CLIAMS:1. A pharmaceutical composition comprising hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of onset of pre-diabetes in normoglycemic individuals or diabetes mellitus induced by statin in a subject in need of statin therapy or likely to be prescribed statin therapy.

2. The pharmaceutical composition according to claim 1, for prevention or delay of prediabetic condition in normoglycemic individuals or diabetic condition in prediabetic individuals.

3. The pharmaceutical composition according to claim 1, for reversal from diabetic to prediabetic or prediabetic to normoglycemic condition or relative decrease in HbA1c levels.

4. The pharmaceutical composition according to claim 1, for preventing, delaying the development of diabetes or reducing the risk of development of diabetes in individuals with cardiovascular disease receiving statin therapy.

5. The pharmaceutical composition according to claim 1, for prevention or delay of onset or progression of diabetes in dyslipidemic patients receiving statin therapy or likely to receive statin therapy.

6. The pharmaceutical composition according to claim 1, for treatment of atherosclerotic cardiovascular disease (ASCVD) and statin induced diabetes.

7. The pharmaceutical composition according to claim 1, wherein said formulation comprises hydroxychloroquine in the range from 50 mg to 500 mg calculated based on the weight of hydroxychloroquine free base.

8. The pharmaceutical composition according to claim 1,wherein the statin is selected from the group consisting of atorvastatin, simvastatin, pravastatin, rosuvastatin, compactin, fluvastatin, dalvastatin, lovastatin or pitavastatin, or mixtures thereof and their pharmaceutically acceptable salts or solvates or prodrug thereof.

9. The pharmaceutical composition according to claim 8, wherein the statin is atorvastatin.

10. The pharmaceutical composition according to claim 9, wherein Atorvastatin is in a range from 10 mg to 80 mg.

11. The pharmaceutical composition according to any of the preceding claims, wherein said formulation is in a suitable dosage form optionally comprising one or more pharmaceutically acceptable carriers or diluents.

12. The pharmaceutical composition according to claim 11, wherein said composition is suitable for simultaneous, separate or sequential, including in alternation, or in combined use along with statin.

13. The pharmaceutical composition according to claim 11, wherein said composition is in the form of a fixed dose combination.

14. The pharmaceutical composition according to claim 11, wherein the said dosage form is suitable for administration selected from oral, rectal, transdermal, transmucosal, intestinal and parenteral administration, including intramuscular, subcutaneous and intravenous injections.

15. The pharmaceutical composition according to claim 1, wherein Hydroxychloroquine or its enantiomers or its salts thereof and statin are present in one single dosage form or each in separate dosage form in a kit.

16. A pharmaceutical composition comprising Hydroxychloroquine or its enantiomers or its salts thereof and a statin in the manufacture of a medicament for treating the ischemic complications of established or end-stage diabetes unrelated to preventing the occurrence of diabetes or treating the condition itself.

17. A pharmaceutical composition comprising hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof useful for prophylaxis and/or treatment of onset of pre-diabetes in normoglycemic individuals or diabetes mellitus induced by statin in a subject in need of statin therapy or likely to be prescribed statin therapy.

18. A pharmaceutical composition comprising hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof useful in prevention or delay of prediabetic condition in normoglycemic individuals or diabetic condition in prediabetic individuals.

19. A pharmaceutical composition comprising hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof useful in preventing, delaying the development of diabetes or reducing the risk of development of diabetes in individuals with cardiovascular disease receiving statin therapy.

20. A Pharmaceutical composition comprising hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof used in prevention or delay of onset or progression of diabetes in dyslipidemic patients receiving statin therapy or likely to receive statin therapy.

21. A pharmaceutical composition comprising hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof useful for treatment of atherosclerotic cardiovascular disease (ASCVD) and statin induced diabetes. ,TagSPECI:FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:

“HCQS for Prophylaxis and Treatment of Statin Induced Diabetes”

2. APPLICANT(S):

(a) NAME: IPCA LABORATORIES LIMITED

(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956

(c) ADDRESS: 125, Charkop Road, Kandivli Industrial Estate, Kandivli (West),
Mumbai–400 067, Maharashtra, India.

3. PREAMBLE TO THE DESCRIPTION:

The following specification describes the nature of this invention and the manner in which it is to be performed:

FIELD OF INVENTION:
The present invention relates generally to a method to prevent and/or to delay the onset of developing diabetes as well as a treatment of drug induced pre-diabetic or diabetic condition in a human who is treated or likely be treated with a HMG-CoA reductase inhibitor (hereinafter also referred as Statin(s). The method of the present invention is particularly useful for the prevention, slow down the progression of disease in normal/prediabetic subjects to develop diabetes as well as reversal of effect of statin induced diabetic or prediabetic condition that results from therapy with Statin(s). The present invention further relates to pharmaceutical composition for administering therapeutically effective amount of hydroxychloroquine or its enantiomers or its salts thereof along with Statin(s) to the person who is in need of Statin therapy.

