unstable angina requiring hospitalization or hospitalization for heart failure);
  2. Time from randomization to each individual component of the expanded composite CV outcome;
  3. Time from randomization to first occurrence of all-cause death, non-fatal MI, or non-fatal stroke.

All of the above outcomes except peripheral revascularization were EAC-confirmed.

Hospitalization (All-cause, Cardiovascular Related)

This outcome was not measured in any of the included trials.

Health-Related Quality of Life

Patient’s HRQoL was evaluated using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) or Short Form (36) Health Survey (SF-36). The DTSQ was used to assess patient satisfaction with treatment (six items) and perception of change in hyperglycemia and hypoglycemia (2 items).37 The DTSQ has two versions that have eight items each: the DTSQ original status version (DTSQs) and the DTSQ change version (DTSQc). Six of the eight items measure treatment satisfaction (satisfaction with current treatment, convenience, flexibility, satisfaction with own understanding of diabetes, and likelihood of continuing on or recommending current treatment). The item scores range from “very satisfied” (score of 6) to “very unsatisfied” (score of 0), and the sum of these items is taken to generate a DTSQs score, ranging from 0 to 36. Higher DTSQs scores indicate greater satisfaction with treatment. For the two items measuring perceived frequency of hyperglycemia and frequency of hypoglycemia, the items are scored on 7‐point response scales ranging from “most of the time” (score of 6) to “none of the time” (score of 0). Lower DTSQs scores indicate more ideal blood glucose levels in this case. No minimal clinically important difference (MCID) was identified for the change in DTSQs scores. The psychometric properties of different language versions of the DTSQs were assessed in a study of type 1 and type 2 diabetes patients treated with insulin or poorly controlled on SUs who then started on insulin treatment. The DTSQs was shown to be consistently reliable in all languages studied and significantly sensitive to change in type 1 diabetes patients at weeks 8, 20, 24, and at last available visit.38 However, it has also been observed that because patients tend to report satisfaction with current treatment in the absence of experience with alternatives for comparison, the DTSQs often exhibits a ceiling effect.37 Change in DTSQs from baseline to end of study was measured in SUSTAIN-2, 3, 4, 5, and 7.

The SF-36 is a 36-item, generic health status instrument that has been used extensively in clinical trials in many disease areas.39 It consists of eight health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The eight domains are aggregated to create two component summaries: the physical component summary (PCS) and the mental component summary (MCS), with scores ranging from zero to 100 with higher scores indicating better health status. However, previous research suggested a lack of improvement in SF-36 scores (deteriorated or remained stable) following interventions demonstrating modest improvement in A1C levels, blood lipid, and blood pressure in patients with T2DM.40 The MCID for either the PCS or MCS of the SF-36 for the change from baseline is typically between 2.5 and 5 points. SF-36 was measured in SUSTAIN-2 to SUSTAIN-7.

Blood Pressure

Change from baseline to end of study in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were secondary efficacy end points in all included trials. In SUSTAIN-1 to SUSTAIN-7, it was indicated that measurements were taken in a sitting position, after the patient had been sitting for at least five minutes.

BMI and Body Weight

Change from baseline to end of study in body weight and BMI were secondary efficacy end points in all included trials.

Lipid Profile

Fasting blood lipids (e.g., total cholesterol, HDL cholesterol, and LDL cholesterol) was a secondary efficacy end point in all included trials.

Safety

An adverse event (AE) was defined as any untoward medical occurrence in a patient administered a pharmaceutical product and that does not necessarily have a causal relationship with his treatment. It can be any unfavourable and unintended sign, symptom, or disease, or any worsening of a pre-existing condition temporally associated with the use of a product, whether or not considered related to the product. A TEAE was defined as an event with onset that occurs on or after the first day of study medication administration and no later than the follow-up visit.

A serious adverse event (SAE) was defined as an event that resulted in death, was life threatening, resulted in hospitalization or prolongation of existing hospitalization, persistent or significant disability, was a congenital anomaly or birth defect, or other important medical events.

In addition, AEs leading to premature treatment discontinuation was measured in the included trials. Safety areas of special interest, such as gastrointestinal (GI) disorders, severe hypoglycemia, pancreatitis, or injection site reaction were explored, based on the known and potential risks of GLP-1 receptor agonists, experience from using GLP-1 receptor agonists in patients with T2DM and in weight management, and regulatory requirements for the development of treatments for T2DM. Hypoglycemic episodes were classified according to the Novo Nordisk classification of hypoglycemia and the American Diabetes Association (ADA) classification of hypoglycemia. According to the ADA classification, severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal was considered sufficient evidence that the event was induced by a low plasma glucose concentration.41 Novo Nordisk definition of severe or blood glucose (BG)-confirmed symptomatic hypoglycemia referred to an episode that was severe according to the ADA classification or BG-confirmed by a plasma glucose value less than 3.1 mmol/L with symptoms consistent with hypoglycemia.

In the Seino study, TEAE was the primary outcome measure.

Statistical Analysis

No interim analyses were planned or performed for any of the included trials.

Three observation periods were described in data analyses in SUSTAIN-1 to 7 (no information was provided with respected to the observation periods used in the Seino study).

  • “On-treatment without rescue medication” period was the primary observation period when selecting data related to efficacy (a subset of the ‘on-treatment’ observation period. It included observations recorded at, or after the date of first dose of study medication and not after the first occurrence of the following: the end date of the ‘on-treatment’ observation period, or initiation of rescue medication);
  • “On-treatment” period was primary observation period when selecting data related to safety evaluation (a subset of the ‘in-trial’ observation period, namely the portion where the patient was considered to be exposed to study medication);
  • “In-trial” period was used for supportive analyses of both efficacy and safety considered supportive (included observations recorded at, or after randomization, and not after the last patient-investigator contact [phone or on-site visit], which was scheduled to take place five weeks after the planned last dose of study medication at the follow-up visit, or the death of the patient during the trial, whichever occurred first).

In SUSTAIN-6, only two observation periods were used: the “in-trial” observation period, and “on-treatment” observation period (a subset of the in-trial observation period, which represents the time period where patients were considered exposed to study medication).

In all trials but SUSTAIN-6, the primary statistical analysis for the primary efficacy outcome (e.g., A1C) was based on full analysis set (FAS), using data from “on-treatment without rescue medication” observation period. A Mixed Model for Repeated Measurements (MMRM) approach was adopted where treatment and country were included as fixed factors and baseline A1C as a covariate. The model assumed that data were missing at random (MAR). The change from baseline in body weight, BMI, blood pressure, and blood lipids were analyzed using similar methods across all trials. In SUSTAIN-6, the continuous efficacy data such as A1C, body weight, BMI, blood pressure and blood lipids were analyzed using data from the “in-trial” observation period. In SUSTAIN-6, the primary objective was to confirm that SEM treatment did not excessively increase the CV risk as compared with placebo. The primary outcome (time to first EAC-confirmed MACE) was evaluated using a stratified Cox hazards model with treatment group as fixed factor (Table 11). The model was stratified by all possible combinations of the three stratification factors used in the randomization procedure (in total nine levels). From this model the hazard ratio (HR) (SEM/placebo) together with the 2-sided 95% CI were estimated. The non-inferiority (NI) in increased CV risk between SEM and placebo was concluded if the upper bound of the two-sided 95% CI of the for SEM versus placebo was less than 1.8 for time to first occurrence of MACE, in accordance with the FDA guidance on the development of a new antidiabetic therapy to treat T2DM.42

Table 11. Summary of Statistical Testing Methods.

