Cagrilintide

Cagrilintide is a long-acting, acylated amylin analogue designed as a dual amylin/calcitonin receptor agonist (DACRA). Its lipid modification allows reversible albumin binding, which slows clearance and supports once-weekly subcutaneous dosing ¹, ⁵. Amylin is a hormone released with insulin after meals, and its analogues are developed to carry the satiety signal further.

The compound has been studied as monotherapy for weight management and in the fixed-dose combination with semaglutide 2.4 mg called CagriSema ⁵, ⁶. In a 26-week phase 2 dose-finding trial, once-weekly cagrilintide produced dose-dependent weight loss of roughly 6-10.8 percent, compared with 9.0 percent for liraglutide and 3.0 percent for placebo ², ²³. Completed phase 3 programs include REDEFINE in obesity and REIMAGINE in type 2 diabetes ⁷, ⁸, ⁹, ¹⁹, ²⁰. As of the 2026 evidence base, cagrilintide is not approved for any indication, so it remains investigational ¹, ⁵.

Cagrilintide mimics amylin, a satiety hormone co-secreted with insulin after meals. Native amylin slows gastric emptying, suppresses glucagon, and promotes meal termination through brainstem and hypothalamic circuits, a pathway separate from GLP-1 ⁵, ⁶. Cagrilintide activates amylin receptors, including AMY1 and AMY3, and calcitonin receptors; studies in rats indicate its body-weight lowering depends on brain amylin receptors 1 and 3 ¹⁶, ²⁸.

A cross-species atlas of the dorsal vagal complex identified two conserved populations of calcitonin-receptor neurons that cagrilintide engages. Chronic treatment upregulates prolactin-releasing hormone (Prlh) in nucleus tractus solitarius neurons; knocking down Prlh in the dorsal vagal complex blocks cagrilintide's feeding effect but not semaglutide's ¹⁵. Acute dosing also activates calcitonin-receptor neurons in the arcuate nucleus of the hypothalamus, while longer-term effects shift toward the hindbrain ²⁷.

In a 20-week human mechanistic study, once-weekly cagrilintide 2.4 mg plus semaglutide 2.4 mg reduced ad libitum energy intake by about 65 percent versus placebo, with better craving control and satiety but no measurable delay in gastric emptying at steady state ¹⁷. This places the main clinical effect on appetite and energy intake rather than stomach-motor slowing.

The clinical evidence base is strongest for weight and glycemic outcomes. Most data come from Novo Nordisk-sponsored phase 2 and 3 randomized controlled trials, with durations up to 68 weeks ⁷, ⁸, ⁹, ¹⁹, ²⁰.

Outcome	Reported finding	Strength
Monotherapy weight loss	6-10.8 percent over 26 weeks in dose-finding	Phase 2 RCT 2
Type 2 diabetes monotherapy	8.1 percent weight loss and HbA1c reduction of 0.9 percent at 32 weeks	Phase 2 RCT 4
CagriSema combination	15.6 percent weight loss at 32 weeks in type 2 diabetes	Phase 2 RCT 4
CagriSema 68-week obesity	20.4-22.7 percent weight reduction; 53.6 percent reached 20 percent loss and 34.7 percent reached 25 percent loss	Phase 3 RCT 20
Glycemic control	HbA1c reductions of 1.5-2.33 percentage points across REIMAGINE trials	Phase 3 RCT 7, 8, 9
Blood pressure	Systolic about 10.9 mmHg lower and diastolic about 5.4 mmHg lower than placebo	Phase 3 RCT 18
Energy intake and cravings	Ad libitum intake reduced by about 65 percent versus placebo at 20 weeks	Mechanistic RCT 17

Network meta-analyses also place CagriSema close to tirzepatide 15 mg for mean weight loss, with a stronger response at the 20 percent threshold in one analysis ¹², ¹³. Long-term safety and durability beyond 68 weeks, and confirmation in sponsor-independent studies, remain open questions ¹², ¹⁴.

Human protocols use fixed subcutaneous doses, once weekly, not weight-adjusted doses ². The trial-tested range ran from 0.3 mg to 4.5 mg, and 2.4 mg was selected as the maintenance dose for phase 3 ², ¹¹. Dose escalation is a central feature because gastrointestinal events cluster during the first weeks; trial schedules typically step the dose upward every four weeks over about 16 weeks before reaching 2.4 mg ¹⁷.