BACKGROUND OF INVENTION & PRIOR ART:
Cardiovascular disease is a major cause of illness and death worldwide. According to “Heart Disease and Stroke Statistics 2015 update, a Report from the American Heart Association;” Health data compiled from more than 190 countries show heart disease remains the No. 1 global cause of death with 17.3 million deaths each year. The report found the number expected to rise to more than 23.6 million by 2030. Elevated blood cholesterol levels specifically the low density lipoprotein (LDL) cholesterol is associated with a higher risk of heart attack, stroke and heart failure. It has become clear that elevated LDL cholesterol levels predict future events, and modern risk scores such as the Framingham Risk Score use LDL cholesterol level as an important predictor of future cardiac events.

Statins are one of the most widely prescribed medications in the world for both the primary and secondary prevention of atherosclerotic cardiovascular disease events. In recent years, however, concern has been raised regarding an increased incidence of diabetes or pre-diabetes or New onset of diabetes (NOD) mellitus observed in clinical trials of statin therapy.

Recently, a six year follow up study in 8,749 non-diabetic patients concluded that statin treatment increased the risk of Type 2 Diabetes by 46%, mainly attributable to decreases in insulin sensitivity and insulin secretion. The risk was found to vary with the type of Statin used and in a dose dependent manner (Cederberg et al; 2015).

A large study found that statin therapy leads to a modest increase in weight and subsequent diabetes risk. The study involving nearly 130,000 people, found that statin use increases the risk of Type 2 Diabetes by 12% and is associated with weight gain of around quarter of a kilo over four years. It also found indirect evidence that the protein, which statins target to reduce cholesterol could be at least partly responsible for the effect on type 2 diabetes as well. This evidence was based on looking at the effect of natural genetic variations that affect the protein, and not on a direct analysis of the effect of statins (Swerdlow DI et al; 2014).

The mechanism whereby Statin(s) increase the risk of NOD is uncertain; however, several different possibilities have been put-forth. Statins have been shown to decrease ß-cell secretion of insulin in animal models. In a meta-analysis of 13 large randomized placebo controlled statin trials with 91,140 participants, of whom 4, 278 developed diabetes during a mean follow-up of 4 years, statin treatment was associated with 9 % increased risk of diabetes (Sattar et al; 2010 ). Similar results have been reported from the Justification for use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial using risk factors for NOD: metabolic syndrome, IFG, BMI> 30 kg/m2 and HbA1c > 6%. Study participants with 1 or more of these risk factors had a 28% increase in NOD with rosuvastatin compared with the placebo group during the mean follow-up period of 1.9 years (Ridker et al; 2012).

Statins may decrease insulin sensitivity by decreasing isoprenoids, which up-regulate glucose uptake (James H et al; 2014). Insulin like growth factors have been shown to decrease in a dose dependent fashion after atorvastatin therapy, providing another potential mechanism whereby statins could worsen glucose tolerance. Finally, in an animal model, statin-induced myopathy is associated with an increase in insulin resistance in muscle (Mallinson JE et al; 2009).

Statins have been shown to increase HbA1c and insulin levels both in patients with and without diabetes. For example in a two month study, doses of atorvastatin from 10 mg to 80 mg increased HbA1c by 0.2 % to 0.3 %(Koh KK et al;2010). In a randomized study of patients with established diabetes, HbA1c increased by 0.3% with atorvastatin 20 mg for 4 months (Holman et al; 2009).

In January 2012, the Food and Drug Administration (FDA) released a consumer update outlining some of the risks associated with taking statins, which included an increased risk of raised blood sugar levels and the development of Type 2 diabetes. FDA suggests that the clinical benefit of statins still outweighs the risk involved, but blood glucose levels of patients under statin therapy need to be monitored closely. Going by the FDA statement, potential of statins in preventing Cardiovascular disease (CVD) risk is still high but the risk of developing diabetes in patients under statin therapy need to be better controlled/prevented.

Among patients with CV disease, diabetes is a strong prognostic factor and the converse also holds true i.e. cardiovascular disease is the cause of death for 50-80% diabetics worldwide. In addition, a large percentage of hyperlipidemic population may also be diabetic or may get into the “borderline diabetes” or “prediabetic” zone owing to statin therapy. Hence controlling blood pressure, LDL cholesterol, and glycosylated hemoglobin (HbA1c) levels reduces CV risk in patients with diabetes; however only a minority of them successfully attains these multiple goals.

Worldwide the prevalence of type-II diabetes continues to increase rapidly. According to WHO, about 347 million people worldwide have diabetes. It is predicted to be the 7th leading cause of death by 2030. Diabetes is becoming a more prevalent risk factor for cardiovascular (CV) disease and higher proportion of patients with CV disease has diabetes.

