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Authors; Deepa Jahagirdar, and Quenby Mahood.
Diabetes mellitus is a metabolic disease characterized by persistent hyperglycemia. Over 10 million Canadians are living with the condition. There are 2 main subtypes: type 1 diabetes mellitus, where insulin production is inadequate, and type 2 diabetes mellitus (T2DM), where the body does not use insulin properly. In Canada, T2DM accounts for approximately 90% of cases of diabetes mellitus.1
Genetic risk factors can contribute to the development of T2DM, along with modifiable risk factors such as obesity and smoking.2 T2DM treatment aims to keep blood sugars within a target range. Sometimes this can be achieved with lifestyle changes including a healthy overall diet and exercise.3 When lifestyle changes are not enough to maintain appropriate blood glucose levels, pharmacologic therapy may be required to prevent complications, including high blood pressure, cardiovascular disease, diabetic retinopathy, and kidney damage.3 The first-line treatment is usually a medication called metformin, which helps improve the body’s response to insulin.3 When metformin therapy is not enough for diabetic control, other oral antidiabetic drugs can be used (e.g., sulfonylureas or sodium-glucose cotransporter-2 inhibitors). If these drugs fail, the patient may progress to injectable medication.4
Semaglutide (SEM), marketed as Ozempic, is an injectable medication indicated for use in adult patients with T2DM where metformin therapy alone was insufficient for glycemic control or contraindicated.5 The drug is a selective long-acting glucagon-like peptide 1 (GLP-1) receptor agonist that stimulates insulin production, thus reducing blood glucose levels. It can also have a role in appetite suppression, increasing the feeling of fullness.6 The SUSTAIN trials established efficacy and safety for once-weekly subcutaneous SEM treatment at doses 0.5 mg and 1.0 mg.7 Based on this and other evidence,8 the CADTH Canadian Drug Expert Committee recommended in 2019 that SEM should be reimbursed for adult patients with T2DM with inadequate glycemic control.5 As of 2022 SEM is still being used in doses up to 1.0 mg per week in Canada in 96.4% of claimants nationally,4 despite approval as of January 2022 to use once-weekly doses as high as 2.0 mg in Canada.9
While SEM at higher doses than 1.0 mg are being used in Canada, there is also the potential for increased cost and risks associated with the higher, 2.0 mg once-weekly dose without a comprehensive evidence review for its benefits. Understanding this trade off could help to support decision-making on more widespread use of SEM injectable 2.0 mg instead of lower doses. While off-label use of Ozempic for weight loss is suspected,4 this review excludes weight-related outcomes due to a previous CADTH Reimbursement Review that did not recommend reimbursement of a similar SEM medication (Wegovy) for chronic weight management, including in those with T2DM.10 The purpose of this review is to summarize the evidence regarding the clinical and cost-effectiveness of SEM 2.0 mg subcutaneous once-weekly injection compared to lower 0.5 mg and 1.0 mg doses or placebo for managing T2DM in adults.
An information specialist conducted a literature search on key resources including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were semaglutide, dosage, and type 2 diabetes. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, indirect treatment comparisons, any types of clinical trials or observational studies, or economic studies to a secondary search of the concepts semaglutide and type 2 diabetes. The search was completed on August 15, 2023, and limited to English-language documents published since January 1, 2018.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published before 2018.
The included publication was critically appraised by 1 reviewer using the Downs and Black checklist11 for randomized and nonrandomized studies. A summary score was not calculated for the included study; rather, the strengths and limitations of the included publication were described narratively.
A total of 474 citations were identified in the literature search. Following screening of titles and abstracts, 438 citations were excluded and 36 potentially relevant reports from the electronic search were retrieved for full-text review. Of these potentially relevant articles, 35 publications were excluded for various reasons. One randomized controlled trial (RCT) met the inclusion criteria and was included in this report. Appendix 1 presents the PRISMA12 flow chart of the study selection.
Additional references of potential interest are provided in Appendix 5.
Appendix 2 presents detailed study characteristics of the included publication.