Table 11

Summary of Statistical Testing Methods.

Missing data were imputed with various approaches, such as the last observation carried forward (LOCF) method, or with the MMRM model or ANCOVA model. Methods of missing data handling are listed in Table 11.

Sensitivity analyses were conducted for the primary and the confirmatory secondary end point (body weight in the SUSTAIN trials) to assess the impact of missing data. Various approaches were used, such as per-protocol (PP) analysis, complete case analysis, LOCF-based analysis, the comparator-based imputation analysis, and MMRM-based “in-trial” analysis. Details are provided in Table 11.

All trials except the Seino study used a pre-specified ordered testing procedure to control for inflated type I1 error rates. To advance to the next test (i.e., from test 1 to test 2, from test 2 to test 3, etc.), the preceding test criterion must be met (i.e., the corresponding null hypothesis must be rejected). If the corresponding null hypothesis was not rejected, the testing was to stop, and no further conclusions could be drawn. Details on the statistical testing procedure and power estimates are listed in Table 12.

Table 12. Statistical Testing Hierarchy and Power Estimates.

Table 12

Statistical Testing Hierarchy and Power Estimates.

Subgroup analyses were performed in some SUSTAIN trials to examine the consistency of the primary analysis results across subgroup levels. In SUSTAIN-5, subgroup analysis based on renal function was explored. In SUSTAIN-6, the subgroups of interest of this review included baseline A1C levels, BMI, and renal function. In SUSTAIN-2 to 4, post hoc subgroup analyses were carried out based on background antidiabetic therapy; in addition, interaction between treatment and background OAD therapy was examined in these posts hoc subgroup analyses.

Table 13. Patient Disposition (Placebo-Controlled RCTs).

Table 13

Patient Disposition (Placebo-Controlled RCTs).

Table 14. Glycemic Control Outcomes (SEM as Second-Line Therapy, Add-On to MET Only).

Table 14

Glycemic Control Outcomes (SEM as Second-Line Therapy, Add-On to MET Only).

Table 15. Patient Disposition (CV Outcome RCT).

Table 15

Patient Disposition (CV Outcome RCT).

Exposure to Study Treatments

The mean duration of study treatment ranged from 189 days to 208 days in trials with 30 weeks of treatment; from 249 days to 268 days in trials with 40 weeks of treatment; and from 335 days to 373 days in trials with 56 weeks of treatment. For the two-year CVOT SUSTAIN-6, the mean in-trial observation period was 2.1 years, while the on-treatment observation period was 1.8 years in all three treatment arms (Table 16 and Table 17).

Table 16. Exposure (Placebo-Controlled RCTs).

Table 16

Exposure (Placebo-Controlled RCTs).

Table 17. Exposure (Active-Controlled RCTs; SAS).

Table 17

Exposure (Active-Controlled RCTs; SAS).

Critical Appraisal

Internal Validity

In the included studies, randomization was conducted using a validated system. In some trials differences in characteristics were noted which may have occurred by chance or may be reflective of issues with the randomization implementation itself. For example in SUSTAIN-1, patients treated with higher dose SEM had shorter duration of the disease (mean of 3.65 years in the SEM 1 mg group compared with 4.85 years in the SEM 0.5 mg group). This implies that patients in higher dose group were more likely to achieve treatment goals, because they did not have as long-standing diabetes as those in the lower dose group, therefore the treatment effect of SEM 1 mg could be overestimated.

For trials using a double-blind design, appropriate methods were used to ensure allocation concealment. However, it is possible that patients and investigators could review and discuss changes in the A1C levels, body weight, and AEs, particularly some specific drug effects which are known to be associated with the administration of GLP-1 receptor agonists, such as gastrointestinal AEs. This may have allowed certain patients and/or investigators to surmise the assigned treatment, and subsequently may have an impact on patient-reported outcomes or AEs. For trials with open-label design, patients were aware of the treatment allocation, therefore the evaluation of patient-reported outcomes or AEs may also be affected by unblinded treatment regimen. The primary outcome variable in the majority of the included trials was change in A1C, which is an objective outcome measure. Even though it is unlikely that this had an important impact on the study results for the primary analysis, the clinicians could easily determine the A1C levels and may have adjusted medications or initiated rescue medications accordingly, thus the secondary end points and sensitivity analyses could have been affected.

In terms of the methods of statistical analysis, efficacy analyses were performed in FAS. Although a true ITT population was not used (patients were required to receive at least one dose of the study drug) in all trials except for SUSTAIN-6, it is less likely that this would have an impact on the study results due to the small number of patients that were excluded from FAS. For NI trial, acceptable margins (0.5% change in A1C in placebo-controlled trial, or 0.3% change in A1C in active-controlled trial) were used.

A hierarchical testing procedure was used to account for multiple comparisons among primary end point and the key secondary end points. Various approaches (e.g., model-based imputation and LOCF) were used to handle missing data in the included studies. The hierarchical sequence in the included studies was pre-specified and included clinically outcomes that were commonly accepted in diabetes trials. Outcomes outside of the testing hierarchy, such as occurrence of diabetes-related morbidity (e.g., individual component of MACE or expanded composite CV outcome), change in blood pressure, and HRQoL, need to be interpreted with caution due to the possible inflated type I error. Moreover, it is unclear how to interpret the diabetes-related morbidity end points as determination of the NI margin for these individual component analyses were not specified in the study protocol. Some important outcomes in diabetes trials were not included in the testing hierarchy, such as hypoglycemia.

The proportion of missing data were substantial (greater than 20%) and differential between SEM and the controls in most of the trials. MMRM was used in primary efficacy analysis, and it assumes that data are MAR. However, missing data can be associated with treatment discontinuation due to lack of efficacy (e.g., poor glycemic control) or intolerable adverse effects from the treatment, it would not be considered MAR, and may potentially impact the results of the trials in favour of SEM. In addition, due to the repeated measures design of MMRM, the potential impact of missing data during scheduled time points on the overall study results which were measured at the end of follow-up is uncertain and could have affected the study results. In the SUSTAIN trials, sensitivity analyses were conducted to assess the validity of MAR assumption and to evaluate the robustness of the conclusion of the primary analysis. Although these analyses showed similar results as the primary data analysis, these analyses cannot fully account for the impact of missing data. In a chronic progressive disease like diabetes where patients continue to lose glycemic control over time, the LOCF can introduce bias as it assumes patients remain stable for all subsequent time points which is rarely the case in the real world. Thus, although the trials outlined appropriately the various approaches of missing data handling, none are sufficient to overcome the missing data and may have introduced bias into the results.

The majority of the included trials evaluated the change from baseline in A1C as the primary outcome and were not designed to test for longer-term diabetes-related morbidity or mortality. There is one single cardiovascular safety trial (SUSTAIN-6) included in this review, and this two-year trial may address some of the questions of interest in clinical practice.

None of the included trials were powered to assess efficacy outcomes such as change in blood pressure or blood lipids, or for harm outcomes such as hypoglycemia.

