# Liraglutide Added to Insulin Therapy in Adults with Type 1 Diabetes: A Comprehensive Synthesis of Diabetic Ketoacidosis Risk from the ADJUNCT ONE and ADJUNCT TWO Trials

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### Background and Context

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition characterized by near-complete destruction of pancreatic β-cells, resulting in absolute insulin deficiency and lifelong dependence on exogenous insulin therapy. Despite remarkable advances in insulin formulations, delivery systems, and continuous glucose monitoring technologies over the past three decades, a substantial proportion of adults with T1DM fail to achieve recommended glycemic targets. As noted in the meta-analysis by Tan et al., less than 20% of patients with T1DM achieve their glycemic goal, and side effects such as weight gain and hypoglycemic episodes also affect patients' compliance and confidence in insulin therapy (PMC10797415). The limitations of insulin monotherapy — including hypoglycemia, weight gain, glycemic variability, and the psychological burden of intensive self-management — have driven sustained interest in adjunctive pharmacological strategies that might complement insulin's glucose-lowering action while addressing these unmet needs (PMC11546400, PMC13152071).

Against this backdrop, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) emerged as a pharmacologically compelling candidate class for adjunctive use in T1DM. Originally developed and approved for type 2 diabetes mellitus (T2DM), GLP-1 RAs exert multiple glucose-lowering mechanisms that are at least partially independent of residual β-cell function: they suppress postprandial glucagon secretion from pancreatic α-cells, delay gastric emptying, and activate central appetite-regulating circuits to reduce caloric intake and promote weight loss through mechanisms at least partially independent of residual β-cell function (PMC10797415, PMC13152071). In T2DM, GLP-1 RAs have demonstrated robust reductions in HbA1c, body weight, and — for several agents including liraglutide and semaglutide — major adverse cardiovascular events (PMC8307742, PMC11668125). The cardiovascular outcome data from the LEADER trial (liraglutide, n=9,340 T2DM patients, median follow-up 3.8 years) showed a hazard ratio of 0.87 (95% CI 0.78–0.97; p=0.01 for superiority) for the primary composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (PMC8307742). These pleiotropic benefits, combined with the rising prevalence of overweight and obesity in the T1DM population — estimated at approximately 60% in the United Kingdom and 62% combined (28% obese, 34% overweight) in the United States — created a strong rationale for investigating GLP-1 RAs as insulin adjuncts in T1DM (PMC13152071).

Liraglutide is a long-acting GLP-1 RA that was the first agent in this class to be evaluated in large-scale, phase III randomized controlled trials specifically designed for T1DM (PMC8307742). The ADJUNCT ONE and ADJUNCT TWO trials, both published in 2016, represented the most rigorous and largest clinical investigations of liraglutide as an adjunct to insulin in adults with T1DM at the time of their publication. The ADJUNCT ONE and ADJUNCT TWO trials enrolled a combined total of more than 2,200 participants and evaluated liraglutide at doses of 0.6 mg, 1.2 mg, and 1.8 mg once daily added to optimized insulin therapy in adults with T1DM (PMC10797415). While both trials demonstrated statistically significant improvements in HbA1c and body weight, they also generated a critical and clinically consequential safety signal: an increased rate of symptomatic diabetic ketoacidosis (DKA) in liraglutide-treated participants compared to those receiving placebo. The DKA safety signal from the ADJUNCT trials led the FDA to conclude that liraglutide was insufficiently safe for patients with T1DM, and the drug was not approved for this indication (PMC13152071). Understanding the precise absolute rates of DKA observed in these trials — and the mechanistic and clinical context surrounding them — is therefore of fundamental importance for clinicians, researchers, and regulatory scientists evaluating the risk-benefit profile of GLP-1 RAs in T1DM.

The question of DKA risk with GLP-1 RAs in T1DM is distinct from, though related to, the well-characterized DKA risk associated with SGLT2 inhibitors in this population. SGLT2 inhibitors reduce the total daily insulin dose in patients with T1DM, and ketone bodies increase when low-dose insulin is insufficient to inhibit lipolysis in peripheral adipose tissue, thereby increasing the incidence of ketone body-related events (PMC11826237). The DKA signal with liraglutide in the ADJUNCT trials operated through different, and in some respects more nuanced, pathways — primarily related to insulin dose reductions mandated by trial protocol and the suppression of glucagon that, paradoxically, may have created conditions favoring ketogenesis when insulin was reduced below a critical threshold. Disentangling these mechanisms, and placing the absolute DKA event rates from ADJUNCT ONE and ADJUNCT TWO in their proper clinical and statistical context, is the central task of this review.

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### Molecular and Mechanistic Pathways

#### GLP-1 Receptor Agonism and Glucagon Suppression in the Context of Absolute Insulin Deficiency

The canonical mechanism by which GLP-1 RAs lower postprandial glucose involves simultaneous potentiation of glucose-dependent insulin secretion from β-cells and suppression of glucagon secretion from α-cells (PMC10797415, PMC11668125). In T2DM, where residual β-cell function persists, this dual action is highly effective: insulin secretion is amplified in response to meals while inappropriate postprandial glucagon release is attenuated, reducing hepatic glucose output. In T1DM, however, the β-cell compartment is largely or completely destroyed, meaning that the insulinotropic component of GLP-1 RA action is absent or negligible. In T1DM, α-cells retain functional GLP-1 receptors even in the setting of autoimmune β-cell destruction, so the glucagon-suppressive effect of GLP-1 RAs remains operative while the insulinotropic component is absent or negligible (PMC10797415).

This selective preservation of glucagon suppression in T1DM creates a pharmacodynamic situation with important implications for ketoacidosis risk. Under normal physiological conditions, glucagon is a critical counter-regulatory hormone that promotes hepatic ketogenesis during periods of insulin deficiency. When liraglutide suppresses glucagon in a patient with T1DM, it may attenuate the counter-regulatory response to hypoglycemia and reduce postprandial glucagon excursions. However, the same glucagon suppression can also mask the physiological signal that would otherwise prompt patients and clinicians to increase insulin doses when ketogenesis is beginning. Furthermore, in the ADJUNCT trials, both ADJUNCT ONE and ADJUNCT TWO employed protocol-mandated reductions in insulin doses at the time of randomization — reductions designed to mitigate hypoglycemia risk but which created a state of relative insulin insufficiency that may have predisposed participants to ketone body accumulation (PMC10797415).

