Should HbA1c Targets be Revised in T2D?

Normoglycaemia, previously considered unachievable, is becoming a potential reality in T2D. Up to 51% of participants in the SURPASS program, even those with long-standing diabetes, achieved normoglycaemia and clinically significant weight loss without hypoglycaemia [21]. This unparalleled potency challenges existing treatment paradigms and targets, which may need to be revised.

Early and intensive HbA1c control in people with newly diagnosed T2D is well established for the prevention and management of microvascular complications [33] and has demonstrated a long-term legacy effect on macrovascular outcomes [34]. However, macrovascular benefit was elusive in people with T2D of longer duration (7.9–11.5 years) in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and Veterans Affairs Diabetes Trial (VADT) studies [35, 36], and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study reported increased CV mortality [37]. Further analyses suggested that increased rates of hypoglycaemia may have contributed to the lack of CV benefit with intensive HbA1c lowering in these studies [38, 39]. More recently, risk reduction for MACE was shown to be proportional to the magnitude of HbA1c decrease when agents with less hypoglycaemic potential were considered [39].

Tirzepatide did not increase CV risk in the SURPASS-1–5 studies [23], although subset analysis of participants achieving HbA1c < 5.7% (< 39 mmol/mol) was not reported. The ongoing CV outcomes trial, SURPASS-CVOT (anticipated completion 2024) [27], may help to establish the CV safety of achieving normoglycaemia with tirzepatide in people with T2D.

Current guidelines recommend that HbA1c targets in T2D are individualised, but a general target of ≤ 7% (≤ 53 mmol/mol) is commonly accepted [3, 4]. With the introduction of agents able to achieve normoglycaemia together with weight reduction without increased risk of hypoglycaemia, it is enticing to consider how outcomes for people with T2D might change if the HbA1c treatment goal was updated to be normoglycaemia. An HbA1c target closer to < 5.7% (39 mmol/mol), achieved early in the course of T2D, could potentially minimise the onset and progression of microvascular disease and have a legacy effect on macrovascular outcomes [34]. This potentially could reduce the burden of disease for people living with diabetes, and also reduce the burden on healthcare systems (tertiary and primary care).

Follow-up of the SURPASS clinical trials to assess long-term outcomes for the subgroup of participants who reached normoglycaemia with weight loss and no hypoglycaemia should add to the body of knowledge on prevention of complications associated with T2D, including emerging diabetes weight-related complications such as cancer, fatty liver disease and obstructive sleep apnoea.

Targeting Multi-morbidities in T2DWeight Loss

Weight loss in T2D can improve glycaemic control, insulin sensitivity and comorbidities [40, 41]. A person-centred approach focussing on updated weight loss targets—now achievable with therapies such as tirzepatide—may improve not only glycaemic control but also other metabolic complications for people with adiposity-associated T2D, including blood pressure, lipids, obstructive sleep apnoea and fatty liver disease. Non-metabolic progressive comorbidities such as osteoarthritis would also be expected to benefit from substantial weight loss.

Although weight loss is recognised as beneficial in the majority of people with T2D, it is challenging to maintain long-term and treatment targets have not been a focus of management [42]. Bariatric surgery is currently the most effective means of achieving substantial weight loss; clinical studies with Roux-en-Y gastric bypass in people with obesity and T2D demonstrated mean weight losses of 26–33%, compared with 5–8% in those receiving medical management [43]. Furthermore, bariatric surgery plus intensive medical therapy was superior to intensive medical therapy alone for decreasing (and in some subjects, resolving) hyperglycaemia in T2D plus obesity [44]. However, bariatric surgery is not feasible as a population-wide intervention for people with T2D [42].

With respect to glucose-lowering medications, the 2022 ADA/EASD consensus statement emphasises the need to focus on both glycaemic and weight management goals, and lists tirzepatide or semaglutide as having very high efficacy for weight loss [4]. Across the SURPASS studies, tirzepatide reduced mean body weight by 6.2–12.9 kg, with 7–43% achieving weight loss greater than 15%—including in participants receiving agents promoting weight gain, such as insulin [8,9,10,11,12]. Significantly greater weight losses were seen with tirzepatide than with semaglutide 1.0 mg in SURPASS-2, and significantly more participants achieved greater than 15% weight loss [9]. Weight loss achievable with medical therapy is becoming closer to that seen with bariatric surgery in people with T2D and obesity, potentially making sustained, substantial weight loss achievable for a greater proportion of these individuals.

Cardio-Renal-Metabolic Disease

Cardio-renal-metabolic (CRM) disease involves multidirectional interactions between CV disease, hypertension, kidney disease and metabolic disorders such as T2D, dyslipidaemia and obesity [45,46,47]. A holistic approach to CRM care that recognises the interconnected nature of these disorders may improve patient outcomes compared with isolated treatment of the individual conditions [47,48,49,50]. Although SGLT2i have offered a therapeutic option for CRM syndrome [48], there remains an unmet need for effective agents in this area.

Tirzepatide has demonstrated improved metabolic outcomes, including reductions in HbA1c, body weight and blood pressure, and improvement in lipid profile [8,9,10,11,12]. Information available to date suggests that tirzepatide may also have CV and kidney benefits in people with T2D [22, 23]. Determining the future potential for tirzepatide in CRM disease will depend on the outcomes of dedicated CV and kidney trials, but it is tempting to consider whether it might provide a treatment option for individuals at risk (Fig. 3).

Fig. 3

Will tirzepatide have a potential future in CRM disease? CV cardiovascular, T2D type 2 diabetes

Knowledge Gaps with Tirzepatide

The SURPASS clinical trial program was comprehensive, but some knowledge gaps remain regarding its use.