Some of the drugs including Statins used to reduce CV risk have been shown either to increase the risk of NOD or to interfere with glucose control in patients with established diabetes. On the contrary, ACC and AHA guidelines 2013 recommends use of statin therapy for patients with diabetes mellitus and LDL cholesterol level of 70-189 mg/dl. This looks like a very critical stage wherein statin therapy is inevitable and the long terms consequences of this therapy are also undesirable as they further aggravate CV risk. However, till date there is no effective/approved therapy available to reduce the risk of statin induced diabetes which is emerging as a major consequence of statin therapy.

Hydroxychloroquine (HCQ), a commonly used antimalarial drug, is relatively inexpensive and well tolerated. It has been a mainstream treatment option in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

HCQ is reported to have effect on reducing LDL, blood glucose levels and its effect on diabetes and dyslipidemia condition are reported, however the promise of this drug in effectively improving the conditions of diabetes & dyslipidemia is not well-established to offer a therapeutic option. Streptozotocin-induced diabetic rats treated with HCQ had lower insulin clearance and subsequently lower glucose levels (Emami et al. 1999).

EP2331099B1 discloses a pharmaceutical combination of hydroxychloroquine and one or more antidiabetic drug for treatment of Diabetes Mellitus. The combination is proposed to be an effective therapeutic option in sulfonylurea refractory patients with uncontrolled type 2 Diabetes, and has additional effect on hyperlipidemia or platelet aggregation. Further a favorable effect of hydroxychloroquine as a third line treatment in combination with metformin and glimepiride/gliclazide on blood glucose and lipid profile has been demonstrated when compared with pioglitazone in patients with uncontrolled TD2M (Pareek et al; 2014). Hydroxychloroquine was found to be safe and well tolerated when compared to pioglitazone as a third line treatment and suggested as a therapeutic option for uncontrolled T2DM in patients on conventional therapy. 1840/MUM/2007 discusses a combination of Statin & a disease modifying antirheumatic agent i.e. hydroxychloroquine for treatment in Rheumatoid Arthiritis and SLE patients. It is also suggested in patients at high risk of atherosclerosis, patients with unstable angina and in post-angioplasty where additional antiplatelet agents apart from aspirin and clopidogrel are required.

WO2011051966 discloses a novel synergistic pharmaceutical composition comprising combinations of hydroxychloroquine, statin as a lipid lowering agent and an insulin sensitizing agent for treatment /prophylaxis of Non Alcoholic Fatty liver Disease. It discusses the effectiveness of hydroxychloroquine in resistant diabetes as well as in lowering lipid levels. WO2014153424A1 discloses administration of adenosine receptor antagonist to reduce insulin resistance or risk of diabetes in subjects taking statins. The method is proposed to be effective by blocking statin-induced adenosine production by inhibiting a 5 '-nucleosidase, or by blocking an adenosine receptor with a receptor antagonist. This would in turn inhibit or suppress insulin resistance. US20110275649A1 also describes a combination of statin and pFOX inhibitor to prevent or reduce the risk of developing diabetes in statin therapy.

Given the percentage of patients under statin therapy and its importance in reducing cardiovascular risk, there is an immediate need to address the problem of increased risk of developing diabetes in such patients. As a matter of fact, the American Diabetes Association suggests that diabetic patients above 40 years of age should be put on “moderate” statin therapy to reduce cardiovascular risk. The impaired glucose levels/development of pre-diabetic symptoms in patients on statin therapy often remain undiagnosed in absence of any clinical symptoms or a family history and this makes the management difficult in future. Therefore, there is a need in the art to reduce the incidence of developing diabetes in patients needing a statin therapy and also to reverse the effect of stain induced diabetes or prediabetes condition in a patient.

SUMMARY OF INVENTION:
Accordingly, the present invention provides a method for delaying or preventing the onset of Diabetes manifested in patients receiving statin therapy. Thus the present invention provides a new method of treatment of cardiovascular disease comprising administration of hydroxychloroquine or its enantiomer or a pharmaceutically acceptable salt thereof along with Statin (s) therapy for prophylaxis against Onset of Diabetes Mellitus in individuals prescribed statin.

In an aspect, the present invention provides a method of prophylaxis and/or treatment of new onset of pre-diabetes in normoglycemic individuals or diabetes mellitus induced by Statin in a subject in need of statin therapy or likely to receive statin therapy comprising administration of a therapeutically effective amount of Hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a method of reversal of the condition induced by Statin therapy in subjects who are prediabetic or diabetic comprising administration of a therapeutically effective amount of Hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a method for prevention or delay of onset or progression of diabetes in individuals with Cardiovascular Disease comprising administering hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof.