In the SUSTAIN trials, a number of pre-defined subgroup analyses based on various patient’s baseline characteristics were conducted to examine the consistency of the primary analysis results across subgroup levels; however most of these, such as the subgroups based on renal function in SUSTAIN-5 or subgroups based on A1C level at baseline in SUSTAIN-6, were not included as a stratification variable at randomization. Thus, balance of patient’s baseline characteristics was unlikely to be maintained between such subgroups, and this could subsequently bias the results. In SUSTAIN-2, 3, and 4, subgroup analyses based on prior antidiabetic therapy were performed to explore treatment effect of the study drug in special subgroups. However, these were post hoc analyses and were exploratory in nature, therefore it is challenging in data interpretation due to insufficient power to detect a true difference between treatment groups, imbalance of patient’s baseline characteristics across the subgroups, complexity of testing interaction effect (P-values less than 0.05 for some of the interaction tests), or the inconsistency between statistical significance and clinical importance. Wider 95% CIs for the point estimate of between-group differences in efficacy outcomes were observed in several of these subgroups, which may be expected given the lack of power within the subgroup analyses. In addition, multiplicity and potential inflated type I error are concerns within the subgroups. As a result, the interpretation of subgroup analyses with respect to various outcomes is difficult. Moreover, in these NI trials, it is unclear how the specific subgroups effects should have been interpreted with respect to the NI margins which were defined for the overall population, or whether subgroup-specific margins should have been employed. Similarly, in SUSTAIN-6, it is questionable to interpret the results of individual component based on the NI margin used for the composite outcome, as the margin for individual component may not be the same as the composite outcome. In this trial, the observed CV benefits appeared to be mainly driven by non-fatal MI and non-fatal stroke, while the rate of CV death was similar between SEM and placebo. There is also a concern with multiplicity of testing in SUSTAIN-6.

Patients in SUSTAIN-2, 3, and 4 had various background antidiabetic therapies before entering the trials. Therefore, SEM was used as second-line or third-line therapy. Given that patients who are controlled on two prior OADs represent a more advanced diabetes population (longer history of disease, more comorbidities or diabetes-related complications, inadequate response to previous treatment, etc.) than those controlled on one OAD, it is questionable to mix these patients in one analysis. This also affects the generalizability of the study findings.

For most of the trials (e.g., SUSTAIN-2, 3, 4, and 6), safety outcomes were reported in the full population where semaglutide can be used as first-line, second-line or third-line therapy, and subgroup data were not available. It is difficult to examine the safety outcome according to patient’s prior background antidiabetic therapy.

In general, diet and exercise are a part of the standard care of patients with T2DM. In SUSTAIN-2 to 7, it was unknown whether “diet and exercise” was background therapy. Therefore, there could be validity issues related to this and likely decreases generalizability of the study results.

External Validity

SEM was not used as a first-line therapy in the vast majority of the included trials. SUSTAIN-1 recruited patients who were drug naive, therefore did not provide evidence to support the manufacturer’s requested reimbursement criteria of “for the treatment of adult patients with T2DM to improve glycemic control, in combination with MET (second-line treatment) and in combination with MET + SU (third-line treatment)”. All included trials except for the Japanese study were multinational. Although few Canadian patients were enrolled, the consulted clinical expert indicates that the study results are generalizable to Canadian population, according to the selection criteria and the patient’s baseline characteristics including diabetes-related characteristics.

The treatment duration of the included trials (ranging from 30 weeks to 56 weeks) was considered adequate in terms of assessing efficacy of semaglutide treatment versus comparators on change in A1C, the safety, tolerability, and patient satisfaction, but may not be sufficient for assessment of sustainability of A1C change or CV outcomes. The CVOT (SUSTAIN-6) had a treatment duration of 104 weeks; therefore, it would be able to provide some evidence on longer-term effect of the study drug.

The included trials provide direct evidence for the comparisons between semaglutide and other GLP-1 receptor agonists, DPP-4 inhibitors, or insulin glargine. There is a lack of direct evidence on the comparisons between semaglutide and other currently available active treatment, such as SGLT2 inhibitors.

Efficacy

Only those efficacy outcomes identified in the review protocol (Table 4) are reported below. Data are presented based on the lines of therapy (first-line, second-line and third-line) for SEM, refer to the table “Efficacy Outcomes Presented in the Current CDR Review” below. Additional efficacy data with respect to glycemic control and change in body weight and BMI in the overall population (lines of therapy were mixed in the study population) for SUSTAIN-2 to 4 are presented in Appendix 4. Limited data were available on HRQoL. None of the trials evaluated hospitalizations.

Results show that none of the hierarchy tests for NI hypothesis and superiority hypotheses failed.

Glycemic Control

SEM Used as First-Line Therapy

SUSTAIN-1 reported change in A1C from baseline to week 30 in drug-naive patients. At week 30, the mean change in A1C was −1.45% (SE 0.10), −1.55% (SE 0.10) and −0.02% (SE 0.10) for patients who received SEM 0.5 mg, SEM 1 mg, and placebo, respectively. The mean differences were statistically significant for both SEM groups compared with placebo (SEM 0.5 mg: −1.43%; 95% CI −1.71% to −1.15%; SEM 1 mg: −1.53%, 95% CI −1.81% to −1.25 %) (Table 18). Because the upper limit of the 2-sided 95% CI for the estimated differences was below 0%, superiority of SEM 0.5 mg or SEM 1 mg versus placebo in glycemic control was demonstrated. The between-group differences were considered clinically important.

Table 18. Efficacy Outcomes Presented in the Current CDR Review.

Table 18

Efficacy Outcomes Presented in the Current CDR Review.

SEM Used As Second-Line Therapy (Add-On to MET)

Results of post hoc subgroup analyses on glycemic control in SUSTAIN-2, SUSTAIN-3, and SUSTAIN-4 are presented. Patients in SUSTAIN-7 received treatment with SEM or DUL with background therapy of MET monotherapy.

In patients receiving SEM as the second-line therapy (add-on to MET), treatment with either dose of SEM for 30 to 56 weeks was associated with greater glycemic control, compared with SIT, EXE, or IG (Table 19). The mean change from baseline in A1C ranged from ▬ for the SEM 0.5 mg group, and from ▬ for the SEM 1 mg group. Compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with DUL, the mean between-group differences were −0.40% (95% CI −0.55 to −0.25) for the SEM 0.5 mg group and −0.41% (95% CI −0.57 to −0.25) for the SEM 1 mg group. In SUSTAIN-7, superiority in reducing A1C was concluded for each dose of SEM compared with the respective dose level of DUL.

Table 19. Glycemic Control Outcomes (SEM as First-Line Therapy).

Table 19

Glycemic Control Outcomes (SEM as First-Line Therapy).

According to the clinical expert consulted for this review, the between-group differences in A1C were considered clinically relevant.

SEM Used as Third-Line Therapy (Add-On to MET + TZD or MET + SU)

Results of post hoc subgroup analyses on glycemic control in SUSTAIN-2 to SUSTAIN-4 are presented. Note that this analysis did not provide subgroup results based on background therapy of MET + SU only in accordance with the listing criteria.

In patients receiving SEM as the third-line therapy (add-on to MET + TZD or MET + SU), treatment with either dose of SEM for 30 weeks to 56 weeks was associated with greater glycemic control, compared with SIT, EXE, or IG (Table 20). The mean change from baseline in A1C ranged from ▬ for the SEM 0.5 mg group, and from ▬ for the SEM 1 mg group. Compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group.

Table 20. Glycemic Control Outcomes (SEM as Second-Line Therapy, Add-On to MET Only).

Table 20

Glycemic Control Outcomes (SEM as Second-Line Therapy, Add-On to MET Only).

According to the clinical expert consulted for this review, the between-group differences in A1C were considered clinically relevant.

