The number of people living with T2DM is projected to increase to 700 million in 2045. The greatest increase will be seen in Africa. In 2017, an estimated 16 million South Africans adults (>25-years) were living with T2DM, of which 69% were unaware of their status.1
Dr Zaheer Bayat, Head of the Department of Endocrinology at Helen Joseph Hospital in Johannesburg, said the main reasons why so many South Africans remain undiagnosed are:1
1. Patients are hesitant to get tested
2. Lack of access to healthcare (many live far from hospitals and clinics)
3. Denial (do not want to accept diagnosis)
4. Availability of therapies in the public versus the private sector.
The situation is not unique to South Africa, noted Dr Bayat. Similar scenarios are prevalent in other African countries as well as the Middle East. Education and awareness about the diagnosis of T2DM and the availability of effective treatments are needed to overcome these challenges.1
Keynote speaker presentations
A number of international and local experts presented at the launch of semaglutide. This article summarises some of the presentations.
Incretin-based therapies: How do they work? Dr Daniel Drucker, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto (Canada)
The first incretin hormone, glucose-dependent insulinotropic polypeptide, was isolated in the 1970s. In 1985 a GLP-1, GLP-1 amide was characterised and was shown to have insulinotropic properties. In 1987 the GLP-1 sequence was discovered. This discovery revealed that GLP-1 was an insulin-stimulating glucoregulatory hormone.10
In 1993, researchers demonstrated that in patients with poorly controlled T2DM, a single exogenous infusion of GLP-1 increased insulin levels in a glucose-dependent manner.10
It has subsequently been recognised that GLP-1 is degraded by the ubiquitous protease dipeptidyl peptidase-4 (DPP-4), and thus that GLP-1 not only stimulates glucose-mediated insulin secretion but also has inhibitory effects on glucagon secretion, gastric emptying, and enhancing satiety, facilitating weight loss.10
Pivotal studies in patients with T2DM resulted in the approval of the first GLP-1RA in 2005. Today, multiple GLP-1RAs are approved for the treatment of T2DM.10
Once-weekly semaglutide was approved by the American Food and Drug Administration in 2017 as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM.11
In 2021, semaglutide was approved for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, T2DM, or high cholesterol), for use in addition to a reduced-calorie diet and increased physical activity.12
CV benefit of GLP-1RAs
Subsequent research led to the discovery that GLP-1RAs have cardiovascular (CV) benefits, said Dr Drucker.1 Scott et al investigated the association of variants in six genes that encode drug targets for obesity or T2DM with a range of metabolic traits.13
They compared associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials and tested the association of those variants with disease outcomes, including coronary heart disease, in order to predict the CV safety of GLP-1RAs. They found that a low-frequency missense variant in the gene encoding GLP1 (the target of GLP1RA) was associated with lower fasting glucose and lower T2DM risk. The minor allele was also associated with protection against CV diseases, thus providing evidence that GLP1RA are not likely to be associated with an unacceptable increase in CV risk.13
Dr Drucker pointed out that it is important to not only look at the CV benefits of this class of drug, but also on overall health. GLP-1RAs have been shown to reduce the risk of all-cause mortality1 as shown in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. The LEADER trial showed GLP1-RAs decrease the rate of the first occurrence of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke among patients with T2DM compared to placebo.6
About a decade ago, concerns were raised about an increased risk of pancreatitis and pancreatic cancer with the use of GLP-1RAs. Subsequently, real-world data show that GLP-1RAs are not associated with an increased risk, said Dr Drucker.1
El Aziz et al performed a meta-analysis of cases of acute pancreatitis and pancreatic cancer as well as any malignant neoplasm reported in CV outcomes trials (CVOTs) with GLP-1RAs and DPP-4 inhibitors. Individual CVOT data of GLP-1RA indicated a significantly elevated risk of acute pancreatitis, pancreatic cancer, or malignant neoplasms. However, a 75% risk increase for the development of an acute pancreatitis was seen in the meta-analysis of DPP-4 inhibitor CVOTs.14
Subgroups that benefit from GLP-1RAs
In the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) trial, a post-hoc analysis assessed the CV protective effects of semaglutide in various patient populations (gender, age, and baseline CV risk). The researchers found that once-weekly semaglutide versus placebo reduced the risk of major adverse cardiovascular events in all participants regardless of gender, age, or baseline CV risk profile.15
Efficacy of short- versus long-acting GLP1-RAs
The Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial found that semaglutide was superior to exenatide extended release in improving glycaemic control and reducing weight after 56 weeks of treatment. These results indicate that semaglutide treatment is highly effective in patients with T2DM inadequately controlled on oral antidiabetic drugs.3
The Semaglutide versus Dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial found that semaglutide was superior to dulaglutide in improving glycaemic control and reducing body weight, enabling a significantly greater number of patients with T2DM to achieve clinically meaningful glycaemic targets and weight loss.5
SUSTAIN clinical programme
Dr Aslam Amod, endocrinologist based in KwaZulu-Natal and co-author of the South African T2DM guideline
The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) clinical trial programme involved more than 20 000 patients globally and comprises 17 phase 3 studies.1
Dr Amod focused on the findings of the following studies:
- Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial: semaglutide significantly improved HbA1c and weight in patients with T2DM compared with placebo.16
- Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial: once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing weight in patients on metformin, thiazolidinediones, or both. Semaglutide seems to be an effective add-on treatment option for this patient population.2
- Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial: compared with insulin glargine, semaglutide resulted in greater reductions in HbA1c and weight, with fewer hypoglycaemic episodes, and was well tolerated, with a safety profile similar to that of other GLP-1 receptor agonists.4
- Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial: Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D vs placebo.17
- Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial: Once-weekly semaglutide 1mg was superior to daily canagliflozin 300mg in reducing HbA1c and weight in patients with T2DM uncontrolled on metformin therapy. These outcomes might guide treatment intensification choices.18
- Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial: adding semaglutide to Sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT-2i) therapy significantly improves glycaemic control and reduces weight in patients with inadequately controlled T2DM and is well tolerated.19
- Efficacy And Safety Of Semaglutide 1.0 mg Once Weekly Versus Liraglutide 1.2 mg Once Daily (SUSTAIN 10): both treatments were effective in reducing HbA1c and weight in patients with T2DM and demonstrated superior efficacy with semaglutide 1mg once weekly compared with liraglutide 1.2mg once daily. These findings are consistent with those from the SUSTAIN 3 and 7 trials (see above). In conclusion, the SUSTAIN 10 results support semaglutide as a favourable treatment option in clinical practice.20
- Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial: semaglutide 2mg was superior to 1mg in reducing HbA1c, with additional weight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with T2DM treated with semaglutide in need of additional glycaemic control.21
Results across SUSTAIN 1-5 and 7-10
- Reductions in HbA1c greater with semaglutide than comparators (placebo, sitagliptin, exenatide extended release, insulin glargine, dulaglutide, canagliflozin, liraglutide)2,3,4,5,6,16,17,18,19,20
- Semaglutide consistently improved glycaemic control, regardless of:
- Baseline BMI15
- Background treatment
- Diabetes duration15
- Baseline estimated glomerular filtration rate or pre-existing chronic kidney disease.
- Semaglutide consistently reduced fasting PG and/or PPG suggesting both contribute to significantly better glycaemic control versus comparators2,3,4,5,6,17,18,19,20,21
- Reductions in HbA1c were greater in patient with higher baseline HbA1c.4,5
- A Research Study to Compare Semaglutide to Insulin Aspart, When Taken Together With Metformin and Insulin Glargine, in People With Type 2 Diabetes (SUSTAIN 11): will compare the effect of semaglutide once weekly to insulin aspart three times daily as add on to metformin and insulin glargine in patients with T2DM.22
- A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW): will look at whether semaglutide can slow down the growth and worsening of chronic kidney disease in people with T2DM.23
Multifactorial and individualised patient-centred care: the art of medicine
Dr Landi Lombard, endocrinologist, and Director of the Cape Town Medical Centre
The art of medicine comprises individualised care that depends on the knowledge and experience of the healthcare professional. The better and more comprehensive his or her knowledge and experience, the easier it will be to individualise the care of patients, said Dr Lombard.1
The aims of diabetes care are to:1
1. Optimise patient survival by addressing all CV risk factors
2. Control glucose with hypoglycaemia, weight gain or side effects to reduce the risk of diabetes-related complications
3. Improve patients’ quality of life.
Numerous studies have shown an association between the degree of hyperglycaemia and increased risk of microvascular complications, sensory neuropathy, myocardial infarction, stroke, macrovascular mortality, and all-cause mortality in patients with T2DM.24
The UK prospective diabetes study looked at the effect of intensive control of blood glucose (HbA1c of 7% versus 7.9%). The study found that each 1% reduction in mean HbA1c was associated with reductions in risk of 21% for any end point related to diabetes, 21% for deaths related to diabetes, 14% for myocardial infarction, and 37% for microvascular complications.24
The researchers concluded that the risk of diabetic complications was strongly associated with previous episodes of hyperglycaemia. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6%).24
How do we modify CV risk in T2DM?
The effective management of T2DM requires a multifactorial approach, which has been shown to improve patient outcomes. A multifactorial approach focuses on addressing the different risk factors in patient with T2DM, said Dr Lombard.1
Gaedi et al (2008) evaluated whether intensified multifactorial intervention (tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents) reduces the risk of nonfatal CV disease among patients with T2DM and microalbuminuria. The mean treatment period was 7.8 years and patients were followed observationally for a mean of 5.5 years. The primary endpoint at 13.3 years of follow-up was the time to death from any cause. Intensive therapy was associated with a lower risk of death from CV causes (45%) and of cardiovascular events (42%).25
In their 21-year old follow-up study, Gaedi et al (2016) studied the potential long-term impact of a 7.8 years intensified, multifactorial intervention in patients with T2DM and microalbuminuria in terms of gained years of life and years free from incident CVD. The patients in the intensive-therapy group survived for a median of 7.9 years longer than the conventional-therapy group patients. Median time before first CV event after randomisation was 8.1 years longer in the intensive-therapy group. Patients in the intensified group had a 33%-45% decreased risk of microvascular complication, except for peripheral neuropathy, which increased by 12%.26
Rawshani et al investigated whether the excess risk of death and CV events among patients with T2DM could be reduced or eliminated. They assessed patients with diabetes according to age categories and the presence of five risk factors:27