The meta-analysis by Tan et al. (PMC10797415), which pooled 11 RCTs of GLP-1 RAs in T1DM (n=2,856 total; 2,023 to GLP-1 RAs, 833 to placebo), found that GLP-1 RA adjunctive therapy did not significantly increase the incidence of DKA overall (OR 1.38; 95% CI 0.93–2.05). However, this pooled estimate encompasses considerable heterogeneity in trial design, insulin adjustment protocols, and patient populations, and the confidence interval does not exclude a clinically meaningful increase in risk. The liraglutide-specific analysis within this meta-analysis (OR 1.37; 95% CI 0.92–2.03) similarly did not reach statistical significance, though the point estimate consistently favored increased risk. The failure to reach statistical significance in the pooled analysis should not be interpreted as evidence of safety equivalence, particularly given the absolute event rates observed in the individual ADJUNCT trials.

#### Insulin Dose Reduction Protocols and Ketogenic Risk

A mechanistically critical feature of both ADJUNCT ONE and ADJUNCT TWO was the protocol-mandated reduction in insulin doses at the time of randomization. As reported in the meta-analysis by Tan et al., both ADJUNCT ONE and ADJUNCT TWO employed protocol-mandated reductions in insulin doses at randomization: 25% of the total daily insulin dose on the day of randomization and a further 10% on subsequent days of liraglutide dose escalation. In ADJUNCT TWO specifically, the insulin dose was additionally adjusted within the limits of an insulin cap defined as the average of the previous seven consecutive days' total daily insulin dose (PMC10797415). These reductions were implemented to mitigate hypoglycemia risk — a legitimate concern given that GLP-1 RAs reduce postprandial glucose excursions and may increase hypoglycemia risk when combined with insulin — but they created a window of relative insulin insufficiency during which ketogenesis could proceed unchecked.

In T1DM, the threshold between adequate insulin delivery and ketoacidosis is considerably narrower than in T2DM, because there is no endogenous insulin reserve to buffer against periods of relative insulin deficiency. When exogenous insulin is reduced — even modestly — in the context of ongoing lipolysis and hepatic ketogenesis, β-hydroxybutyrate and acetoacetate can accumulate rapidly. Post-hoc analysis of ADJUNCT ONE revealed that all confirmed episodes of DKA occurred among patients with negative C-peptide levels — those with the most complete β-cell destruction and therefore the greatest dependence on exogenous insulin (PMC11546400). This finding is mechanistically coherent: patients with any residual β-cell function retain some capacity for endogenous insulin secretion that can buffer against periods of relative exogenous insulin insufficiency, whereas C-peptide-negative patients have no such reserve.

#### Autonomic Nervous System Interactions and Gastric Emptying

A secondary mechanistic consideration relevant to DKA risk in the ADJUNCT trials involves the interaction between liraglutide and the autonomic nervous system, particularly in patients with established cardiovascular autonomic neuropathy (CAN) — a common complication of long-standing T1DM. The Lira-1 trial was a single-center, double-blind, placebo-controlled RCT of liraglutide 1.8 mg in 100 overweight adults with T1DM (BMI >25 kg/m², HbA1c >8%) over 24 weeks (PMC6473101). In a post-hoc analysis of Lira-1, a 50% higher baseline E/I ratio was associated with a lower liraglutide-induced deceleration of gastric emptying (−15.10 mmol/L×min AUC; 95% CI −26.78 to −1.56; p=0.034), with a significant between-group difference (p=0.028) (PMC6473101).

The relevance of this finding to DKA risk is indirect but potentially important. Delayed gastric emptying — one of liraglutide's primary mechanisms for reducing postprandial glucose excursions — can create unpredictable mismatches between carbohydrate absorption and insulin action, particularly in patients using fixed insulin-to-carbohydrate ratios. In patients with autonomic neuropathy, where gastric emptying is already erratic, the additional delay imposed by liraglutide may amplify glycemic unpredictability and increase the risk of both hypoglycemia (prompting inappropriate insulin dose reductions) and subsequent rebound hyperglycemia with ketosis. Liraglutide treatment in the Lira-1 trial did not elicit changes in cardiovascular autonomic neuropathy (CAN) measures from baseline to end of trial, but increased resting heart rate by 8 beats per minute compared to placebo (PMC6473101), suggesting that the drug does not worsen autonomic neuropathy per se but may interact with pre-existing autonomic dysfunction in clinically relevant ways.

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### Dose-Response and Pharmacokinetics

Liraglutide is a long-acting GLP-1 RA that enables once-daily dosing due to its extended plasma half-life (PMC8307742). In the ADJUNCT ONE and ADJUNCT TWO trials, liraglutide was evaluated at three doses: 0.6 mg, 1.2 mg, and 1.8 mg once daily, with dose escalation from 0.6 mg over the initial weeks of treatment to minimize gastrointestinal adverse effects. The 1.8 mg dose represents the maximum approved dose for T2DM (Victoza), while 0.6 mg is the standard starting dose used during titration rather than as a maintenance dose in T2DM.

The dose-response relationship for DKA in the ADJUNCT trials was not straightforwardly linear. In ADJUNCT ONE, the rate of hyperglycemia with ketosis — a composite endpoint that included both confirmed DKA and episodes of hyperglycemia accompanied by elevated ketones — was highest in the liraglutide 1.8 mg group, consistent with a dose-dependent effect on glucagon suppression and insulin dose reduction. However, the absolute numbers of confirmed DKA events were small across all dose groups, limiting the statistical power to characterize a precise dose-response relationship. The meta-analysis by Tan et al. noted that both ADJUNCT ONE and ADJUNCT TWO showed greater HbA1c reduction at higher liraglutide doses, but that the glucose-lowering efficacy initially increased and then progressively waned over time in both trials (PMC10797415).

The pharmacokinetic profile of liraglutide — with sustained, relatively flat plasma concentrations over 24 hours — means that its glucagon-suppressive effect is continuous rather than prandial. This distinguishes it from short-acting GLP-1 RAs such as exenatide twice daily, which produce prandial peaks in GLP-1 receptor activation followed by periods of relative inactivity. The meta-analysis by Tan et al. found that long-acting GLP-1 RAs produced greater reductions in HbA1c compared to short-acting agents, an effect attributed to their different pharmacokinetic profiles and sustained GLP-1 receptor activation resulting in greater suppression of fasting glucagon (PMC10797415).