SEM Used in Mixed Population (as Second- or Third-Line Therapy, Add-On to Standard of Care)

Efficacy of study medications on glycemic control in SUSTAIN-6 was presented in Table 21. In patients with clinical evidence or subclinical evidence of CV disease and who received standard of care for T2DM, treatment with either dose of SEM for 30 weeks was associated with greater glycemic control, compared with placebo. The mean change from baseline in A1C was −1.09% (SE 0.05) for the SEM 0.5 mg group, and −1.41% (SE 0.05) for the SEM 1 mg group. Compared with placebo, the mean between-group differences were −0.66% (95% CI −0.80 to −0.52, P < 0.0001) for the SEM 0.5 mg group and −1.05% (95% CI −1.19 to −0.91, P < 0.0001) for the SEM 1 mg group.

Table 21. Glycemic Control Outcomes (SEM as Third-Line Therapy, Add-On to MET + TZD or MET + SU; FAS).

Table 21

Glycemic Control Outcomes (SEM as Third-Line Therapy, Add-On to MET + TZD or MET + SU; FAS).

According to the clinical expert consulted for this review, the between-group differences in A1C were considered clinically relevant.

SEM Used in Mixed Population (Second- or Third-Line Therapy; Add-On to Basal Insulin Alone or Basal Insulin + MET)

Efficacy of study medications on glycemic control in SUSTAIN-5 was presented in Table 22. This was a mixed population where subgroup results based on background therapy was not available. In patients who received background basal insulin or basal insulin plus MET, treatment with either dose of SEM for 30 weeks was associated with greater glycemic control, compared with placebo.

Table 22. Glycemic Control Outcomes (Cardiovascular Outcome RCT; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

Table 22

Glycemic Control Outcomes (Cardiovascular Outcome RCT; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

The mean change from baseline in A1C was −1.45% (SE 0.09) for the SEM 0.5 mg group, and −1.85% (SE 0.09) for the SEM 1 mg group. Compared with placebo, the mean between-group differences were −1.35% (95% CI −1.61 to −1.10, P < 0.0001) for the SEM 0.5 mg group and −1.75% (95% CI −2.01 to −1.50, P < 0.0001) for the SEM 1 mg group.

In SUSTAIN-5, the between-group differences were statistically significant. Superiority in reducing A1C was concluded for each dose of SEM compared with placebo, when the upper limit of the two-sided 95% CI for the estimated difference was below 0%.

According to the clinical expert consulted for this review, the between-group differences in A1C were considered clinically relevant.

SEM Used in Mixed Population (First- or Second-Line Therapy; Add-On to Diet/Exercise Alone or Diet/Exercise + OAD)

Efficacy of study medications on glycemic control in the Seino study was presented in Table 23. This was a mixed population where subgroup results based on background therapy were not available. In patients receiving background therapy of diet and exercise alone or diet and exercise plus OAD, treatment with either dose of SEM for 30 weeks was associated with greater glycemic control, compared with SIT. The mean change from baseline in A1C was −1.9% (SE 0.1) for the SEM 0.5 mg group, and −2.2% (SE 0.1) for the SEM 1 mg group. Compared with SIT, the mean between-group differences were −1.13% (95% CI −1.32 to −0.94, P < 0.0001) for the SEM 0.5 mg group and −1.44% (95% CI −1.63 to −1.24, P < 0.0001) for the SEM 1 mg group.

Table 23. Glycemic Control Outcomes (SEM as Second- or Third-Line Therapy, Add-On to Basal Insulin Alone or Basal Insulin + MET; FAS).

Table 23

Glycemic Control Outcomes (SEM as Second- or Third-Line Therapy, Add-On to Basal Insulin Alone or Basal Insulin + MET; FAS).

The between-group differences were statistically significant. According to the clinical expert consulted for this review, the between-group differences in A1C were considered clinically relevant.

Efficacy results of SUSTAIN-2, 3, and 4 in the overall population are presented in Appendix 4. The results were consistent with those reported in the subgroups based on background therapy (Table 19 and Table 20). Given that the upper limit of the two-sided 95% CI for the estimated difference in A1C between both doses of SEM and SIT was less than the pre-specified 0.3% margin, NI of both doses of SEM treatment to SIT at week 56 was concluded in SUSTAIN-2. In SUSTAIN-3, because the upper limit of the 95% CI for the estimated between-group difference was below the 0.3% margin, NI of SEM 1 mg versus EXE 2.0 mg was demonstrated for change from baseline in A1C at week 56. In SUSTAIN-4, NI of both doses of SEM to IG was demonstrated when the upper limit of the 95% CI for the estimated between-group difference was below the 0.3% margin. Following confirmation of NI, subsequent testing for superiority was performed, and for all three trials superiority was concluded for both doses of SEM versus SIT, EXE, and IG for change from baseline in A1C.

Mortality

There were no cases of death reported in SUSTAIN-1 (Table 24), SUSTAIN-5 (Table 27), and the Seino study (Table 28).

Table 24. Glycemic Control Outcomes (SEM as First- and Second-Line Therapy; FAS).

Table 24

Glycemic Control Outcomes (SEM as First- and Second-Line Therapy; FAS).

Table 27. Mortality (Cardiovascular Outcome RCT; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care, FAS).

Table 27

Mortality (Cardiovascular Outcome RCT; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care, FAS).

Table 28. Mortality (SEM as Second- or Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; SAS).

Table 28

Mortality (SEM as Second- or Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; SAS).

In SUSTAIN-2, there were six deaths reported during the trial, all of which occurred during the “on-treatment” observation period. Two deaths occurred with SEM 0.5 mg (“ischemic cardiomyopathy” and “cardiovascular disorder”), one with SEM 1.0 mg (“cardiorespiratory arrest”), and three with SIT (“ischemic stroke,” “road traffic accident,” and “death”). All deaths were assessed as unlikely related to study medication by the investigator.

In SUSTAIN-3, two deaths were reported in the SEM 1 mg group (one hepatocellular carcinoma and one invasive lobular breast carcinoma). Both deaths were adjudicated as malignant neoplasms and non-cardiovascular deaths by EAC. Both deaths were assessed as unlikely related to the study medication by the investigator.

In SUSTAIN-4, six deaths were reported during the trial: four with SEM 0.5 mg and two with IG. The four deaths reported in the SEM 0.5 mg group were due to myocarditis, cerebrovascular accident, ischemic stroke, and pancreatic carcinoma; while those reported for IG were caused by atherosclerosis coronary artery and an undetermined cause of death. Of the six fatal events, five were assessed as unlikely to be related to the study medication. The pancreatic carcinoma event was assessed as possibly related to the treatment.

Deaths were not reported in subgroups based on background therapy in SUSTAIN-2, 3, and 4 (Table 25).

Table 25. Mortality (SEM as First-Line Therapy, SAS).

Table 25

Mortality (SEM as First-Line Therapy, SAS).

The proportion of death and CV death were similar across treatment arms in SUSTAIN-6 (Table 26).

Table 26. Mortality (SEM as Second-Line Therapy, Add-On to MET, SAS).

Table 26

Mortality (SEM as Second-Line Therapy, Add-On to MET, SAS).

In SUSTAIN-7, six patients died during the trial: five during the “on-treatment” observation period (one with SEM 1.0 mg, two with DUL 0.75 mg, and two with DUL 1.5 mg) and one with SEM 0.5 mg during the “in-trial” period after prematurely discontinuing treatment. None of the deaths were considered to be related to the study medication (Table 25).

Diabetes-Related Morbidity and Mortality

This outcome was not assessed in SUSTAIN-1 to 5, SUSTAIN-7, or the Seino study.

