Pre-emptive Insulin to Prevent High Glucose After a Knee Steroid Injection in Adults With Type 2 Diabetes

Intra-articular corticosteroid injections can produce clinically important but transient hyperglycaemia in people with type 2 diabetes. Published studies have largely characterised this glucose response rather than testing a standardised strategy to prevent it.

PREVENT-SIH is a phase 2, randomised, parallel-group trial in adults with type 2 diabetes managed without insulin or insulin secretagogues. All participants will receive a clinically indicated, standardised intra-articular injection of triamcinolone acetonide crystalline suspension 40 mg into one index knee for symptomatic knee osteoarthritis.

Participants will be randomly assigned 1:1 to a pre-emptive NPH insulin pathway or usual reactive diabetes management. The pre-emptive pathway comprises three weight-based NPH doses starting immediately after the corticosteroid injection, with prespecified glucose-based dose modification, withholding and discontinuation rules. Both groups will continue stable background diabetes medication and will receive identical blinded continuous glucose monitoring, capillary glucose monitoring, safety instructions, scheduled contacts and rescue thresholds.

Continuous glucose monitoring data will be collected for a 72-hour baseline period and for at least 96 hours after injection. The primary analysis will compare the percentage of valid readings above 180 mg/dL during the first 72 hours after injection, adjusted for baseline continuous glucose monitoring time above 180 mg/dL, site and HbA1c stratum. Rescue treatment and other post-randomisation diabetes treatment changes will be retained in the primary treatment-policy analysis.

• Insulin Isophane Human, NPH, Pre-emptive Algorithm (Drug), also known as Human NPH Insulin, Neutral Protamine Hagedorn Insulin: Human NPH insulin U-100 will be administered subcutaneously within 30 minutes after the knee injection at 0.10 units/kg actual body weight, rounded to the nearest whole unit, maximum 16 units. Doses are repeated approximately 24 and 48 hours later. For doses 2 and 3, predose glucose below 90 mg/dL requires withholding; 90 to 109 mg/dL requires 50% of the initial dose; 110 to 180 mg/dL requires 100%; 181 to 250 mg/dL requires 120%; and above 250 mg/dL requires 120%, maximum 20 units, plus clinician contact. Any glucose below 54 mg/dL or level 3 hypoglycaemia permanently discontinues study NPH.
• Triamcinolone Acetonide Knee Injection (Drug), also known as Triamcinolone Acetonide Crystalline Suspension: A single 1 mL intra-articular injection of triamcinolone acetonide crystalline suspension 40 mg/mL, total dose 40 mg, will be administered into one index knee using a standardised landmark-guided procedure. Up to 2 mL lidocaine 1% without epinephrine may be used for skin and subcutaneous anaesthesia but will not be mixed with or injected into the joint. No repeat or additional injected corticosteroid is permitted through day 7.

Primary outcomes

• Percentage of Continuous Glucose Monitoring Time Above 180 mg/dL During the First 72 Hours After Corticosteroid Injection [From completion of the intra-articular corticosteroid injection through 72 hours after injection]: The numerator is the number of valid continuous glucose monitoring readings above 180 mg/dL from the recorded completion time of the intra-articular injection through exactly 72 hours. The denominator is the total number of valid readings during that window. The result is expressed as a percentage. A directly observed outcome requires at least 80% of expected readings and no uninterrupted data gap longer than 6 hours. Participants not meeting this requirement have a missing primary outcome for statistical handling; missing readings are not counted as being within or above range.

Secondary outcomes

• Percentage of Continuous Glucose Monitoring Time Above 250 mg/dL [From completion of the injection through 72 hours after injection]: Number of valid continuous glucose monitoring readings above 250 mg/dL divided by all valid readings, multiplied by 100. The primary-outcome valid-data requirements apply.
• Continuous Glucose Monitoring Area Under the Curve Above 180 mg/dL [From completion of the injection through 72 hours after injection]: Incremental area above 180 mg/dL calculated using the trapezoidal rule across adjacent valid readings separated by no more than 30 minutes. The observed mean excess above 180 mg/dL is standardised to a 72-hour period and reported in mg/dL-hours.
• Mean Sensor Glucose [From completion of the injection through 72 hours after injection]: Arithmetic mean of all valid continuous glucose monitoring readings during the assessment window, reported in mg/dL.
• Peak Sensor Glucose [From completion of the injection through 72 hours after injection]: Highest valid continuous glucose monitoring glucose value during the assessment window, reported in mg/dL.
• Time to Peak Sensor Glucose [From completion of the injection through 72 hours after injection]: Elapsed time in hours from completion of the injection to the first occurrence of the participant's peak valid sensor glucose.
• Percentage of Continuous Glucose Monitoring Time in Range, 70 to 180 mg/dL [From completion of the injection through 72 hours after injection]: Number of valid continuous glucose monitoring readings from 70 through 180 mg/dL divided by all valid readings, multiplied by 100.
• Percentage of Continuous Glucose Monitoring Time Below 70 mg/dL [From completion of the injection through 72 hours after injection]: Number of valid continuous glucose monitoring readings below 70 mg/dL divided by all valid readings, multiplied by 100.
• Percentage of Continuous Glucose Monitoring Time Below 54 mg/dL [From completion of the injection through 72 hours after injection]: Number of valid continuous glucose monitoring readings below 54 mg/dL divided by all valid readings, multiplied by 100.
• Participants With Clinically Significant Hypoglycaemia [From completion of the injection through day 7]: Number and percentage of participants with capillary glucose below 54 mg/dL, continuous glucose monitoring glucose below 54 mg/dL lasting at least 15 consecutive minutes, or level 3 hypoglycaemia requiring third-party assistance.
• Participants Requiring Rescue Glucose-Lowering Treatment [From completion of the injection through 72 hours after injection]: Number and percentage of participants receiving protocol rescue insulin or any additional glucose-lowering medication initiated for post-injection hyperglycaemia.
• Number of Unscheduled Diabetes-Related Clinical Contacts or Healthcare Encounters [From completion of the injection through day 7]: Count per participant of unscheduled telephone calls, electronic contacts, clinic visits, urgent-care visits or emergency-department encounters primarily related to glucose management.
• Participant-Reported Treatment Burden Score [Day 4]: Study-specific numerical rating from 0 to 10, where 0 means no treatment burden and 10 means extreme treatment burden.