We identified 1 double-blinded RCT (SUSTAIN FORTE) published in 2021.13
The study had 129 trial sites from 10 countries, including Bulgaria, Canada, Czech Republic, Greece, Hungary, Japan, Poland, Slovakia, Ukraine, US.13
The study was limited to adults aged 18 and older who had inadequately controlled type 2 diabetes for at least 180 days. ‘Inadequate control’ was defined as glycated hemoglobin (hemoglobin A1C) 64 to 86 mmol/mol or 8% to 10%. In addition, patients had to be on a stable metformin dose for at least 90 days. The final randomized sample (N = 961) had a mean overall age of 58; 88% of patients were white with a mean duration of diabetes of 9.5 years. 41% were female, while all patients took metformin at randomization, and 53% took sulfonylurea. The average baseline hemoglobin A1C was 73.3 mmol/mol or 8.9%, and the body mass index was 34.6 kg/m2.13
The intervention and comparator group had SEM once-weekly subcutaneous injection dose escalation from 0.25 mg to 1.0 mg over 8 weeks. The 1.0 mg dose was then maintained for an additional 4 weeks. Starting at week 13, the intervention group received an additional 1.0 mg pen, for a total of 2.0 mg, once-weekly, while the control group was maintained at 1.0 mg using a placebo pen. Follow-up was at week 40.13
The primary outcome was the percentage point change from baseline in hemoglobin A1C.13
Secondary outcomes that were relevant to this report included change in fasting plasma glucose. Additional group-level outcomes included the number of patients who reached hemoglobin A1C less than 7%, and the number of patients who reached hemoglobin A1C less than 6.5%.13
While not a protocol-defined outcome, the authors also measured changes to blood pressure for completeness.
The included study13 achieved randomization using an interactive web response system, limiting the possibility that randomization was inadequate. Further demonstrating successful randomization, the patients in both groups had balanced characteristics. Bias favouring either the intervention or control group was also limited through masking among patients, site personnel, the investigators, and those conducting the study (the clinical study group). Patients in the SEM 1.0 mg and SEM 2.0 mg dose group received an identical injection pen; 1 was a placebo, while the other provided an additional SEM 1.0 mg dose. Discontinuation was similar in both groups. In the SEM 2.0 mg arm, 447 of 481 completed treatment while 34 prematurely discontinued, while in the 1.0 mg arm, 442 of 480 completed treatment and 38 patients discontinued prematurely.
Regarding the statistical analysis, the study13 had adequate power (87%) to detect a 0.22 percentage point reduction from baseline in hemoglobin A1C. The authors conducted both a traditional intention-to-treat analysis (termed ‘treatment policy estimand’), where outcomes are analyzed regardless of discontinuation or change in treatment dose, which limits bias associated with dropout, as well as an analysis where observations were regardless of change in treatment dose only (‘trial product estimand’).
Missing data were handled through multiple imputations, assuming they were ‘missing at random,’ or the missingness was unrelated to the patient’s outcome once other observed characteristics were accounted for. This assumption was not explained, and the extent of missing data were unclear, making it difficult to assess whether outstanding bias could be significant. However, sensitivity analysis was conducted to assess the impact of handling missing data on the results; the findings supported the main results.
Two concerns about study quality included the exclusive funding by the drug manufacturer, Novo Nordisk, and the lack of clear outcomes reporting by analysis method. The manufacturer funding may not have influenced the study results; however, objective funders are usually preferred. Lastly, the authors also state 2 analysis methods (trial product and treatment policy estimand), but, for example, only the trial product estimand results were shown for the reduction in fasting plasma glucose and the proportion of patients achieving hemoglobin A1C lower than 6.5%.13 Showing both results would have enabled a clearer interpretation of the findings.
Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.
Appendix 4 presents the main study findings.
The 1 eligible RCT (SUSTAIN FORTE)13 found that SEM 2.0 mg.
was superior to SEM 1.0 mg to achieve glycemic control. The intervention group experienced a 2.1 percentage point reduction in hemoglobin A1C, while the control group had an average 1.9 percentage point reduction in hemoglobin A1C. The estimated absolute difference in percentage point reduction between the groups was 0.18 (95% confidence interval = 0.04 to 0.31, P < 0.001), which was statistically significant at the 5% level.
In terms of secondary outcomes, SEM 2.0 mg, patients also achieved statistically significantly greater reductions in fasting plasma glucose than SEM 1.0 mg patients. Finally, the SEM 2.0 mg group had statistically significantly greater proportions of patients who achieved hemoglobin A1C less than 6.5%, or less than 7%, than the SEM 1.0 mg group.13
The changes to blood pressure were not assessed for statistical significance; however, in the intervention group systolic and diastolic blood pressure were 5.3 mm Hg and 0.8 mm Hg lower than baseline respectively, while in the comparator group systolic and diastolic blood pressure were 4.5 mm Hg and 0.4 mm Hg lower, respectively.