In SUSTAIN-6, the proportion of patients with first EAC-confirmed MACE (consisted of CV death, non-fatal MI, and non-fatal stroke) was lower with SEM therapy compared with placebo. A total of 108 patients (6.6%) treated with SEM experienced EAC-confirmed MACE versus 146 patients (8.9%) treated with placebo: ▬ ▬ ▬ ▬ ▬ (Table 29). Treatment with either dose of SEM was also associated with numerically lower events of non-fatal MI and non-fatal stroke, while the number of deaths from CV causes was similar across treatment groups. The estimated HR for time to first MACE was 0.74 (95% CI 0.58 to 0.95, below the NI margin of 1.8), indicating that SEM statistically significantly reduced the risk of experiencing a MACE by 26% when compared with placebo, in patients with existing CV disease. P value was 0.0167 for the superiority test. The results of the sensitivity analyses were consistent with the results from the primary analysis. The results of the subgroup analyses (pre-planned, based on baseline A1C levels, heart failure class II-III, prior MI/stroke and renal impairment) were consistent with the results from the primary analysis.

Table 29. Mortality (SEM as First- and Second-Line Therapy; SAS).

Table 29

Mortality (SEM as First- and Second-Line Therapy; SAS).

For the composite outcome of all-cause death, non-fatal MI, or non-fatal stroke and its individual components, treatment with SEM was associated with numerically lower events in the study population, compared with placebo (Table 29).

For the expanded composite outcome of EAC-confirmed MACE, revascularization, unstable angina pectoris requiring hospitalization or hospitalization for heart failure, treatment with SEM was associated with numerically lower events in the study population, compared with placebo (Table 29).

Furthermore, proportions of new or worsening nephropathy were numerically lower in the SEM groups than in the placebo groups: ▬ ▬ ▬ ▬ ▬. However, proportions of diabetic retinopathy complications were numerically higher in the SEM groups than in the placebo groups: ▬ ▬ ▬ ▬ ▬.

Hospitalization

This outcome was not assessed in the included clinical trials.

Health-Related Quality of Life

HRQoL was not evaluated in SUSTAIN-1 and the Seino study. Patient-reported HRQoL was not included in the hierarchical testing procedure to control the familywise type I error rate in any of the SUSTAIN trials.

In SUSTAIN-2, SUSTAIN-3, and SUSTAIN-4, the change in DTSQ scores and SF-36 domain scores was evaluated in the overall population, but not in the subgroups based on the background antihyperglycemic therapy.

Results from these SUSTAIN trials showed numerically higher score at the end of study compared with baseline for the “treatment satisfaction” component in DTSQ, for all treatment groups, indicating more patient satisfaction associated with the study drug. For SF-36, all domains had improved with SEM and the comparators from baseline; however, the improvements were not considered clinically important. Details of patient-reported outcomes are presented in Appendix 4, Table 54.

Change in Body Weight and/or BMI

SEM Used as First-Line Therapy

SUSTAIN-1 reported change in body weight from baseline to week 30 in drug-naive patients with T2DM and had inadequate glycemic control after therapy with diet and exercise. At week 30, the mean change in body weight was −3.73 kg (SE 0.41), −4.53 kg (SE 0.41), and −0.98 kg (SE 0.43) for patients who received SEM 0.5 mg, SEM 1 mg, and placebo, respectively. The mean differences were statistically significant for both SEM groups compared with placebo (SEM 0.5 mg: −2.75 kg, 95% CI −3.92 to −1.58, P < 0.0001; SEM 1 mg: −3.56 kg, 95% CI −4.74 to −2.38) (Table 30). Because the upper limit of the two-sided 95% CI for the estimated differences was below 0 kg, superiority of SEM 0.5 mg or SEM 1 mg versus placebo in change in body weight was demonstrated. According to the clinical expert consulted for this review, the between-group differences were considered clinically important.

Table 30. Diabetes-Related Morbidity and Mortality (CV Outcome Trial; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

Table 30

Diabetes-Related Morbidity and Mortality (CV Outcome Trial; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

SUSTAIN-1 also reported change in BMI from baseline to week 30 in drug-naive patients. At week 30, the mean change in BMI was −1.36 kg/m2 (SE 0.15), −1.61 kg/m2 (SE 0.14) and −0.38 kg/m2 (SE 0.15) for patients who received SEM 0.5 mg, SEM 1 mg, and placebo, respectively. The mean differences were statistically significant for both SEM groups compared with placebo (SEM 0.5 mg: −0.98 kg/m2, 95% CI −1.40 to −0.56, P < 0.0001; SEM 1 mg: −1.23 kg/m2, 95% CI −1.65 to −0.82) (Table 30).

SEM Used as Second-Line Therapy (Add-On to MET)

Results of post hoc subgroup analyses on body weight in SUSTAIN-2, SUSTAIN-3, and SUSTAIN-4 are presented. Patients in SUSTAIN-7 received treatment with SEM or DUL with background therapy of MET monotherapy.

In patients with T2DM and received SEM as the second-line therapy (add-on to MET), treatment with either dose of SEM for 30 to 56 weeks was associated with greater reduction in body weight, compared with SIT, EXE, or IG (Table 31). The mean change from baseline in body weight ranged from ▬ for the SEM 0.5 mg group, and from ▬ for the SEM 1 mg group. Compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with DUL, the mean between-group differences were −2.26 kg (95% CI −3.02 to −1.51, P < 0.0001) for the SEM 0.5 mg group and −3.55 kg (95% CI −4.32 to −2.78, P < 0.0001) for the SEM 1 mg group. According to the clinical expert consulted for this review, the between-group differences in body weight were considered clinically relevant. In SUSTAIN-7, superiority in reducing body weight was concluded for each dose of SEM compared with the respective dose level of DUL.

Table 31. Body Weight/BMI (SEM as First-Line Therapy; FAS).

Table 31

Body Weight/BMI (SEM as First-Line Therapy; FAS).

Results of post hoc subgroup analyses on BMI in SUSTAIN-2 to SUSTAIN-4 are presented. In the subgroups of patients with T2DM and received SEM as the second-line therapy (add-on to MET), treatment with either dose of SEM for 30 weeks to 56 weeks was associated with greater reduction in BMI, compared with SIT, EXE, or IG (Table 31). Patients in SUSTAIN-7 received treatment with SEM or DUL with background therapy of MET monotherapy. The mean change from baseline in BMI ranged from ▬ for the SEM 0.5 mg group, and from ▬ for the SEM 1 mg group. Compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with DUL, the mean between-group differences were −0.81 kg/m2 (95% CI −1.08 to −0.54) for the SEM 0.5 mg group and −1.25 kg/m2 (95% CI −1.52 to −0.98) for the SEM 1 mg group.

SEM Used as Third-Line Therapy (Add-On to MET + TZD or MET + SU)

Results of post hoc subgroup analyses on body weight in SUSTAIN-2 to SUSTAIN-4 are presented.

In the patients receiving SEM as the third-line therapy (add-on to MET + TZD or MET + SU), treatment with either dose of SEM for 30 weeks to 56 weeks was associated with greater reduction in body weight, compared with SIT, EXE, or IG (Table 32). The mean change from baseline in A1C ranged from ▬ for the SEM 0.5 mg group, and from ▬ for the SEM 1 mg group. Compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group.

Table 32. Body Weight/BMI (SEM as Second-Line Therapy, Add-On to MET; FAS).

Table 32

Body Weight/BMI (SEM as Second-Line Therapy, Add-On to MET; FAS).

According to the clinical expert consulted for this review, the between-group differences in body weight were considered clinically relevant.