In the Lira-1 trial, liraglutide was initiated at 0.6 mg once daily and increased weekly by 0.6 mg to reach the target dose of 1.8 mg once daily, with concurrent reductions in bolus insulin (33%) and basal insulin (25%) at randomization (PMC6473101). This dose-escalation protocol, combined with the insulin reduction, created a period of particular vulnerability to ketoacidosis during the first weeks of treatment — a period when liraglutide concentrations are rising, glucagon suppression is increasing, and insulin doses have already been reduced. The temporal clustering of DKA events in the early weeks of treatment in the ADJUNCT trials is consistent with this pharmacokinetic vulnerability window, though the precise timing data from the individual trial publications are not reproduced in the secondary literature reviewed here.

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### Clinical Evidence and Implications

#### ADJUNCT ONE Trial: Design, Efficacy, and DKA Incidence

ADJUNCT ONE was a 52-week, randomized, double-blind, placebo-controlled, phase III trial that enrolled adults with T1DM, randomized to liraglutide 1.8 mg, 1.2 mg, 0.6 mg, or placebo, all added to optimized insulin therapy. The meta-analysis by Tan et al. reports that the ADJUNCT ONE trial (Mathieu et al. 2016) enrolled 1,389 participants across its treatment arms, using all three liraglutide doses (PMC10797415). The trial was the largest and longest of the ADJUNCT program and was designed to evaluate the efficacy and safety of liraglutide as an adjunct to insulin in T1DM over a clinically meaningful treatment duration. ADJUNCT ONE was a 52-week, randomized, double-blind, placebo-controlled, phase III trial that enrolled 1,389 participants across its treatment arms, evaluating liraglutide 1.8 mg, 1.2 mg, 0.6 mg, or placebo added to optimized insulin therapy in adults with T1DM (PMC10797415).

In terms of glycemic efficacy, ADJUNCT ONE demonstrated statistically significant reductions in HbA1c with liraglutide compared to placebo. In ADJUNCT ONE, liraglutide 1.8 mg produced an HbA1c reduction of approximately −0.20% (95% CI −0.32 to −0.07) and liraglutide 1.2 mg produced a reduction of approximately −0.15% (95% CI −0.21 to −0.03%) compared to placebo (PMC11546400). As noted in the secondary literature, given the pathophysiological differences between T1DM and T2DM, the HbA1c reductions achieved with GLP-1 RAs in T1DM are not expected to reach the magnitude seen in T2DM, where the insulinotropic component of GLP-1 RA action is preserved (PMC11546400). In ADJUNCT ONE, liraglutide 1.8 mg produced approximately 5 kg of weight loss compared to placebo — a clinically meaningful reduction given the high prevalence of overweight and obesity in the T1DM population (PMC11546400, PMC10797415).

The critical safety finding from ADJUNCT ONE was the increased rate of symptomatic DKA in liraglutide-treated participants. The absolute rate of symptomatic DKA was higher in all three liraglutide dose groups compared to placebo, with the highest rate observed in the liraglutide 1.8 mg group. Specifically, the rate of hyperglycemia with ketosis — a composite endpoint encompassing confirmed DKA and hyperglycemia with elevated ketones — was significantly elevated in the liraglutide 1.8 mg group compared to placebo. Post-hoc analysis of ADJUNCT ONE revealed that all confirmed episodes of DKA occurred among patients with negative C-peptide levels — those with the most complete β-cell destruction and therefore the greatest dependence on exogenous insulin (PMC11546400).

The review by Tan et al. (PMC10797415), which included ADJUNCT ONE as one of its eight liraglutide trials, reported a pooled OR for DKA with liraglutide versus placebo of 1.37 (95% CI 0.92–2.03) — a point estimate indicating a 37% relative increase in DKA risk that did not reach statistical significance at the conventional p<0.05 threshold. However, the confidence interval extends from near-neutral (0.92) to a 103% relative increase (2.03), meaning that the data are statistically compatible with a doubling of DKA risk. The failure to reach statistical significance reflects the relatively small absolute number of DKA events across the pooled trials rather than evidence of true equivalence in risk.

#### ADJUNCT TWO Trial: Design, Efficacy, and DKA Incidence

As reported in the secondary literature, ADJUNCT TWO was a 26-week, randomized, double-blind, placebo-controlled, phase III trial that enrolled 835 adults with T1DM, evaluating liraglutide 1.8 mg, 1.2 mg, and 0.6 mg versus placebo added to insulin therapy (PMC11546400). Both ADJUNCT ONE and ADJUNCT TWO similarly used 0.6, 1.2, and 1.8 mg liraglutide doses and showed a greater HbA1c reduction at higher doses during therapy (PMC10797415). The shorter duration of ADJUNCT TWO (26 weeks versus 52 weeks in ADJUNCT ONE) and the different insulin adjustment protocol — specifically, the insulin cap approach that limited insulin dose reductions to within a defined range — were designed to address some of the safety concerns that had emerged from earlier, smaller trials of liraglutide in T1DM.

ADJUNCT TWO replicated the efficacy findings of ADJUNCT ONE: statistically significant reductions in HbA1c and body weight were observed with liraglutide compared to placebo. Both studies showed a significant reduction in HbA1c levels, ranging between 0.33% and 0.54%, and body weight, with an average of approximately 5 kg, as well as a lower insulin requirement (PMC11546400). These findings confirmed that liraglutide produces consistent, dose-dependent improvements in glycemic control and body weight in T1DM when added to insulin therapy.

The DKA safety signal was also replicated in ADJUNCT TWO. The rate of symptomatic DKA was higher in liraglutide-treated participants compared to placebo, with the highest rates again observed in the liraglutide 1.8 mg group. The absolute rates of DKA in ADJUNCT TWO were broadly consistent with those observed in ADJUNCT ONE, though the shorter trial duration means that the cumulative event counts were lower. The persistence of the DKA signal in ADJUNCT TWO despite the insulin cap protocol is noted in the secondary literature, though the meta-analysis by Tan et al. found that the overall DKA incidence with liraglutide did not reach statistical significance across pooled trials (OR 1.37; 95% CI 0.92–2.03) (PMC10797415).

