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People with HIV are at a higher risk of cardiovascular diseases (CVD) due to the effects of the virus and its treatment. Integrase strand transfer inhibitors (INSTIs), a common HIV treatment, are associated with increased CVD risk and metabolic issues, such as weight gain and high blood pressure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, however, have been working well in reducing CVD events and hospitalizations due to heart failure, irrespective of diabetes presence. They also help in reducing weight and blood pressure. Pitavastatin has shown to work in lowering CVD events in people with HIV, but its availability is limited. This benefit is thought to be common to all statins, but this has not yet been confirmed. This study will examine the impact of dapagliflozin vs. placebo on metabolic parameters in people with HIV with high metabolic risk who are on INSTI-based ART.
This is a 2x2 factorial, randomised, placebo-controlled, double-blind, phase III/IV trial with two randomisations performed centrally via an on-line system, stratified by site. Participants will be randomised 1:1 to dapagliflozin 10mg vs. Placebo; this randomisation will be blinded. Participants will also be randomised 1:1 within each group to pitavastatin 4mg vs. rosuvastatin 10mg/ezetimibe 10mg; this randomisation will be open label.
Therefore, participants will be randomised to one of 4 groups:
With the following 2-arm randomised comparisons:
The study's primary and secondary endpoints described will assess both efficacy and safety/tolerability across randomisation arms. Follow up will continue to 48 weeks and endpoint measures will be obtained at 4, 12, 24, and 48 weeks. Primary endpoint is at 24 weeks. The total number of participants is 300, with 75 randomised to each of the groups as listed above.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dapagliflozin 10mg + pitavastatin 4mg | Active Comparator | Dapagliflozin 10mg + pitavastatin 4mg given as daily tablets for 48 weeks |
|
| Dapagliflozin 10mg + rosuvastatin 10mg/ezetimibe 10mg | Active Comparator | Dapagliflozin 10mg + rosuvastatin 10mg/ezetimibe 10mg given as daily tablets for 48 weeks |
|
| Placebo + pitavastatin 4mg | Placebo Comparator | Placebo + pitavastatin 4mg given as daily tablets for 48 weeks |
|
| Placebo + rosuvastatin 10mg/ezetimibe 10mg | Placebo Comparator | Placebo + rosuvastatin 10mg/ezetimibe 10mg given as daily tablets for 48 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dapagliflozin 10mg Tab | Drug | Dapagliflozin will be administered as a comparator to the placebo to assess its effects on weight reduction |
|
| Measure | Description | Time Frame |
|---|---|---|
| To assess the impact of dapagliflozin vs. placebo on weight reduction | Mean reduction change in body weight across treatment arms at 24 weeks, defined as absolute body weight change. | 24 weeks |
| To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe on low-density lipoproteins (LDL) concentration | Mean change in LDL as absolute change from baseline to 24 weeks across treatment arms | 24 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on body mass index (BMI )- weight and height will be combined to report BMI in kg/m^2 | 48 weeks | |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on waist (cm) to hip (cm) ratio |
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Inclusion Criteria:
Age 40-75 years and at least one of the following risk factors:
BMI ≥18 kg/m2 prior to INSTI commencement
Currently taking INSTI-based ART
Sustained virologic response, defined as viral load <200 copies/mL for at least 12 months
Current CD4 >250 cells/mm3
Informed consent for trial participation
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Gail Matthews, MD | Kirby Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Ramos MejÃa | Buenos Aires | Argentina | ||||
| St Vincent's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42050587 | Derived | Nyein PP, Haskelberg H, Martinello M, Lowe M, Goodman-Meza D, Avihingsanon A, Kelleher AD, Rodgers A, Schutte AE, Nnakelu EC, Byakwaga H, Trevillyan J, Losso M, Kumarasamy N, Azwa RISR, Kaplan R, Clifton B, Arnott C, Dharan NJ, Petoumenos K, Matthews GV. Optimizing metabolic management on integrase-based ART (OPTIMAR): study protocol for a 2 x 2 factorial, randomised, double-blind placebo-controlled trial to compare the addition of dapagliflozin versus placebo, and rosuvastatin plus ezetimibe versus pitavastatin, in people with HIV on integrase strand transfer inhibitor-based antiretroviral therapy with elevated metabolic risk. Trials. 2026 Apr 29;27(1):445. doi: 10.1186/s13063-026-09723-2. |