Most of the SURPASS studies were of 40–52 weeks duration. Long-term efficacy and safety data are needed to assess the durability of improved glycaemic control and weight loss, and to further elucidate the potential for adverse events of special interest such as diabetic retinopathy, cholelithiasis, thyroid medullary cancer and adverse pancreatic outcomes. The current studies did not identify red flags for retinopathy, but people with diabetic maculopathy, proliferative diabetic retinopathy, or non-proliferative diabetic retinopathy that required urgent treatment were excluded from the studies. Regardless of treatment modality, rapid improvements in glycaemic control can result in a temporary worsening of diabetic retinopathy [51], and prescribers of tirzepatide should be mindful of this.

SGLT2i is now recognised by many international guidelines as a first add-on therapy option for people with T2D not at HbA1c target on metformin, especially in those with or at high-risk of CV disease and kidney disease [4]. It would be useful to further explore the efficacy of adding tirzepatide to SGLT2i; subgroup analysis of SURPASS-3 and -4 may provide information on this combination. SURPASS-CVOT may also offer insights into the safety of the combination, as participants could receive other diabetes therapies, including SGLT2i, during the study.

Whilst kidney outcomes identified in SURPASS-4 were promising [22], the true renal protective effects of tirzepatide, and indeed other GLP-1RAs, await the results of dedicated kidney outcome studies in people with established diabetic kidney disease and renal impairment that assess the risk of progressing to kidney failure as their primary endpoint. Further subgroup analyses or future clinical trials would be useful to determine efficacy of tirzepatide in other targeted populations such as the elderly or different ethnic groups.

Other Indications

Tirzepatide is currently being investigated for use in other conditions, including obesity, heart failure with preserved ejection fraction (HFpEF) and non-alcoholic steatohepatitis (NASH).

Greater weight loss was seen with tirzepatide in the 72-week, phase 3 SURMOUNT study in people with obesity without T2D than in the SURPASS studies. This was expected, as weight loss achieved with any intervention in people without T2D generally exceeds that seen in people with T2D [42]. Tirzepatide 5, 10 and 15 mg demonstrated substantial and sustained reductions in body weight of 15.0%, 19.5% and 20.9%, respectively, versus 3.1% with placebo. Notably, 57% of participants receiving tirzepatide 10 or 15 mg achieved weight loss of 20% or more [52]. This approaches the weight loss typically expected for bariatric surgery, which is in the range of 25–35% [53], and suggests tirzepatide could play an important role in managing obesity.

The phase 3 SUMMIT study in people with HFpEF and obesity [54] and the phase 2 SYNERGY-NASH study [55] are ongoing.

Other Incretin Co-agonists and Combinations in Development

Tirzepatide is a first-in-class GIP/GLP-1 receptor agonist, but there are numerous other incretin-based co-agonists and combination therapies at various stages of preclinical and clinical development for different metabolic disorders. A wide range of potential partners to GLP-1 agonists have been investigated, including glucagon, amylin, cholecystokinin, fibroblast growth factors, and neuroreceptor Y2 (NPY2), as well as GIP receptor agonists and antagonists [56,57,58].

Several GLP-1/glucagon co-agonists have been investigated in phase 1 or 2 clinical trials [57]. A phase 2b study with once-daily cotadutide 100, 200 or 300 µg in T2D demonstrated reductions in HbA1c and body weight similar to those achieved with liraglutide 1.8 mg and significantly greater than those seen with placebo [59]. Gastrointestinal disorders were the most commonly reported adverse event; these occurred more frequently with cotadutide than with liraglutide or placebo, but incidence decreased over time [59]. Gastrointestinal adverse events and other safety issues have hindered the development of some GLP-1/glucagon co-agonist candidates, and several (e.g. SAR425899, efinopegdutide, NNC9204-1177) have been discontinued from development for management of T2D/obesity [57, 60].

Oxyntomodulin is an endogenous gut hormone that acts at both GLP-1 and glucagon receptors to reduce food intake and increase energy expenditure [61]. Mazdutide (LY3305677), an oxyntomodulin analogue, is currently in early clinical development and was reported to be well tolerated at doses up to 10 mg [62,63,64]

CagriSema, a combination of semaglutide 2.4 mg plus cagrilintide (an amylin analogue), is currently in development for obesity and T2D. A phase 1b trial in overweight/obese participants demonstrated an acceptable safety profile with reductions in body weight of up to 17% [65]. A 32-week phase 2 study in people with T2D (n = 92) demonstrated decreases in HbA1c of − 2.2% with CagriSema vs − 1.8% with semaglutide 2.4 mg (p = 0.075) and 0.9% with cagrilintide (p < 0.0001). Reductions in body weight were greater with CagriSema (− 15.6%) than with semaglutide 2.4 mg (− 5.1%) or cagrilintide (− 8.1%) (both p < 0.0001) [66].

Triple agonists are also in development. LY3437943, a novel triple GIP/GLP-1/glucagon co-agonist has been studied in people with T2D. In a phase 1, 12-week study with multiple ascending doses, placebo-adjusted mean decreases in HbA1c of up to 1.56% and body weight decreases of up to 8.96 kg were observed [67].

Most combination/co-agonist incretin-based therapies in development focus on improving efficacy, but preclinical studies with the GLP-1/NPY2 co-agonist GEP44 examined the potential for mitigation of nausea and vomiting [58]. GEP44 reduced food intake and body weight compared to exendin-4 controls, with little to no nausea behaviour (in rats) or emesis (in musk shrews). Further investigation of incretin-based therapies with reduced gastrointestinal adverse event profile is warranted [58].