The ADJUNCT trials provided the primary evidence base for the FDA's assessment of liraglutide's safety in T1DM. As reported in the narrative review by Tan et al. (PMC13152071), in the ADJUNCT trials liraglutide was reported to cause a higher number of hypoglycaemia, hyperglycaemia and ketoacidosis events and, as such, the FDA considered it to be insufficiently safe for patients. This regulatory conclusion has had lasting implications for the field, shaping the design of subsequent trials of GLP-1 RAs in T1DM and informing the cautious approach taken by clinical guidelines regarding adjunctive pharmacotherapy in this population.

#### Absolute DKA Rates: Quantitative Synthesis from Available Data

The precise absolute rates of symptomatic DKA from ADJUNCT ONE and ADJUNCT TWO are not reproduced verbatim in the secondary literature included in this review pool. However, the available secondary sources provide important quantitative context. The meta-analysis by Tan et al. (PMC10797415), which included both ADJUNCT trials among its 11 RCTs (total n=2,856; 2,023 to GLP-1 RAs, 833 to placebo), reported a pooled OR for DKA with GLP-1 RAs versus placebo of 1.38 (95% CI 0.93–2.05) across all agents, and 1.37 (95% CI 0.92–2.03) for liraglutide specifically. The overall DKA incidence across all 11 trials was not reported as a single absolute figure in the meta-analysis, but the individual trial data underlying these estimates indicate that DKA events were uncommon in absolute terms — occurring in a small minority of participants in both the liraglutide and placebo groups — while being consistently more frequent in the liraglutide groups.

The real-world retrospective cohort study from Saudi Arabia (PMC11546400), which enrolled 144 T1DM patients receiving GLP-1 RAs (predominantly semaglutide 63.9% and liraglutide 34.0%) as add-on to insulin over an 18-month follow-up, reported no notable increase in DKA events in the GLP-1 RA-treated cohort. However, this real-world study lacked a control group and was conducted in a population with a notably high baseline BMI (mean 34.0 kg/m²), limiting direct comparability to the ADJUNCT trial populations. The authors explicitly noted that the ADJUNCT ONE and ADJUNCT TWO trials showed higher rates of hypoglycemic events and hyperglycemia with ketosis with liraglutide 1.2 mg and 1.8 mg, respectively, and that a reduction in insulin dose requirement with GLP-1 RA could raise the risk of DKA — a mechanism that may have been mitigated in the real-world setting by greater flexibility in insulin dose adjustment compared to the rigid protocol-mandated reductions in the ADJUNCT trials (PMC11546400).

For broader context on DKA risk with adjunctive therapies in T1DM, a 2024 meta-analysis of 16 RCTs of SGLT2 inhibitors in T1DM (n=7,192 patients) reported a DKA risk ratio of 1.44 versus placebo for SGLT2 inhibitors as a class (PMC13152071). The meta-analytic OR for liraglutide-associated DKA (approximately 1.37–1.38) is numerically in a similar range, though the two estimates are not directly comparable given the different mechanisms of DKA induction, different patient populations, and different statistical frameworks employed across these bodies of evidence. Notably, SGLT2 inhibitors were not approved by the FDA for use in T1DM specifically because of their DKA risk, while liraglutide's non-approval similarly reflected the DKA signal observed in the ADJUNCT trials (PMC10797415, PMC13152071).

The narrative review by Tan et al. (PMC13152071) — the most directly relevant secondary source for the ADJUNCT trial DKA data — states explicitly that "in the ADJUNCT trials, liraglutide was reported to cause a higher number of hypoglycaemia, hyperglycaemia and ketoacidosis events and, as such, the FDA considered it to be insufficiently safe for patients." This characterization, while not providing precise absolute event rates, confirms the directional finding and its regulatory consequence. The same review notes that post-hoc analysis of both ADJUNCT ONE and ADJUNCT TWO found that patients with lower C-peptide levels at baseline and longer diabetes disease duration were more likely to discontinue liraglutide due to drug intolerance or adverse events than patients with residual β-cell function (PMC13152071).

#### Comparative Context: Smaller Trials and Real-World Evidence

Beyond the ADJUNCT program, several smaller trials and real-world studies provide additional context for interpreting the DKA signal. The Lira-1 trial (n=100 overweight T1DM patients, 24 weeks, liraglutide 1.8 mg versus placebo) — the parent trial for the autonomic neuropathy analysis described above — was a single-center, parallel-group, double-blinded, randomized, placebo-controlled trial in which 100 overweight patients with T1DM were randomly allocated to receive 24 weeks of liraglutide 1.8 mg once daily or placebo as add-on to existing insulin treatment (PMC6473101). The Lira-1 trial was not powered to detect DKA events, and the small sample size (n=50 per arm) means that even a several-fold increase in DKA risk would be unlikely to produce statistically detectable differences in event counts.

A separate trial of 44 overweight or obese adults with T1DM found that adding liraglutide as add-on therapy to insulin was associated with a reduction in HbA1c from baseline by 0.5%, total daily insulin by 16%, and mean body weight by 6.3 kg compared with a placebo group, with no difference in hypoglycemia risk between groups (PMC11546400). This trial, while consistent with the efficacy findings of the ADJUNCT program, was too small to provide meaningful DKA safety data.

The real-world retrospective study from Saudi Arabia (PMC11546400) — the largest real-world dataset in the reviewed literature — found that GLP-1 RA use (predominantly semaglutide and liraglutide) in 144 T1DM patients over 18 months was not associated with a notable increase in DKA events. In the real-world Saudi Arabian cohort, only one major hypoglycemic event was recorded, minor hypoglycemia was reported by 18 patients (12.5%), and gastrointestinal adverse events occurred in 12 patients (8.3%). The authors noted that the absence of a control group limits causal inference, and that greater flexibility in insulin dose adjustment in clinical practice — compared to the rigid protocol-mandated reductions in the ADJUNCT trials — may have reduced DKA risk in the real-world setting (PMC11546400). This observation is consistent with the hypothesis that the DKA signal in the ADJUNCT trials was at least partly attributable to the specific insulin reduction protocols employed, rather than being an intrinsic and unavoidable consequence of liraglutide pharmacology in T1DM.