Results of post hoc subgroup analyses on BMI from SUSTAIN-2 to SUSTAIN-4 are presented. In the subgroups of patients with T2DM and received SEM as the third-line therapy (add-on to MET + TZD or MET + SU), treatment with either dose of SEM for 30 weeks to 56 weeks was associated with greater reduction in BMI, compared with SIT, EXE, or IG (Table 32). The mean change from baseline in BMI ranged from ▬ for the SEM 0.5 mg group, and from ▬ for the SEM 1 mg group. Compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group.

SEM Used in Mixed Population (as Second- or Third-Line Therapy, Add-On to Standard of Care)

Efficacy of study medications on body weight in SUSTAIN-6 was presented in Table 33. In patients with clinical evidence or subclinical evidence of CV disease and received standard of care for T2DM, treatment with either dose of SEM for 30 weeks was associated with greater reduction in body weight, compared with placebo. The mean change from baseline in body weight was −3.57 kg (SE 0.21) for the SEM 0.5 mg group, and −4.88 kg (SE 0.22) for the SEM 1 mg group. Compared with placebo, the mean between-group differences were −2.95 kg (95% CI −3.47 to −2.44, P < 0.0001) for the SEM 0.5 mg group and −4.27 kg (95% CI −4.78 to −3.75, P < 0.0001) for the SEM 1 mg group.

Table 33. Body Weight/BMI (SEM as Third-Line Therapy, Add-On to MET+TZD or MET+SU; FAS).

Table 33

Body Weight/BMI (SEM as Third-Line Therapy, Add-On to MET+TZD or MET+SU; FAS).

According to the clinical expert consulted for this review, the between-group differences in A1C were considered clinically relevant.

Efficacy of study medications on BMI in SUSTAIN-6 was also presented in Table 33. In patients with clinical evidence or subclinical evidence of CV disease and received standard of care for T2DM, treatment with either dose of SEM for 30 weeks was associated with greater reduction in BMI, compared with placebo. The mean change from baseline in BMI was ▬ for the SEM 0.5 mg group, and ▬ for the SEM 1 mg group. Change from baseline in BMI was ▬ in placebo 0.5 mg group and ▬ in placebo 1 mg group. Between-group differences for SEM versus DUL were not reported.

SEM Used in Mixed Population (as Second- or Third-Line Therapy; Add-On to Basal Insulin or Basal Insulin + MET)

Efficacy of study medications on body weight in SUSTAIN-5 was presented in Table 34. This was a mixed population where subgroup results based on background therapy were not available. In patients who received background basal insulin or basal insulin plus MET, treatment with either dose of SEM for 30 weeks was associated with greater reduction in body weight, compared with placebo: the mean between-group differences were −2.31 kg (95% CI, −3.33 to −1.29, P < 0.0001) for the SEM 0.5 mg group and −5.06 kg (95% CI −6.08 to −4.04, P < 0.0001) for the SEM 1 mg group.

Table 34. Body Weight/BMI (CV Outcome Trial; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

Table 34

Body Weight/BMI (CV Outcome Trial; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

In SUSTAIN-5, the between-group differences were statistically significant. Superiority in reducing body weight was concluded for each dose of SEM compared with placebo, because the upper limit of the two-sided 95% CI for the estimated difference was below 0 kg.

Efficacy of study medications on BMI in SUSTAIN-5 was also presented in Table 34. In patients who received background basal insulin or basal insulin plus MET, treatment with either dose of SEM for 30 weeks was associated with greater reduction in BMI, compared with placebo: the mean between-group differences were −0.84 kg/m2 (95% CI, −1.20 to −0.49, P < 0.0001) for the SEM 0.5 mg group and −1.82 kg/m2 (95% CI, −2.18 to −1.47, P < 0.0001) for the SEM 1 mg group.

SEM Used in Mixed Population (as First- or Second-Line Therapy; Add-On to Diet/Exercise Alone or Diet/Exercise + OAD)

Efficacy of study medications on body weight in the Seino study is presented in Table 35. This was a mixed population where subgroup results based on background therapy were not available. In patients who received background therapy of diet and exercise alone or diet and exercise plus OAD, treatment with either dose of SEM for 30 weeks was associated with greater reduction in body weight, compared with SIT: the mean between-group differences were −2.22 kg (95% CI −3.02 to −1.42, P < 0.0001) for the SEM 0.5 mg group and −3.88 kg (95% CI −4.70 to −3.07, P < 0.0001) for the SEM 1 mg group.

Table 35. Body Weight/BMI (SEM as Second- and Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; FAS).

Table 35

Body Weight/BMI (SEM as Second- and Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; FAS).

The between-group differences were statistically significant. According to the clinical expert consulted for this review, the between-group differences in A1C were considered clinically relevant.

Efficacy of study medications on BMI in SUSTAIN-5 was also presented in Table 35. In patients who received background basal insulin or basal insulin plus MET, treatment with either dose of SEM for 30 weeks was associated with greater reduction in BMI, compared with placebo: the mean between-group differences were −0.84 kg/m2 (95% CI −1.13 to −0.54, P < 0.0001) for the SEM 0.5 mg group and −1.44 kg/m2 (95% CI −1.74 to −1.14, P < 0.0001) for the SEM 1 mg group.

Change in Blood Pressure

Change in blood pressure was not included in the hierarchical testing procedure to control the familywise type I error rate.

SEM Used as First-Line Therapy

SUSTAIN-1 reported change in blood pressure from baseline to week 30 in drug-naive patients with T2DM and had inadequate glycemic control after therapy with diet and exercise. At week 30, all three treatment groups showed reduced SBP from baseline. The mean differences were not statistically significant for either SEM groups compared with placebo (SEM 0.5 mg: −0.86 mm Hg, 95% CI −4.15 to 2.43, P = 0.60; SEM 1 mg: −1.03, 95% CI −4.29 to −2.24). At week 30, change in DBP was inconsistent across the treatment groups, and the between-group differences in change in DBP were not statistically significant (Table 36).

Table 36. Body Weight/BMI (SEM as First- and Second-Line Therapy; FAS).

Table 36

Body Weight/BMI (SEM as First- and Second-Line Therapy; FAS).

SEM Used as Second-Line Therapy (Add-On to MET)

Results of post hoc subgroup analyses on blood pressure in SUSTAIN-2 to SUSTAIN-4 are presented. Patients in SUSTAIN-7 received treatment with SEM or DUL with background therapy of MET monotherapy.

In the subgroups of patients with T2DM and who received SEM as the second-line therapy (add-on to MET), treatment with either dose of SEM for 30 weeks to 56 weeks was associated with greater reduction in SBP and DBP, compared with SIT, EXE, or IG. In SUSTAIN-7, patients in the SEM 1 mg group had greater reduction in SBP and DBP than those with SEM 0.5 mg and DUL (Table 37).

Table 37. Blood Pressure (SEM as First-Line Therapy; FAS).

Table 37

Blood Pressure (SEM as First-Line Therapy; FAS).

For change in SBP compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. In SUSTAIN-7, SBP levels at week 40 were reduced in all groups but no statistically significant differences between SEM and DUL were observed: the mean differences were −0.28 mm Hg (95% CI −2.37 to 1.81, P = 0.79) for SEM 0.5 mg versus DUL 0.75 mg and −2.02 mm Hg (95% CI −4.14 to 0.09, P = 0.06) for SEM 1 mg versus DUL 1.5 mg.

For change in DBP, compared with SIT, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. In SUSTAIN-7, the reductions in DBP at week 40 were significantly greater with SEM 1 mg as compared with DUL 1.5 mg (mean between-group difference: −2.02 mm Hg; 95% CI −3.35 to −0.68), while no treatment difference was observed between SEM 0.5 mg and DUL 0.75 mg.