Other outcomes

• Participant-Reported Treatment Acceptability [Day 4]: Single study-specific five-category rating: very unacceptable, unacceptable, neither unacceptable nor acceptable, acceptable, or very acceptable.
• Participants With Adverse Events [From completion of the injection through day 7]: Number and percentage of participants experiencing at least one adverse event after the study injection, regardless of relationship.
• Participants With Serious Adverse Events [From completion of the injection through day 7]: Number and percentage of participants experiencing at least one serious adverse event after the study injection.

Sex: All, ages: 40 Years to 80 Years

Inclusion Criteria:

* Age 40 to 80 years at consent.
* Documented diagnosis of type 2 diabetes for at least 6 months.
* HbA1c from 6.5% through 9.0% measured within 30 days before randomisation.
* Symptomatic osteoarthritis of one knee for which the treating clinician has independently determined that an intra-articular corticosteroid injection is clinically indicated.
* Planned administration of one intra-articular injection of triamcinolone acetonide crystalline suspension 40 mg into the index knee.
* Diabetes managed without insulin, sulfonylureas or meglitinides.
* Permitted glucose-lowering medications at stable doses for at least 30 days before randomisation.
* Estimated glomerular filtration rate at least 45 mL/min/1.73 m² within 60 days before randomisation.
* Capillary glucose from 90 through 250 mg/dL immediately before the injection.
* Ability and willingness to perform scheduled capillary glucose testing, administer or receive subcutaneous insulin if assigned, follow hypoglycaemia instructions and remain contactable through day 7.
* Ability to wear the study continuous glucose monitoring device and provide informed consent.

Exclusion Criteria:

* Type 1 diabetes, latent autoimmune diabetes in adults, pancreatogenic diabetes or another specific diabetes type requiring insulin.
* Current basal, prandial, premixed or pump insulin treatment.
* Current sulfonylurea or meglitinide treatment.
* HbA1c below 6.5% or above 9.0%.
* Capillary glucose below 90 mg/dL or above 250 mg/dL immediately before injection.
* Fasting glucose above 250 mg/dL, random glucose above 300 mg/dL, clinically significant ketonaemia or hyperglycaemia requiring immediate treatment during screening.
* Estimated glomerular filtration rate below 45 mL/min/1.73 m².
* Severe hepatic impairment or another condition expected to materially alter insulin clearance or hypoglycaemia risk.
* Level 3 hypoglycaemia requiring third-party assistance during the previous 6 months.
* Documented impaired awareness of hypoglycaemia.
* Pregnancy, planned pregnancy during study participation or breastfeeding.
* Oral, intravenous or intramuscular corticosteroid use within 30 days before the study injection.
* Any intra-articular, epidural, periarticular or soft-tissue corticosteroid injection within 30 days before the study injection.
* Planned additional systemic or injected corticosteroid exposure before the day-7 assessment.
* Acute febrile illness, active systemic infection or acute deterioration in health at screening or injection.
* Suspected septic arthritis, infection over the injection site, prosthetic index knee, uncontrolled bleeding disorder or another contraindication to knee injection.
* Known allergy or clinically significant hypersensitivity to triamcinolone acetonide, human NPH insulin, insulin aspart, protamine, lidocaine or required excipients.
* Known allergy to continuous glucose monitoring adhesive or a skin condition preventing sensor use.
* Cognitive, visual, physical or social limitation that would prevent safe glucose testing, insulin administration, hypoglycaemia treatment or study contact.
* Participation in another interventional study likely to affect glucose or corticosteroid response.
* Any condition that, in the investigator's documented judgement, makes participation unsafe for a reason not otherwise captured above.

• Saima Abbass, MD, PhD, Study director, Shifa hospital