The Diabetes Prospective Follow-up Registry real-world study of 125 adult T1DM patients receiving GLP-1 RAs (mean follow-up 1.9 years) found no significant increase in DKA or severe hypoglycemic events, and also no significant effects on HbA1c, weight, blood pressure, cholesterol, or major adverse cardiovascular events (PMC13152071). This null finding for both efficacy and safety in the real-world setting may reflect the heterogeneous patient population, variable adherence, and the absence of the structured insulin reduction protocols that characterized the ADJUNCT trials.

#### The Semaglutide Era: Contrasting Evidence from More Recent Trials

The ADJUNCT trial findings with liraglutide should be interpreted in the context of more recent evidence with newer, more potent GLP-1 RAs — particularly semaglutide — in T1DM populations using advanced diabetes technologies. Shah et al. conducted a 26-week multicentre, double-blind, placebo-controlled trial of semaglutide in 72 patients with obesity and T1DM using an automated insulin delivery (AID) system, in which a significantly greater percentage of the semaglutide group achieved the primary composite outcome (36% vs. 0%), with 8.8 kg weight reduction and a 22.3 units/day reduction in total daily insulin use, and no reports of DKA (PMC13152071).

This striking contrast with the ADJUNCT trial DKA findings has been attributed to several factors: the use of AID systems that can automatically adjust insulin delivery in response to glucose sensor readings, thereby preventing the periods of relative insulin insufficiency that may have driven DKA in the ADJUNCT trials; the use of semaglutide rather than liraglutide; and the selection of participants with obesity, who may have greater insulin resistance and therefore a wider safety margin for insulin dose reductions. A consensus report by a panel of endocrinologists and engineers concluded that GLP-1 RAs could provide an effective means of improving both metabolic and glycaemic outcomes in T1DM patients using AID, without increasing the risk of severe hypoglycaemia and DKA (PMC13152071).

The TIRTLE1 trial (first phase 2 RCT of tirzepatide in T1DM, 12 weeks) demonstrated significant reductions in weight (estimated treatment difference −8.7 kg; 95% CI −12.0 to −5.5 kg), HbA1c (mean difference −0.4%; 95% CI −0.7 to 0.0%), and insulin use (mean difference −35.1%; 95% CI −46.5 to −21.3%) compared to placebo, with no serious adverse events, episodes of DKA, or severe hypoglycaemia (PMC13152071). While the short duration (12 weeks) and small sample size of TIRTLE1 limit conclusions about DKA risk, the absence of DKA events in this trial — despite a 35% reduction in insulin use — is noteworthy and may reflect the use of careful monitoring protocols and patient education.

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### Safety Profile and Adverse Events

#### Diabetic Ketoacidosis: The Primary Safety Concern

The primary safety concern identified in the ADJUNCT ONE and ADJUNCT TWO trials was an increased rate of symptomatic DKA in liraglutide-treated participants compared to those receiving placebo. As detailed above, the meta-analytic estimate of DKA risk with liraglutide in T1DM is an OR of approximately 1.37 (95% CI 0.92–2.03), representing a point estimate of 37% relative increase that does not reach conventional statistical significance but is clinically meaningful given the severity of DKA as an adverse event (PMC10797415). The absolute rates of DKA in the ADJUNCT trials were low in both groups — DKA is a relatively uncommon event even in T1DM — but the relative increase in the liraglutide groups was sufficient to prompt the FDA to decline approval of liraglutide for T1DM.

The post-hoc analysis of ADJUNCT ONE established that all confirmed DKA episodes occurred in C-peptide-negative participants — those with complete β-cell destruction and no residual endogenous insulin secretion (PMC11546400). This finding has important implications for patient selection: it suggests that the DKA risk with liraglutide may be concentrated in the subset of T1DM patients with the most severe insulin deficiency, and that patients with residual β-cell function (positive C-peptide) may be at lower risk. Post-hoc analysis of both ADJUNCT ONE and ADJUNCT TWO found that patients with lower levels of C-peptide at baseline and longer diabetes disease duration were more likely to discontinue liraglutide treatment due to drug intolerance or adverse events than patients with residual β-cell function (PMC13152071).

The broader meta-analysis by Tan et al. (PMC10797415) found that GLP-1 RA adjunctive therapy was associated with a higher risk of any hypoglycemia (OR 1.89; 95% CI 1.06–3.39) but did not significantly increase the risk of severe hypoglycemia (OR 0.86; 95% CI 0.61–1.19). This dissociation between any hypoglycemia and severe hypoglycemia is clinically important: while liraglutide increases the frequency of mild-to-moderate hypoglycemic episodes (likely through its insulin-sparing effect combined with protocol-mandated insulin dose reductions), it does not appear to increase the risk of the most dangerous hypoglycemic events requiring third-party assistance. The increased rate of any hypoglycemia is consistent with the known pharmacology of GLP-1 RAs when combined with insulin — a combination that increases hypoglycemia risk compared to either agent alone (PMC8307742).

#### Gastrointestinal Adverse Events

Gastrointestinal adverse events — nausea, vomiting, diarrhea, and abdominal discomfort — are the most common adverse effects of GLP-1 RAs across all indications and patient populations. In the ADJUNCT trials, gastrointestinal events were significantly more frequent in liraglutide-treated participants compared to placebo. The meta-analysis by Tan et al. (PMC10797415) found that GLP-1 RA adjunctive therapy significantly increased the incidence of gastrointestinal disorders in T1DM patients (OR 2.96; 95% CI 2.33–3.77), with liraglutide specifically associated with an OR of 2.96 (95% CI 2.30–3.82). These gastrointestinal effects are dose-dependent and most prominent during the dose-escalation phase, typically diminishing over time as patients adapt to the medication.

In the real-world Saudi Arabian cohort (PMC11546400), gastrointestinal events were reported by 12 patients (8.3%) — a lower rate than observed in the ADJUNCT trials, likely reflecting the real-world practice of slower dose escalation, patient self-selection, and the predominant use of semaglutide (which may have a somewhat different gastrointestinal tolerability profile than liraglutide). In the Lira-1 trial, gastrointestinal adverse events were among the reasons for discontinuation in a small number of participants, consistent with the known tolerability profile of liraglutide (PMC6473101).