Phase 3 programs tested cagrilintide 2.4 mg once weekly alone and as CagriSema with semaglutide 2.4 mg once weekly, for 40-68 weeks ⁷, ⁸, ¹⁹, ²⁰. A lower CagriSema 1.0 mg plus 1.0 mg schedule also appears in REIMAGINE 1 ⁷. A dedicated QT study titrated healthy participants up to 4.5 mg once weekly without clinically relevant QT prolongation ¹¹.

No published human body-weight-based dosing exists. Preclinical studies used weight-based doses only in animals, such as 3-10 nmol/kg in diet-induced obese rats ²⁴. The visual timeline provides the standard monotherapy titration steps.

The clinical-stage product used in trials is supplied as a ready-to-use pen for once-weekly subcutaneous administration ², ⁵. Research-grade cagrilintide can also appear as a lyophilized powder that requires reconstitution.

Community research protocols use bacteriostatic water as the diluent for multidose vials. A higher diluent volume can improve measurement precision during low-dose titration steps. Mix gently: add the diluent slowly down the vial wall, then roll or swirl until clear. Avoid shaking, direct-stream impact, and foaming, because peptide co-formulations carry aggregation risk ¹.

For storage, community protocols keep lyophilized powder at -20°C for long-term stability, with 2-8°C acceptable for shorter periods. Reconstituted solution should be refrigerated at 2-8°C and protected from light. Do not freeze reconstituted vials; freeze-thaw cycles promote aggregation and activity loss. Discard reconstituted material after 28-30 days and inspect before each draw for cloudiness, gelling, or particles. The calculator below handles dilution math for a chosen vial and dose.

Documented or trial-based combinations

• Semaglutide (CagriSema): The best-characterized pairing. The combination outperformed either component in type 2 diabetes, and gastrointestinal events were additive versus monotherapy ⁴, ¹⁴. Trials use four-week co-titration to reduce nausea.
• Basal insulin: In REIMAGINE 3, adding CagriSema to basal insulin produced HbA1c reductions of 2.10-2.33 percentage points and 10-12 percent weight loss, with no severe hypoglycemia ⁹. Research protocols anticipate reducing background insulin as intake and weight fall.
• Metformin and SGLT2 inhibitors: No interaction signal or excess hypoglycemia emerged in REIMAGINE 2 or phase 2 type 2 diabetes trials ⁴, ⁸.
• Antihypertensives: CagriSema lowered blood pressure substantially; in REDEFINE 1, 39.6 percent of treated participants reduced or stopped antihypertensive medication versus 18.8 percent on placebo ¹⁸. Blood-pressure monitoring is part of trial follow-up.
• QT-prolonging drugs: No dose adjustment is indicated by the thorough QT study at 4.5 mg once weekly, where upper 90 percent confidence intervals stayed below 10 ms ¹¹.

Theoretical cautions

• Sulfonylureas and other secretagogues may amplify hypoglycemia risk because amylin-class agents suppress glucagon; phase 2 data showed level 1 hypoglycemia in 6-7 percent of cagrilintide-containing groups ⁴.
• Narrow-therapeutic-index oral drugs carry only a theoretical absorption concern because steady-state CagriSema showed no measurable gastric-emptying delay ¹⁷.
• Other incretin-class combinations with tirzepatide or retatrutide remain preclinical and have no human safety data ²⁴, ⁴³.

No randomized trial has evaluated on/off cycled dosing; registration trials dosed continuously for 40-68 weeks without scheduled drug holidays ⁷, ⁸. All structured cycling schedules are therefore community or practitioner derived.

A commonly discussed community-style schedule uses 8-16 weeks at 2.4 mg once weekly, followed by a 2-4 week break, then restarting at 0.3 mg and re-escalating every 2-4 weeks. Shorter breaks provide little receptor reset because cagrilintide is designed for multiweek plasma persistence through reversible albumin binding ¹. Restarting directly at the maintenance dose without re-escalation tends to bring back gastrointestinal events ¹⁷.