A total of 272 (57%) patients in the intervention group and 251 (52%) in the comparator group had at least 1 adverse event. Overall, 4% (n = 21) of patients had serious events in the intervention group, while 5% (n = 25) were serious in the comparator group. Two patients in the 2.0 mg group died, and both deaths were judged as unlikely to be related to treatment, while a single death in the 1.0 mg group was from neuromyelitis optica spectrum disorder. The latter was judged by the investigator as possibly related to treatment, but the sponsor thought this was unlikely as SEM is not previously linked to autoimmune mediated disorders. Two patients had level 3 hypoglycemia (severe hypoglycemia requiring assistance for recovery) in the intervention group while 1 patient had level 3 hypoglycemia in the comparator group. The most common reported side effects were gastrointestinal symptoms including nausea, diarrhea and vomiting, which occurred among 163 (34%) and 148 (31%) of patients in the intervention and control groups, respectively. One patient in the 1.0 mg group and 1 patient in the 2.0 mg group experienced a cardiac disorder resulting in premature discontinuation.
No eligible studies were identified; therefore, no summary can be provided.
There was 1 RCT identified that answered the research question. The study was conducted across several countries, suggesting generalizability to Canada may be appropriate. However, the patient population was overwhelmingly white (88%), thus failing to represent ethnic minorities who have greater prevalence of diabetes in Canada.14 For example, a single participant categorized by study authors as “American Indian or Alaska native” was included, and a breakdown of the 69 “Asian”’ patients was unavailable. At the same time, people of South Asian descent have a prevalence 8 times higher than white adults. For First Nations individuals living off-reserve, the prevalence is 1.72 times higher than in adults who do not identify as Indigenous.14
Not all the relevant outcomes, as stated in the PICO for this review, were explored in this trial. Diabetes-related cardiovascular outcomes were not explored in detail, other than captured as a general organ system (cardiovascular disorders) in terms of safety outcomes. Further, lipid profiles and health-related quality of life were not outcomes in this study.
This is also only 1 clinical trial. A larger evidence base could corroborate the findings in this study. Given that no cost-effectiveness studies were available, future studies assessing the cost of SEM 2.0 mg compared to other doses of semaglutide would also help with policy decision-making.
This review summarizes the most recent evidence regarding a 2.0 mg once-weekly dose of subcutaneous semaglutide for the glycemic management of T2DM, compared with alternative doses of semaglutide. A previous CADTH Reimbursement Review8 summarized evidence for doses up to 1.0 mg once weekly in Canada for this indication. Based on this review, the CADTH Canadian Expert Drug Committee issued a reimbursement recommendation with conditions.5
In this Rapid Review, a single RCT, the SUSTAIN FORTE trial13 was identified that suggests that once-weekly subcutaneous semaglutide 2.0 mg may achieve better glycemic control, with apparently similar rates of adverse events, compared to once-weekly subcutaneous semaglutide 1.0 mg. While the 0.18% difference in hemoglobin A1C between the doses was statistically significant, elsewhere a decline in hemoglobin A1C of at least 0.5% has been considered clinically meaningful.15 Thus, both arms did achieve clinically meaningful within-group reductions in hemoglobin A1C, with the difference between groups failing to achieve that threshold; whether such a difference between the 2 doses is therefore important in terms of long-term outcomes and diabetic control was not clear from this study.
Finally, while this trial was conducted across several countries, there was limited representation of minority groups with higher prevalence of T2DM in Canada such as Indigenous peoples or those of South Asian descent. Further, a single trial may not be enough to alter clinical practice in Canada, and a larger evidence base could further support the findings. Cost-effectiveness studies comparing various doses of semaglutide were also unavailable, comprising a research gap that, if filled, could assist in policy-making.
body mass index
glycated hemoglobin
randomized controlled trial
semaglutide
type 2 diabetes mellitus
Contributors: Calvin Young, Elizabeth Carson, Farhana Shivji
Selection of Included Studies.
Note that this appendix has not been copy-edited.
Characteristics of Included Primary Clinical Study.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Clinical Study Using the Downs and Black Checklist.
Note that this appendix has not been copy-edited.
Summary of Findings.
Note that this appendix has not been copy-edited.
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