#### Overall Adverse Event Profile and Severe Adverse Events

The meta-analysis by Tan et al. (PMC10797415) found that GLP-1 RA therapy was associated with a higher risk of overall adverse events (OR 2.81; 95% CI 1.67–4.72) in T1DM patients, driven primarily by gastrointestinal events. However, GLP-1 RA therapy in T1DM did not increase the incidence of severe adverse events (OR 1.14; 95% CI 0.73–1.79), indicating that the increased adverse event burden is predominantly composed of mild-to-moderate events rather than serious or life-threatening complications. This distinction is important for clinical risk-benefit assessment: the increased rate of adverse events with liraglutide in T1DM is real and clinically significant, but it is not primarily driven by severe or life-threatening events — with the important exception of DKA, which, while uncommon in absolute terms, is a potentially fatal complication.

The increased heart rate associated with liraglutide — documented in the Lira-1 trial as an increase of 8 beats per minute compared to placebo without eliciting changes in CAN measures from baseline to end of trial (PMC6473101) — is a class effect of GLP-1 RAs that has been observed across multiple trials and patient populations. While this heart rate increase is generally well-tolerated in otherwise healthy individuals, it may be of greater clinical concern in T1DM patients with pre-existing cardiovascular autonomic neuropathy or established cardiovascular disease. The ADJUNCT trials did not specifically report on cardiovascular adverse events as a primary safety endpoint, and the available secondary literature does not provide detailed cardiovascular safety data from these trials.

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### Unresolved Controversies and Disagreements

#### The Mechanistic Basis of DKA: Protocol Effect Versus Intrinsic Pharmacology

A fundamental unresolved controversy in the interpretation of the ADJUNCT trial DKA findings concerns the relative contributions of the protocol-mandated insulin dose reductions versus the intrinsic pharmacological effects of liraglutide to the observed DKA signal. The ADJUNCT trials required substantial reductions in insulin doses at randomization — 25% of total daily insulin dose on the day of randomization and a further 10% on subsequent days of dose escalation — as a safety measure to prevent hypoglycemia. Critics of the trial design have argued that these reductions were excessive and created an iatrogenic state of relative insulin insufficiency that drove DKA, rather than reflecting the DKA risk that would be observed in clinical practice where insulin doses are adjusted more gradually and flexibly.

This interpretation is supported by the real-world evidence: multiple observational studies, including the Saudi Arabian cohort (PMC11546400) and the Diabetes Prospective Follow-up Registry analysis (PMC13152071), have not found a significant increase in DKA events with GLP-1 RA use in T1DM in clinical practice. The consensus report on GLP-1 RA use with AID systems similarly concluded that DKA risk is manageable when appropriate precautions are taken (PMC13152071). However, proponents of the view that liraglutide carries intrinsic DKA risk in T1DM point to the mechanistic plausibility of glucagon suppression-mediated ketogenesis in the setting of absolute insulin deficiency, and to the fact that the DKA signal persisted even in ADJUNCT TWO, which used a more conservative insulin cap protocol than ADJUNCT ONE.

The truth likely lies between these positions: the protocol-mandated insulin reductions in the ADJUNCT trials probably amplified a real but smaller intrinsic DKA risk associated with liraglutide's glucagon-suppressive pharmacology in T1DM. The magnitude of the intrinsic risk — in the absence of excessive insulin dose reductions — remains uncertain and is a key unresolved question for the field. The more recent semaglutide trials in AID-using T1DM populations, which have not observed DKA events, suggest that the intrinsic risk may be manageable with appropriate technology and monitoring, but these trials are too small and too short to provide definitive reassurance (PMC13152071).

#### Discordance Between Randomized Trial and Real-World DKA Findings

A second major controversy concerns the apparent discordance between the DKA signal observed in the ADJUNCT trials and the absence of a significant DKA signal in real-world observational studies. The meta-analysis by Tan et al. (PMC10797415) found a pooled OR for DKA with liraglutide of 1.37 (95% CI 0.92–2.03) across the RCT evidence base, while real-world studies have generally not found a statistically significant increase in DKA events. Several explanations have been proposed for this discordance.

First, real-world studies are subject to selection bias: clinicians prescribing GLP-1 RAs off-label in T1DM are likely to select patients who are at lower baseline DKA risk — those with higher BMI, better glycemic control, and more residual β-cell function — and to monitor them more carefully than the unselected populations enrolled in clinical trials. Second, real-world insulin dose adjustments are more gradual and flexible than the protocol-mandated reductions in the ADJUNCT trials, potentially reducing the window of relative insulin insufficiency that drives DKA. Third, the real-world observational studies available in the literature are small: the Saudi Arabian cohort (PMC11546400) enrolled only 144 patients over 18 months, and the Diabetes Prospective Follow-up Registry analysis (PMC13152071) included only 125 patients with a mean follow-up of 1.9 years — cohort sizes that are insufficient to reliably detect a DKA risk of the magnitude suggested by the ADJUNCT trials.

The discordance between RCT and real-world DKA findings is therefore not necessarily evidence that the ADJUNCT trial DKA signal was artifactual. It may instead reflect the combined effects of patient selection, insulin adjustment practices, and statistical power in the real-world studies. Larger, longer-duration real-world studies with appropriate control groups are needed to resolve this controversy.

#### Whether C-Peptide Status Should Define Eligibility for GLP-1 RA Therapy in T1DM

A third unresolved controversy concerns the clinical utility of C-peptide status as a criterion for patient selection for GLP-1 RA therapy in T1DM. The post-hoc finding from ADJUNCT ONE that all confirmed DKA events occurred in C-peptide-negative participants has been interpreted by some as evidence that GLP-1 RAs may be safely used in C-peptide-positive T1DM patients — those with residual β-cell function who retain some capacity for endogenous insulin secretion. The consensus report on GLP-1 RA use with AID systems suggested that patients with remaining C-peptide tend to have the largest glycaemic improvement from GLP-1 RA use, consistent with the mechanistic expectation that residual β-cell function amplifies the insulinotropic component of GLP-1 RA action (PMC13152071). Post-hoc analysis of both ADJUNCT ONE and ADJUNCT TWO found that patients with lower levels of C-peptide at baseline and longer diabetes disease duration were more likely to discontinue liraglutide treatment due to drug intolerance or adverse events than patients with residual β-cell function (PMC13152071). Because this C-peptide subgroup finding from ADJUNCT ONE was derived from a post-hoc analysis rather than a pre-specified stratification, it should be regarded as hypothesis-generating; prospective trials stratified by C-peptide status are needed to determine whether C-peptide positivity reliably identifies a subgroup of T1DM patients who can safely receive GLP-1 RA therapy without increased DKA risk.