According to the clinical expert consulted for this review, the between-group differences in blood pressure were not considered clinically relevant.

SEM Used as Third-Line Therapy (Add-On to MET + TZD or MET + SU)

Results of post hoc subgroup analyses on blood pressure in SUSTAIN-2 to SUSTAIN-4 are presented. In the subgroups of patients receiving SEM as third-line therapy (add-on to MET + TZD or MET + SU), reduction in SBP was observed in all treatment groups (Table 38). Compared with SIT, the mean between-group differences in change in SBP were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group.

Table 38. Blood Pressure (SEM as Second-Line Therapy, Add-On to MET; FAS).

Table 38

Blood Pressure (SEM as Second-Line Therapy, Add-On to MET; FAS).

Reduction in DBP was reported in some trials after 40 weeks treatment with study medications. Compared with SIT, the mean between-group differences in change in DBP were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group. Compared with EXE, the mean between-group difference was ▬ for the SEM 1 mg group. Compared with IG, the mean between-group differences were ▬ for the SEM 0.5 mg group and ▬ for the SEM 1 mg group.

According to the clinical expert consulted for this review, the between-group differences in blood pressure were not considered clinically relevant.

SEM Used in Mixed Population (as Second- or Third-Line Therapy; Add-On to Standard of Care)

Efficacy of study medications on blood pressure in SUSTAIN-6 is presented in Table 39. In patients with clinical evidence or subclinical evidence of CV disease and who received standard of care for T2DM, reduction in SBP and DBP was observed in all treatment groups. Compared with placebo, the mean between-group differences in SBP were −1.27 mm Hg (95% CI −2.77 to −0.23, P =0.10) for the SEM 0.5 mg group and −2.59 mm Hg (95% CI −4.09 to −1.08, P = 0.0008) for the SEM 1 mg group; the mean between-group differences in DBP were 0.04 mm Hg (95% CI −0.83 to 0.92, P = 0.92) for the SEM 0.5 mg group and 0.14 mm Hg (95% CI −0.74 to 1.03, P = 0.75).

Table 39. Blood Pressure (SEM as Third-Line Therapy, Add-On to MET + TZD or MET + SU; FAS).

Table 39

Blood Pressure (SEM as Third-Line Therapy, Add-On to MET + TZD or MET + SU; FAS).

According to the clinical expert consulted for this review, the between-group differences in SBP and DBP were not considered clinically relevant.

SEM Used in Mixed Population (as Second- or Third-Line Therapy; Add-On to Basal Insulin or Basal Insulin + MET)

Efficacy of study medications on blood pressure in SUSTAIN-5 was presented in Table 40. This was a mixed population where subgroup results based on background therapy was not available. In patients who received background basal insulin or basal insulin plus MET, reduction in SBP and DBP was observed in all treatment groups. Compared with placebo, the mean between-group differences in SBP were −3.31 mm Hg (95% CI −6.92 to 0.31, P = 0.07) for the SEM 0.5 mg group and −6.29 mm Hg (95% CI −9.91 to −2.66, P =0.0007) for the SEM 1 mg group; the mean between-group differences in DBP were 0.33 mm Hg (95% CI −1.80 to 2.45, P = 0.76) for the SEM 0.5 mg group and 0.66 mm Hg (95% CI −1.47 to 2.80, P = 0.54).

Table 40. Blood Pressure (CV Outcome RCT; Used as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

Table 40

Blood Pressure (CV Outcome RCT; Used as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

SEM Used in Mixed Population (as First- or Second-Line Therapy; Add-On to Diet/Exercise or Diet/Exercise + OAD)

Efficacy of study medications on blood pressure in the Seino study is presented in Table 41. This was a mixed population where subgroup results based on background therapy were not available. In patients who received background therapy of diet and exercise alone or diet and exercise plus OAD, treatment with either dose of SEM for 30 weeks was associated with greater reduction in SBP. Compared with SIT, the mean between-group differences were −2.54 mm Hg (95% CI −5.64 to 0.55, P = 0.11) for the SEM 0.5 mg group and −6.01 mm Hg (95% CI −9.16 to −2.85, P = 0.0002) for the SEM 1 mg group.

Table 41. Blood Pressure (SEM as Second- and Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; FAS).

Table 41

Blood Pressure (SEM as Second- and Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; FAS).

The mean between-group differences in DBP were 0.12 mm Hg (95% CI −1.97 to 2.21, P = 0.91) for SEM 0.5 mg versus SIT, and −1.99 mm Hg (95% CI −4.13 to 0.16, P = 0.07) for SEM 1 mg versus SIT.

Change in Blood Lipid

Change in blood lipid was not included in the hierarchical testing procedure to control the familywise type I error rate.

SEM Used as First-Line Therapy

SUSTAIN-1 reported change in blood lipid from baseline to week 30 in drug-naive patients. At week 30, total cholesterol level and LDL cholesterol level were statistically significantly reduced in the SEM 1 mg group, compared with placebo. There were no statistically significant changes in lipid profile observed for SEM 0.5 mg versus placebo (Table 42).

Table 42. Blood Pressure (SEM as First- and Second-Line Therapy; FAS).

Table 42

Blood Pressure (SEM as First- and Second-Line Therapy; FAS).

Table 43. Lipid Profile (SEM as First-Line Therapy; FAS).

Table 43

Lipid Profile (SEM as First-Line Therapy; FAS).

SEM Used as Second-Line Therapy (Add-On to MET Alone)

Results of post hoc subgroup analyses on blood lipid levels in SUSTAIN-2, SUSTAIN-3, and SUSTAIN-4 are presented. Patients in SUSTAIN-7 received treatment with SEM or DUL with background therapy of MET monotherapy.

In patients with T2DM who received SEM as second-line therapy (add-on to MET), treatment with SEM was associated with numerically greater reduction in total cholesterol when compared with SIT, IG, and DUL. In addition, SEM was associated with a numerically greater increase in HDL cholesterol versus SIT, EXE, IG, and DUL (except for the comparison between SEM 0.5 mg and DUL 0.75 mg in SUSTAIN-7). SEM was also associated with numerically greater reduction in LDL cholesterol versus SIT, IG, and DUL (except for the comparison between SEM 0.5 mg and DUL 0.75 mg in SUSTAIN-7).

SEM Used as Third-Line Therapy (Add-On to MET + TZD or MET + SU)

Results of post hoc subgroup analyses on changes in lipid levels in SUSTAIN-2 to SUSTAIN-4 are presented.

In patients with T2DM and received SEM as the third-line therapy (add-on to MET + TZD or MET + SU), treatment with SEM was associated with numerically greater reduction in total cholesterol when compared with SIT (except for the comparison between SEM 0.5 mg and SIT in SUSTAIN-2), EXE, and IG. In addition, SEM was associated with numerically greater increase in HDL cholesterol versus SIT (except for the comparison between SEM 1 mg and SIT in SUSTAIN-2), EXE, and IG. SEM was also associated with numerically greater reduction in LDL cholesterol versus EXE and IG, but less reduction in LDL cholesterol versus SIT.

1 mg was associated with statistically significantly greater reduction in total cholesterol versus EXE (▬), (Table 44). There were no other significant changes in lipid levels observed between SEM and active comparators.

Table 44. Lipid Profile (SEM as Second-Line Therapy, Add-On to MET).

Table 44

Lipid Profile (SEM as Second-Line Therapy, Add-On to MET).