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|
| Pitavastatin 4 Mg Oral Tablet | Drug | Pitavastatin tablets will be administered as a comparator to Rosuvastatin/Ezetimibe 10mg/10mg tablets to assess and compare their effects on LDL concentrations |
|
|
| Rosuvastatin and Ezetimibe | Drug | Rosuvastatin/Ezetimibe 10mg/10mg tablets will be administered as a comparator to pitavastatin to assess and compare their effects on LDL concentrations |
|
| Placebo | Drug | The placebo tablets are visually identical to the active drug tablets and will be administered as a comparator to Dapagliflozin. |
|
| 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on waist (cm) to height (cm) ratio | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on systolic and diastolic blood pressure (mm Hg) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on Atherosclerotic cardiovascular disease risk score (ASCVD) - calculation of a person's10-year risk (%) of having a cardiovascular problem. | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on fasting lipids including: Total Cholesterol (mmol/L), LDL (mmol/L), High-Density Lipoproteins (HDL) (mmol/L), Triglycerides (mmol/L) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on fasting glucose (mmol/L) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on haemoglobin A1C (%) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on measures of fatty liver disease: Liver Function Tests - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (U/L), FibroScan (kPa) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on inflammatory biomarkers (tested centrally on stored research samples) | 48 weeks |
| To assess the impact of dapagliflozin vs. placebo from baseline to 48 weeks on Serious adverse events. | 48 weeks |
| To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on fasting lipids including: Total Cholesterol (mmol/L), LDL (mmol/L), High-Density Lipoproteins (HDL) (mmol/L), Triglycerides (mmol/L) | 48 weeks |
| To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on Atherosclerotic cardiovascular disease risk score (ASCVD) - calculation of a person's10-year risk (%) of having a cardiovascular problem. | 48 weeks |
| To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on inflammatory biomarkers (tested centrally on stored research samples) | 48 weeks |
| To assess the impact of pitavastatin vs. rosuvastatin/ezetimibe from baseline to 48 weeks on serious adverse events | 48 weeks |
| Sydney |
| New South Wales |
| 2010 |
| Australia |
| Austin Health | Melbourne | Victoria | 3084 | Australia |
| CART-CRS | Chennai | Tamil Nadu | 600113 | India |
| Universiti Malaya Medical Centre | Kuala Lumpur | Malaysia |
| Institute of Human Virology, Nigeria | Abuja | Nigeria |
| Desmond Tutu Health Foundation | Cape Town | 7925 | South Africa |
| HIV-NAT | Bangkok | Thailand |
| Infectious Diseases Institute, Makerere University | Kampala | Uganda |
| University of Zimbabwe Clinical Research Centre | Harare | Zimbabwe |
| ID | Term |
|---|---|
| D015658 | HIV Infections |
| D015430 | Weight Gain |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D015229 | Sexually Transmitted Diseases, Viral |
| D012749 | Sexually Transmitted Diseases |
| D016180 | Lentivirus Infections |
| D012192 | Retroviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D007153 | Immunologic Deficiency Syndromes |
| D007154 | Immune System Diseases |
| D001836 | Body Weight Changes |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C529054 | dapagliflozin |
| C108475 | pitavastatin |
| D013607 | Tablets |
| D000068718 | Rosuvastatin Calcium |
| D000069438 | Ezetimibe |
| ID | Term |
|---|---|
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D005464 | Fluorobenzenes |
| D006845 | Hydrocarbons, Fluorinated |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001384 | Azetidines |
| D001385 | Azetines |
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