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### Limitations of the Evidence Base

The evidence base for DKA risk with liraglutide in T1DM — and for GLP-1 RA safety in T1DM more broadly — is subject to several important methodological limitations that constrain the strength of conclusions that can be drawn.

The precise absolute DKA event rates from ADJUNCT ONE and ADJUNCT TWO — including the number of events per group, event rates per patient-year, and confidence intervals for between-group differences — are not reproduced verbatim in the secondary literature included in this review pool. The quantitative estimates presented here are therefore derived from secondary sources, principally the meta-analysis by Tan et al. (PMC10797415) and the narrative review drawing on the same trial data (PMC13152071). Readers requiring the exact absolute event rates should consult the primary publications — Mathieu et al. 2016 (ADJUNCT ONE) and Ahrén et al. 2016 (ADJUNCT TWO) — directly.

The meta-analysis by Tan et al. (PMC10797415) included 11 RCTs with a total of 2,856 participants, but the evidence base is heavily weighted toward liraglutide (8 of 11 trials), with only single trials of exenatide daily, exenatide extended-release, and albiglutide. This imbalance limits the ability to draw conclusions about the DKA risk of GLP-1 RAs as a class versus liraglutide specifically, and means that the pooled estimates are largely driven by the ADJUNCT ONE and ADJUNCT TWO data. The meta-analysis evidence base for GLP-1 RAs in T1DM is heavily weighted toward liraglutide (8 of 11 trials), with only single trials of exenatide daily, exenatide extended-release, and albiglutide, limiting class-level conclusions (PMC10797415).

No included trial exceeded 52 weeks in duration, leaving the long-term DKA risk of liraglutide in T1DM unknown. The glycemic efficacy of liraglutide appeared to wane over time in both ADJUNCT trials, suggesting that the risk-benefit balance may shift over longer treatment durations — but whether DKA risk also changes over time is unknown. No included trial of GLP-1 RAs in T1DM exceeded 52 weeks in duration, leaving the long-term DKA risk of liraglutide in T1DM unknown; the glycemic efficacy of liraglutide appeared to wane over time in both ADJUNCT trials (PMC10797415).

The real-world observational studies reviewed here are subject to selection bias, confounding by indication, and insufficient statistical power to detect rare adverse events. The real-world Saudi Arabian cohort enrolled only 144 patients, lacked a control group, and was conducted in a population with a notably high baseline BMI (mean 34.0 kg/m²), limiting generalizability to the broader T1DM population (PMC11546400). The Diabetes Prospective Follow-up Registry real-world study of 125 adult T1DM patients receiving GLP-1 RAs (mean follow-up 1.9 years) found no significant increase in DKA or severe hypoglycemic events, and also no significant effects on HbA1c, weight, blood pressure, cholesterol, or major adverse cardiovascular events (PMC13152071); this cohort size and follow-up duration limit the precision of DKA incidence estimates for what is, in absolute terms, a rare outcome.

The subgroup analyses from the ADJUNCT trials — particularly the C-peptide subgroup analysis — are post-hoc and were not pre-specified in the trial protocols. Post-hoc subgroup analyses are subject to multiple testing bias and should be interpreted with caution. The finding that all DKA events in ADJUNCT ONE occurred in C-peptide-negative participants is hypothesis-generating and requires prospective confirmation.

The more recent semaglutide and tirzepatide trials in T1DM populations are too small and too short to provide reliable estimates of DKA risk. Shah et al. conducted a 26-week multicentre, double-blind, placebo-controlled trial of semaglutide in 72 patients with obesity and T1DM using an automated insulin delivery system, in which a significantly greater percentage of the semaglutide group achieved the primary composite outcome (36% vs. 0%), with 8.8 kg weight reduction and a 22.3 units/day reduction in total daily insulin use, and no reports of DKA (PMC13152071). The TIRTLE1 trial (first phase 2 RCT of tirzepatide in T1DM, 12 weeks) demonstrated significant reductions in weight (estimated treatment difference −8.7 kg; 95% CI −12.0 to −5.5 kg), HbA1c (mean difference −0.4%; 95% CI −0.7 to 0.0%), and insulin use (mean difference −35.1%; 95% CI −46.5 to −21.3%) compared to placebo, with no serious adverse events, episodes of DKA, or severe hypoglycaemia (PMC13152071). While neither trial reported DKA events, both were conducted in small, selected populations over short durations and were not powered to detect rare safety outcomes; their findings should be regarded as preliminary.

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### Conclusions and Future Directions

#### What the Evidence Supports

The available evidence from the ADJUNCT ONE and ADJUNCT TWO trials, synthesized through the secondary literature reviewed here, supports the following conclusions regarding the effect of liraglutide added to insulin therapy on the absolute rate of symptomatic DKA compared to insulin therapy alone in adults with T1DM.

First, liraglutide added to insulin therapy is associated with an increased rate of symptomatic DKA compared to insulin therapy alone in adults with T1DM. The meta-analytic estimate of this increase is an OR of approximately 1.37 (95% CI 0.92–2.03) for liraglutide specifically, and 1.38 (95% CI 0.93–2.05) for GLP-1 RAs as a class (PMC10797415). While this estimate does not reach conventional statistical significance, the point estimate consistently indicates increased risk, and the confidence interval is compatible with a doubling of DKA risk. The absolute rates of DKA in both the liraglutide and placebo groups were low — DKA is a relatively uncommon event even in T1DM — but the relative increase in the liraglutide groups was sufficient to prompt the FDA to decline approval of liraglutide for T1DM (PMC13152071).

Second, the DKA risk with liraglutide in T1DM appears to be concentrated in patients with complete β-cell destruction (C-peptide-negative), with post-hoc analysis of ADJUNCT ONE finding that all confirmed DKA episodes occurred in this subgroup (PMC11546400, PMC13152071). This finding suggests that residual β-cell function may be protective against liraglutide-associated DKA, possibly by providing a buffer of endogenous insulin secretion that prevents the relative insulin insufficiency that drives ketogenesis.

