SURPASS Trials – the future of diabetes management

Therapeutics through the ages

The journey of insulin discovery began in the late 19th century, spotlighting the pancreas as key in diabetes management. Pioneer Paul Langerhans first described pancreatic islets in 1869, propelling animal studies to explore pancreatic extracts’ role in glucose regulation. Early 20th-century trials by Georg Zuelzer and Nicolae Paulescu showed potential in these extracts, but their work was overshadowed by the groundbreaking insulin discovery by Frederick Banting and Charles Best in 1921-22, built on preceding research. The categorisation of diabetes into insulin-sensitive (type 1) and insulin-insensitive (type 2) forms in the mid-20th century, however, indicated that insulin wasn’t the panacea for all diabetes types, signalling the need for additional therapeutic agents, especially for type 2 diabetes.

The most common therapeutic agent used today is that of Metformin, or metformin hydrochloride. Metformin, an oral glucose-lowering agent, traces its lineage back to the 1700s with the use of Galega officinalis, or goat’s-rue, rich in guanidine, for diabetes symptoms. Though first synthesised in 1922, metformin was initially overlooked due to its perceived insufficient potency. In the 1940s, its blood glucose-lowering effects were recognized during antimalarial studies and used as an anti-influenza agent. The game-changer came in 1956 when Jean Sterne reassessed biguanides’ glucose-lowering properties, showing metformin’s effectiveness and tolerability. By 1958, metformin was introduced in Europe as a treatment for maturity-onset diabetes. Despite other biguanides’ initial preference, they were discontinued due to a high risk of lactic acidosis. The benefits of metformin were confirmed by extensive studies from the 1960s till now, eventually replacing sulphonylureas as the primary oral glucose-lowering therapy for type 2 diabetes. It seems that diabetic agents through the years have been used in waves, even ‘fads’, and it’s unlikely we’ve seen the end of the ever-evolving diabetic therapeutics market. 

In the continuous pursuit of more effective diabetes therapies, the underutilised potential of incretin hormones, GLP-1 and GIP, has been harnessed in the innovation of a new medication, Tirzepatide. Its unique characteristic of having greater affinity to GIP receptors and its long half-life enabling once-weekly dosing offers an exciting novel angle for diabetes management. Initial studies indicate that it not only improves beta cell function but also enhances insulin sensitivity, compared to selective GLP-1 receptor agonist therapy. Following recent encouraging results from the SURPASS clinical trial programme, Tirzepatide has reached the pivotal milestone of new drug application submissions to the FDA and TGA. This progress sets the stage for a potential revolutionary treatment for type 2 diabetes, one that taps into the synergistic and complementary actions of two essential incretin hormones to optimise metabolic and cardiovascular outcomes. Can Tirzepatide be the next Metformin and completely revolutionise diabetes management?

What the SURPASS trials and recent research has found

A recent meta-analysis of Tirzepatide by Karrigianis et al. was conclusive in assessing available evidence from over 202 peer-reviewed trials. The study focused on randomised controlled trials that lasted a minimum of 12 weeks, comparing the effects of once-weekly 5, 10, or 15 mg doses of Tirzepatide against a placebo or other glucose-lowering drugs in adults with type 2 diabetes, regardless of their existing glucose-lowering treatment regimen. The primary objective was to evaluate the change in HbA1c levels from the baseline. Secondary efficacy goals included alterations in body weight, the percentage of participants achieving HbA1c targets of less than 53 mmol/mol (less than 7.0%), 48 mmol/mol (6.5% or less), or 39 mmol/mol (less than 5.7%), and the proportion of participants experiencing body weight loss of at least 5%, 10% or 15%. In terms of safety, the outcomes analysed were instances of hypoglycemia, gastrointestinal side effects, discontinuation of treatment due to adverse events, serious adverse events, and mortality rates.

The trials included participants who had an average HbA1c of 66.47 mmol/mol (8.2%), an average body weight of 91.5 kg, and an average age of 58 years. In five studies, the participants’ existing glucose-lowering treatment involved metformin, either alone or combined with another oral medication. Based on these studies, very few participants required additional therapy (ranging between 0.3% and 3.5% of participants), with one exception: in one study, 25% of participants in the placebo group needed extra therapy. Certain medications, such as GLP-1 RAs, dipeptidyl peptidase 4 inhibitors, and pramlintide, were not permitted as additional therapies.

Compared to a placebo, the drop in HbA1c levels varied between 17.71 mmol/mol (1.62%) with 5 mg of Tirzepatide and 22.35 mmol/mol (2.06%) with 15 mg of Tirzepatide. The results were consistent, and there was less statistical inconsistency in a sensitivity analysis that excluded a trial of short duration and a trial that involved participants already on insulin therapy. All Tirzepatide doses outperformed the placebo in terms of reaching the HbA1c target of less than 53 mmol/mol (less than 7.0%), 48 mmol/mol (6.5% or less), or 39 mmol/mol (less than 5.7%). Compared to GLP-1 RAs, 5, 10, and 15 mg of Tirzepatide reduced HbA1c levels by 3.22 mmol/mol (0.29%), 7.11 mmol/mol (0.65%), and 10.06 mmol/mol (0.92%), respectively. More participants on any dose of Tirzepatide achieved the three HbA1c targets compared to those on a GLP-1 RA, except for the target of less than 53 mmol/mol (less than 7.0%) with 10 mg of Tirzepatide. All three Tirzepatide doses were more effective than basal insulin in both reducing HbA1c and reaching the three HbA1c targets. It’s worth noting that the average basal insulin dose at the end of the study (week 52) was 48.8 U with insulin degludec in the SURPASS-3 trial and 43.5 U with insulin glargine in the SURPASS-4 trial. The results assessed in this meta-analysis were undeniably impressive, however, what are the applications for Tirzepatide in the current market against classical therapies?