1. Elevated glycated haemoglobin level
2. Elevated low-density lipoprotein cholesterol (LDL-C) level
5. Elevated blood pressure (BP).
Among patients with T2DM, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. Among patients who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06, the hazard ratio for acute myocardial infarction (AMI) was 0.84, and the hazard ratio for stroke was 0.95.27
The risk of hospitalisation for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio 1.45). In patients with T2DM, a glycated haemoglobin level outside the target range was the strongest predictor of stroke and AMI, and smoking was the strongest predictor of death. The researchers concluded that patients with T2DM who had five risk-factor variables within the target ranges appeared to have little or no excess risk of death, MI, or stroke, compared to the general population.27
Targeted prevention strategies to reduce CVD in patients with diabetes and pre-diabetes
Risk factors in patients with T2DM can be modified through:28,29,30
- Lifestyle modification
- Reduce calorie intake to reduce excessive weight
- Moderate to vigorous physical activity for more than 150 minutes a week is recommended for the prevention and control of diabetes
- Smoking cessation
- Glycaemic target
- Appy tight glucose control, targeting a near normal HbA1c (<7%) to decrease microvascular complication.
- BP targets
- Target systolic BP to 130mm/Hg and <130mm/Hg if tolerated, but not <120mm/Hg
- In older patients (>65 years), the systolic BP target should be between 130-139mm/Hg
- Dyslipidaemia targets
- In patients at extremely high CV risk, the recommended LDL-C target is <1.4mmol/L or LDL-C reduction of ≥50%
- In patients at high CV risk, the recommended LDL-C target is <1.8mmol/L or LDL-C reduction of ≥50%
- In patients at moderate CV risk, the recommended LDL-C target is <2.5mmol/L.
- Platelet target
- In patients at high/extremely high CV risk, aspirin may be considered in primary prevention
- In patients at moderate CV risk, aspirin for primary prevention is not recommended.
1. Novo Nordisk. Ozempic launch, 21 August 2021.
2. Ahrén B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): A 56-week, double-blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol, 2017.
3. Ahmann AJ, et al. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. Diabetes Care, 2018.
4. Aroda VR, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol, 2017.
5. Pratley RE, et al. Semaglutide once weekly versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol, 2018.
6. Marso SP, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016.
7. Ozempic® South Africa PI.
8. Foresight Global Health. Addressing the Unmet Needs of People Living with Diabetes: 100 years after the discovery of insulin. https://foresightglobalhealth.com/addressing-the-unmet-needs-of-people-living-with-diabetes-100-years-after-the-discovery-of-insulin/.
9. International Diabetes Foundation. IDF Diabetes Atlas, 9th edition. Worldwide toll of diabetes. https://www.diabetesatlas.org/en/sections/worldwide-toll-of-diabetes.html.
10. Drucker DJ, et al. Discovery, characterization, and clinical development of the glucagon-like peptides. The Journal of Clinical Investigation, 2017.
11. FDA. FDA Approves Semaglutide Injection For the Treatment of Adults with Type 2 Diabetes. Endocrine News, 2017.
12. FDA. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA News Release, 4 June 2021.
13. Scott RA et al. Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Sci Transl Med, 2016.
14. El Aziz MA, et al. Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials. Diabetes, Obesity and Metabolism, 2019.
15. Leiter LA, et al. Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial. Cardiovascular Diabetology, 2019.
16. Sorli C, et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. The Lancet, 2017.
17. Rodbard HW, et al. Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial. J Clin Endocrinol Metab, 2018.
18. Lingvay I, et al. Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial. The Lancet, 2019.
19. Zinman B, et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. The Lancet, 2019.
20. Capehorn MS, et al. SUSTAIN 10: efficacy and safety of semaglutide 1.0 mg once weekly versus liraglutide 1.2 mg once DAI. EMJ Diabet, 2019.
21. Frias JP, et al. Efficacy and safety of once-weekly semaglutide 2.0 mg versus 1.0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial. The Lancet, 2021.
22. US National Library of Medicine. A Research Study to Compare Semaglutide to Insulin Aspart, When Taken Together With Metformin and Insulin Glargine, in People With Type 2 Diabetes(SUSTAIN 11).
23. US National Library of Medicine. A Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW).
24. Stratton IM, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ, 2000.
Gaede P, et al. Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. NEJM, 2008.
25. Gaede P, et al. Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial. Diabetologia, 2016.
26. Rawhani A, et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. NEJM, 2018.
27. American Diabetes Association. Standards Of Medical Care In Diabetes -2016. Diabetes Care, 2016.
28. Ross SA. Breaking Down Patient and Physician Barriers to Optimize Glycemic Control in Type 2 Diabetes. The American Journal of Medicine, 2013.
29. Cosentino F. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes(EASD). European Heart Journal, 2020.