The rationale for cycling includes weight-loss plateau reset, gastrointestinal tolerability management, and the observation that the acute hypothalamic pathway can adapt while hindbrain-mediated weight effects persist ¹⁵, ²⁷. Breaks remain elective rather than evidence-based. An off period longer than about four weeks is typically paired with a full re-escalation schedule in community protocols. Discontinuation itself does not require tapering, but appetite rebound after stopping is expected because the satiety effect depends on continuous receptor engagement ¹⁵.

Established combination

Cagrilintide plus semaglutide 2.4 mg, known as CagriSema, is the only clinically validated combination. Phase 2 and phase 3 data show greater weight loss and glycemic benefit than either component ⁴, ²⁰. It is the reference stack for cagrilintide.

Preclinical combinations

• Tirzepatide: In diet-induced obese rats, cagrilintide 3 nmol/kg plus tirzepatide 3 nmol/kg produced about 11.0 percent body-weight reduction over 12 days, versus 7.2 percent for cagrilintide and 2.5 percent for tirzepatide alone ²⁴.
• Retatrutide: A rat study showed cagrilintide plus retatrutide exceeded matched semaglutide or tirzepatide combinations, with effects beyond food-intake suppression ⁴³.
• GIP-receptor antagonist AT7687: In obese insulin-resistant monkeys, this combination achieved about 11.4 percent vehicle-adjusted weight loss, improved fat-to-lean mass ratio, and better glucose disposal than cagrilintide alone ²⁵.

These non-CagriSema stacks lack human safety data. Other amylin receptor agonists are generally viewed as redundant rather than synergistic because they share receptor pharmacology ⁵, ⁶. Growth-hormone secretagogues and healing peptides have no published interaction data with cagrilintide.

Cagrilintide is not FDA-approved and is not marketed for any indication as of the 2026 evidence base. Its phase 3 REDEFINE and REIMAGINE programs are complete, placing it in late-stage but pre-approval development ¹, ⁵, ⁷, ⁸, ⁹. No NDA or BLA approval, and no EMA, MHRA, or TGA marketing authorization, is recorded in the reference set ⁵.

It is not scheduled under the U.S. Controlled Substances Act. Compounded pharmacy pathways are not documented, and any non-trial supply operates outside FDA premarket oversight.

In sport, cagrilintide is not on the WADA Prohibited List as of the reference period. Surveillance interest is increasing: semaglutide entered the WADA Monitoring Program in 2024, and preventive anti-doping research has characterized cagrilintide metabolites and developed LC-MS/MS detection methods ²¹. Monitoring is not prohibition, but athletes under anti-doping jurisdiction should assume detectability if testing expands.

Gastrointestinal side effects dominate the cagrilintide profile. Nausea occurred in about 55 percent of CagriSema participants in REDEFINE 1, and gastrointestinal disorders were the most common adverse events in REIMAGINE 2 ⁸, ²⁰. Events are usually mild to moderate and cluster during the 16-week dose-escalation phase ¹⁷.

Other reported signals include:

• Injection-site reactions: more frequent than with semaglutide alone (RR 3.27) ¹⁴.
• Fatigue: network meta-analysis estimated RR 3.2 versus lifestyle modification, or roughly 92 extra cases per 1,000 users over one year ¹².
• Hypoglycemia: level 1 events (55-69 mg/dL) occurred in 6-7 percent of type 2 diabetes participants in phase 2, with no severe hypoglycemia in phase 3 including as basal-insulin add-on ⁴, ⁹.
• Blood-pressure lowering: systolic pressure fell about 10.9 mmHg versus placebo, so antihypertensive de-escalation was common ¹⁸.

No clinically relevant QT prolongation appeared at a supratherapeutic 4.5 mg weekly dose ¹¹. No cagrilintide dose adjustment is needed for renal or hepatic impairment in single-dose studies ¹⁰. Preclinical data show conditioned taste avoidance and greater lean-mass loss with cagrilintide than with the more amylin-selective analogue eloralintide ²⁶. A meta-analysis of anti-obesity medicines found no increased obesity-associated cancer risk, and in fact reported reduced risk for co-agonist classes including cagrilintide ⁴².