Adverse events prove minimal limitations

Mishura et al. 2023 investigated the common adverse events (AEs) related to Tirzepatide in those with type 2 diabetes mellitus. The meta analysis assessed 10 trials, spanning over 6800 participants, finding common adverse events such as GI irritation and pancreatic events at the forefront. They found a significantly higher proportion of patients experiencing gastrointestinal adverse events (GI AEs) with Tirzepatide, increasing with the dosage. Nausea and diarrhoea were the most frequently reported GI AEs across all doses throughout these studies. Surprisingly, dyspepsia and constipation were most frequently seen with the 10-mg dose of Tirzepatide. The proportion of abdominal distension, abdominal discomfort, eructation, and abdominal pain was highest with the 15-mg dose of Tirzepatide.

The incidence of cholelithiasis and cholecystitis was insignificant and decreased with higher doses of the new medication. The incidence of acute pancreatitis did not differ significantly with different doses, however, there was an increase in elevated lipase levels with higher doses, with a higher incidence in patients treated with any dose of Tirzepatide compared to placebo.

There was no significant difference in the proportion of hypoglycemic events across different doses of Tirzepatide, marking a significant breakthrough in safety of the drug. Glucose levels ≤70 mg/dL were highest with the 10-mg dose, followed by the 15-mg dose, then the 5-mg dose. The incidence of glucose levels ≤54 mg/dL was nearly the same for all 3 doses. The incidence of injection site reactions increased with the dosage, whereas interestingly, hypersensitivity reactions were higher in the placebo group and 5-mg and 10-mg doses compared to the 15-mg dose. 

Weight loss at the front of this push

The transformational impact of Tirzepatide on weight loss is undeniable. When compared to the insulin group, the use of this exciting new drug resulted in an impressive decrease in patient body weight by 1.93 kg (95% Confidence Interval (CI) -2.81 to -1.05). Even more astoundingly, trials that employed three different doses of Tirzepatide (5 mg, 10 mg, and 15 mg) all demonstrated a substantial and noteworthy reduction in patient body weight relative to the insulin group. Specifically, the 5 mg dose elicited an admirable mean decrease of 1.09 kg (95% CI -1.87 to -0.30, P = 0.007). The 10 mg dose, even more potent, led to an extraordinary mean decrease of 1.50 kg (95% CI -2.26 to -0.73, P = 0.0001). Yet, the 15 mg dose, the most powerful of all, prompted a staggering mean decrease of 3.21 kg (95% CI -5.64 to -0.78, P = 0.01). 

In a stunning testament to tirzepatide’s efficacy, when compared to both the placebo group and those receiving GLP-1 RAs or insulin, a greater proportion of patients treated with any of the three Tirzepatide doses reached awe-inspiring reductions in body weight of at least 5%, 10%, or 15%. These findings are indeed cause for celebration in the ongoing battle against obesity.

A promising future

In conclusion, the introduction of Tirzepatide onto the market for the treatment of type 2 diabetes is indeed exciting. Evidently, it stands as a very effective therapy, contributing to the growing arsenal of advanced pharmaceutical interventions for this prevalent condition. Its efficacy is reminiscent of GLP-1 receptor agonists, which are currently being utilised off-label in Australia for weight management due to their significant results in populations without diabetes. As such, Tirzepatide might well follow a similar trajectory, becoming a dual-purpose treatment for both type 2 diabetes and obesity.

It is critical to closely monitor the progression and usage of this promising drug, especially as it becomes routine practice in primary health care. This is particularly relevant given that diabetes and obesity form a substantial proportion of the patient population seen by general practitioners. The potential broader use of Tirzepatide could revolutionise treatment approaches, ushering in an era of more holistic and effective management of these interconnected metabolic conditions.

BAILEY, C.J. (2022) View of the origins of type 2 diabetes medications: British Journal of diabetes, View of The origins of type 2 diabetes medications | British Journal of Diabetes. Available at: https://bjd-abcd.com

Berman C, Vidmar AP, Chao LC. Glucagon-like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes in Youth. touchREV Endocrinol. 2023 May;19(1):38-45. doi: 10.17925/EE.2023.19.1.38. Epub 2023 May 23. PMID: 37313232; PMCID: PMC10258616.

de Mesquita YLL, Pera Calvi I, Reis Marques I, Almeida Cruz S, Padrao EMH, Carvalho PEP, da Silva CHA, Cardoso R, Moura FA, Rafalskiy VV. Efficacy and safety of the dual GIP and GLP-1 receptor agonist tirzepatide for weight loss: a meta-analysis of randomised controlled trials. Int J Obes (Lond). 2023 Jul 17. doi: 10.1038/s41366-023-01337-x. Epub ahead of print. PMID: 37460681.