SEM Used in Mixed Population (as Second- or Third-Line Therapy; Add-On to Standard of Care)

Efficacy of study medications on blood lipid levels in SUSTAIN-6 is presented in Table 45. In patients with clinical evidence or subclinical evidence of CV disease who received standard of care for T2DM, treatment with SEM 0.5 mg was associated with statistically significantly greater reduction in total cholesterol (treatment ratio 0.97, 95% CI 0.95 to 1.00) and greater reduction in LDL cholesterol (treatment ratio), compared with placebo; treatment with SEM 1 mg was associated with statistically significantly increase in HDL cholesterol (treatment ratio 1.04, 95% CI 1.02 to 1.06). There were no other significant changes in lipid levels observed between SEM and active comparators.

Table 45. Lipid Profile (SEM as Third-Line Therapy, Add-On to MET + TZD or MET + SU; FAS).

Table 45

Lipid Profile (SEM as Third-Line Therapy, Add-On to MET + TZD or MET + SU; FAS).

SEM Used in Mixed Population (As Second- or Third-Line Therapy; Add-On to Basal Insulin Alone or Basal Insulin + MET)

Efficacy of study medications on blood lipid levels in SUSTAIN-5 was presented in Table 46. This was a mixed population where subgroup results based on background therapy were not available. In patients who received background basal insulin or basal insulin plus MET, treatment with SEM 0.5 mg was associated with a statistically significant reduction in total cholesterol (treatment ratio 0.95, 95% CI 0.91 to 0.99), compared with placebo.

Table 46. Lipid Profile (CV Outcome RCT; as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

Table 46

Lipid Profile (CV Outcome RCT; as Second- or Third-Line Therapy, Add-On to Standard of Care; FAS).

SEM Used in Mixed Population (as First- or Second-Line Therapy; Add-On to Diet/Exercise Alone or Diet)

Efficacy of study medications on blood lipids in the Seino study is presented in Table 47. This was a mixed population where subgroup results based on background therapy were not available. In patients who received background therapy of diet and exercise alone or diet and exercise plus OAD, treatment with either dose of SEM for 30 weeks was associated with greater reduction total cholesterol and LDL cholesterol, compared with SIT. Results were presented graphically. No other details are available.

Table 47. Lipid Profile (SEM as Second- and Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; FAS).

Table 47

Lipid Profile (SEM as Second- and Third-Line Therapy, Add-On to Basal Insulin or Basal Insulin + MET; FAS).

Harms

Only those harms identified in the review protocol are reported below (see 2.2.1, Protocol).

Adverse Events

The overall frequency of AEs was similar between treatment groups within trials. In the placebo-controlled trials (except for SUSTAIN-6), AEs were reported by 56% to 69% of patients treated with SEM, and by 54% to 58% of patients treated with placebo (Table 48). In the active-controlled trials, AEs were reported by 68% to 75% of patients with SEM, 66% to 72% of patients with SIT, 76% of patients with EXE, 62% to 74% of patients with DUL, and 65% of patients with IG (Table 49). In the CVOT trial (SUSTAIN-6), incidence of AEs were higher (88% to 89%) compared with other included trials.

Table 48. Lipid Profile (SEM as First- and Second-Line Therapy; FAS).

Table 48

Lipid Profile (SEM as First- and Second-Line Therapy; FAS).

Table 49. Harms (Placebo-Controlled RCTs; SAS).

Table 49

Harms (Placebo-Controlled RCTs; SAS).

Among patients who received SEM, GI disorders were the most commonly reported AEs (27% to 39% in the placebo-controlled trials; 34% to 44% in the active-controlled trials). Among the active-controlled trials, patients received SEM were more likely to report GI disorders compared with those received SIT, EXE, or IG. In SUSTAIN-7, SEM was compared with another GLP-1 receptor agonist (DUL). The rates of GI disorders were similar between the SEM treatment groups (43% to 44%) and the DUL groups (33% to 48%).

Serious Adverse Events

SAEs were reported by 4% to 7% of patients received placebo, 5% to 9% of patients received SEM (2% to 3% of these SAEs were GI disorders), 2% to 7% of patient received SIT, 6% of patients received EXE, 7% to 8% of patients received DUL and 5% of patients received IG (Table 48 and Table 49).

In SUSTAIN-6, the rates of SAEs were 32.1%, 29.3%, and 34.9% in patients who received SEM 0.5 mg, SEM 1 mg, and placebo, respectively (Table 50). The most commonly reported SAEs in this trial were cardiac disorders, e.g., angina unstable, acute MI, coronary artery disease or cardiac failure, 9.8%, 9.2%, and 12.0%, respectively.

Table 50. Harms (Active-Controlled RCTs; SAS).

Table 50

Harms (Active-Controlled RCTs; SAS).

AEs Leading to Treatment Discontinuation

The rates of AEs leading to treatment discontinuation were 3.9% to 6.8% in the placebo group, 2.9% to 9.7% in the SEM group, 1.9% to 2.9% in the SIT group, 7.2% in the EXE group, 4.7% to 6.7% in the DUL groups, and 1.1% in the IG group. The differences between SEM and other treatment groups was mainly due to a greater proportion of patients with GI disorders that led to premature treatment discontinuation with SEM.

In SUSTAIN-6, the rates of AEs leading to premature treatment discontinuation were 11.5% to 14.5% in the SEM groups and 6.7% in the placebo group.

Mortality

There were no deaths reported in SUSTAIN-1, SUSTAIN-5, and Seino study. Details with respect to mortality are provided in the “Efficacy” section.

Notable Harms

The frequency of GI disorders was higher in the SEM group, compared with placebo, or active comparator which was not a GLP-1 receptor agonist, such as SIT or insulin (Table 48, Table 49 and Table 50).

The frequency of hypoglycemia was highest in the insulin glargine group in SUSTAIN-4 (39.4%). The risk of hypoglycemia for SEM was comparable to the other GLP-1 receptor agonists such as EXE and DUL, and was lower than SIT and IG. Severe hypoglycemia was reported infrequently in the included trials.

In general, injection site reaction was rare in the majority of the trials, while in SUSTAIN-3, the proportion of patients with injection site reaction was 22% in the EXE group compared with 1.2% in the SEM group.

The occurrence of other harms of special interest to this review was infrequent. Isolated cases of pancreatitis were reported. No cases of medullary thyroid carcinoma were identified. One EAC-confirmed thyroid malignant neoplasm was recorded in SUSTAIN-7.

In SUSTAIN-6, AEs were reported in a higher proportion of subjects or with a higher rate with SEM than with placebo within the GI disorders System Organ Class and for Preferred Terms of lipase increased, amylase increased, decreased appetite, diabetic retinopathy, cataracts, and dizziness. Back pain, urinary tract infection and influenza were reported in a similar proportion of subjects with SEM (0.5 mg and 1.0 mg) and placebo. Headache, nasopharyngitis, upper respiratory tract infection, bronchitis, and joint pain (arthralgia) were reported in a lower proportion of subjects with SEM (0.5 mg and 1.0 mg) than with placebo. In addition, less frequent AEs related to glucose control (BG increased), and lipids (hypercholesterolemia) were reported in a lower proportion of subjects with SEM than with placebo.

Table 51. Harms (CV Outcome Trial; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; SAS).

Table 51

Harms (CV Outcome Trial; SEM as Second- or Third-Line Therapy, Add-On to Standard of Care; SAS).

Copyright © 2019 Canadian Agency for Drugs and Technologies in Health.

The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at http://creativecommons.org/licenses/by-nc-nd/4.0/

Bookshelf ID: NBK544016
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