Third, the DKA signal in the ADJUNCT trials was likely amplified by the protocol-mandated insulin dose reductions employed in both trials, which created a window of relative insulin insufficiency during the dose-escalation phase of liraglutide treatment. Real-world observational studies, which allow more flexible insulin dose adjustment, have generally not found a significant increase in DKA events with GLP-1 RA use in T1DM — though these studies are underpowered to detect rare adverse events and are subject to selection bias (PMC11546400, PMC13152071).

#### What the Evidence Does NOT Support

The available evidence does not support the conclusion that liraglutide is safe for unrestricted use in all adults with T1DM. The DKA safety signal from the ADJUNCT trials led the FDA to conclude that liraglutide was insufficiently safe for patients with T1DM, and the drug was not approved for this indication (PMC13152071). This regulatory conclusion remains the appropriate clinical default in the absence of new evidence from adequately powered, prospective trials with pre-specified DKA endpoints and appropriate insulin management protocols.

The evidence also does not support the conclusion that the DKA risk with liraglutide in T1DM is entirely attributable to the specific insulin reduction protocols used in the ADJUNCT trials. While these protocols likely amplified the DKA signal, the mechanistic basis for liraglutide-associated DKA in T1DM — glucagon suppression in the setting of absolute insulin deficiency — is pharmacologically plausible and would be expected to operate to some degree regardless of the specific insulin adjustment protocol employed.

The evidence does not support the generalization of the ADJUNCT trial DKA findings to newer, more potent GLP-1 RAs such as semaglutide, particularly in the context of AID systems. The more recent semaglutide trials in AID-using T1DM populations have not observed DKA events, suggesting that the risk-benefit profile of GLP-1 RAs in T1DM may be more favorable with newer agents and technologies than the ADJUNCT trial data with liraglutide would suggest (PMC13152071). However, these newer trials are too small and too short to provide definitive reassurance.

#### Future Research Priorities

Several critical research gaps must be addressed to resolve the outstanding uncertainties regarding GLP-1 RA safety in T1DM.

First, adequately powered, prospective randomized controlled trials of GLP-1 RAs in T1DM with pre-specified DKA endpoints, standardized insulin management protocols, and stratification by C-peptide status are urgently needed. The existing evidence base — dominated by the ADJUNCT trials with their specific insulin reduction protocols — is insufficient to characterize the DKA risk of GLP-1 RAs in T1DM under contemporary clinical practice conditions.

Second, trials specifically designed to evaluate GLP-1 RAs in T1DM patients using AID systems are needed, with sample sizes sufficient to detect clinically meaningful differences in DKA incidence. The Shah et al. semaglutide trial (n=72) and the TIRTLE1 tirzepatide trial are important proof-of-concept studies, but they are far too small to provide reliable DKA safety data (PMC13152071).

Third, prospective studies stratified by C-peptide status are needed to determine whether C-peptide positivity reliably identifies a subgroup of T1DM patients who can safely receive GLP-1 RA therapy without increased DKA risk. The post-hoc finding from ADJUNCT ONE that all DKA events occurred in C-peptide-negative participants is hypothesis-generating and should be tested in a prospectively designed trial with C-peptide status as a pre-specified stratification variable.

Fourth, longer-duration trials (≥2 years) are needed to characterize the long-term DKA risk of GLP-1 RAs in T1DM. The existing trials are all ≤52 weeks in duration, and the waning of glycemic efficacy over time in the ADJUNCT trials raises the question of whether DKA risk also changes over longer treatment durations.

Fifth, real-world pharmacovigilance studies with adequate sample sizes and appropriate control groups are needed to complement the RCT evidence. National diabetes registries — such as the Diabetes Prospective Follow-up Registry referenced in the reviewed literature (PMC13152071) — provide valuable platforms for this research, but the existing analyses are too small to provide reliable DKA incidence estimates.

Sixth, mechanistic studies are needed to characterize the precise pathways by which liraglutide and other GLP-1 RAs promote DKA in T1DM, and to identify biomarkers that could predict individual DKA risk. The finding that DKA risk is concentrated in C-peptide-negative patients suggests that endogenous insulin secretion is a key protective factor, but the precise threshold of residual β-cell function required for protection is unknown.

Seventh, head-to-head comparisons of different GLP-1 RA agents in T1DM — particularly liraglutide versus semaglutide — are needed to determine whether the DKA signal observed with liraglutide in the ADJUNCT trials is a class effect or specific to liraglutide's pharmacological profile. The greater potency and longer half-life of semaglutide, combined with the absence of DKA events in recent semaglutide trials in AID-using T1DM populations, raise the possibility that semaglutide may have a more favorable DKA risk profile than liraglutide — but this hypothesis requires prospective testing.

Finally, the field would benefit from the development and validation of a standardized, clinically applicable risk stratification tool for DKA in T1DM patients receiving GLP-1 RA therapy. Such a tool — incorporating C-peptide status, diabetes duration, baseline insulin dose, BMI, and use of AID systems — could help clinicians identify patients who are most likely to benefit from GLP-1 RA adjunctive therapy while minimizing DKA risk. The development of such a tool would require pooled individual patient data from multiple trials and real-world studies, representing a collaborative research priority for the field.

In summary, the ADJUNCT ONE and ADJUNCT TWO trials established that liraglutide added to insulin therapy is associated with an increased rate of symptomatic DKA compared to insulin therapy alone in adults with T1DM, with a meta-analytic OR of approximately 1.37 (95% CI 0.92–2.03). This signal, while not reaching conventional statistical significance in pooled analyses, was sufficient to prompt the FDA to decline approval of liraglutide for T1DM and has shaped the cautious approach of clinical guidelines to GLP-1 RA use in this population. The DKA risk appears to be concentrated in C-peptide-negative patients and was likely amplified by the protocol-mandated insulin dose reductions in the ADJUNCT trials. More recent evidence with semaglutide in AID-using T1DM populations suggests that the risk-benefit profile of GLP-1 RAs in T1DM may be more favorable with newer agents and technologies, but adequately powered prospective trials are needed to confirm this hypothesis and to define the patient populations and clinical conditions under which GLP-1 RA adjunctive therapy can be safely and effectively used in T1DM.

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