In yet another aspect, the invention provides a method for prevention or delay of onset or progression of diabetes in dyslipidemic patients receiving statin therapy or likely to receive statin therapy comprising administering hydroxychloroquine or its enantiomers or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides a method for treatment of atherosclerotic cardiovascular disease (ASCVD) and statin induced diabetes and in maintaining and or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and or insulin resistance, in a patient in need thereof comprising administering hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof.

In another aspect, , the present invention provides pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of onset of pre-diabetes in normoglycemic individuals or diabetes mellitus induced by Statin in a subject in need of statin therapy or likely to be prescribed statin therapy.

In an aspect, the present invention provides a pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for prevention or delay of onset or progression of diabetes in individuals with Cardiovascular Disease, receiving statin therapy or likely to receive statin therapy.
In yet another aspect, the invention provides a pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for prevention or delay of onset or progression of diabetes in dyslipidemic patients receiving statin therapy or likely to receive statin therapy.

In yet another aspect, the present invention comprises administration of hydroxychloroquine or its enantiomers or a pharmaceutically acceptable salt thereof to patients in need of Statin therapy to prevent the onset of pre-diabetes in normoglycemic individuals or diabetes mellitus induced by Statin, to avert the risk involved in statin therapy.

In another aspect, the hydroxychloroquine or its enantiomer or a pharmaceutically acceptable salt thereof may be administered along with a statin selected from the group consisting of atorvastatin, simvastatin, pravastatin, rosuvastatin, compactin, fluvastatin, dalvastatin, lovastatin or pitavastatin, or their mixtures and their pharmaceutically acceptable salts or solvates or prodrug thereof.

In another aspect the pharmaceutical composition of the present invention involves combining statin and hydroxychloroquine or its enantiomers or its salts thereof in one single dosage form or each in separate dosage form in a kit for administration through any pharmaceutically acceptable medium/route.

In an aspect, the pharmaceutical composition of the present invention can be in the form of an extended or sustained release or conventional immediate release or controlled release formulation.

Brief description of drawings
Figure 1: Prediabetic population redistribution in different HbA1c categories post treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ for a period of 24 weeks
Figure 2: Diabetic population redistribution in different HbA1c categories post treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ for a period of 24 weeks
Figure 3: HbA1c Change from baseline in Normoglycemic individuals, who were not given any prior anti-diabetic medication, after 12 and 24 weeks of treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ.
Figure 4: HbA1c Change from baseline in Prediabetic individuals, who were not given any prior anti-diabetic medication, after 12 and 24 weeks of treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ.
Figure 5: HbA1c Change from baseline in Diabetic individuals, who had history of anti-diabetic medication, after 12 and 24 weeks of treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ.
Figure 6: Fasting Blood Glucose Change from baseline in Normoglycemic individuals, who were not given any prior anti-diabetic medication, after 12 and 24 weeks of treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ.
Figure 7: Fasting Blood Glucose Change from baseline in Prediabetic individuals, who were not given any prior anti-diabetic medication, after 12 and 24 weeks of treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ.
Figure 8: Fasting Blood Glucose Change from baseline in Diabetic individuals, who had history of anti-diabetic medication, after 12 and 24 weeks of treatment with either Atorvastatin alone or with a combination of Atorvastatin and HCQ.

DETAILED DESCRIPTION OF INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. As used herein, the following terms and phrases shall have the meaning set forth below.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims.

The term “Prophylaxis” as used herein, while referring to a preventive measure to fend off a disease or another unwanted consequence, specifically means the prevention of disease. As used in the present invention, preventing the development of diabetes means that diabetes does not occur or the start/onset of a disease condition is delayed. The term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The phrase "therapeutically effective amount" means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The therapeutically effective amount of each substance will vary depending upon the subject, severity of disease or condition being treated, body weight and age of the subject, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, certain compositions described herein may be administered in a sufficient amount to produce a desired effect at a reasonable benefit/risk ratio applicable to such treatment.

Prediabetes also referred as borderline diabetes, impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG) is the state in which some but not all of the diagnostic criteria for diabetes are met. It is often described as the “gray area” between normal blood sugar and diabetic levels. While in this range, patients are at risk for not only developing type 2 diabetes, but also for cardiovascular complications. In a way, prediabetes is a misnomer since it is an early stage of diabetes and hence is recommended as a parameter to identify those who are at increased risk of developing the disease.

As per American Diabetes Association, individuals having HbA1c =6.5% have been classified as Diabetic, while individuals with HbA1c< 5.7% are referred to as normoglycemic and those having HbA1c between 5.7% and 6.4% fall within the prediabetic condition. Since HbA1c levels give an average effect of blood sugar levels over a period of time in an individual, we have adhered to the same criteria for classification of patients in the following study.

New onset of diabetes refers to the occurrence of diabetes in previously non-diabetic persons and includes, but not limited to, newly diagnosed cases of diabetes by physicians or those exhibiting clinical manifestation of diabetes for the first time.

As used in the present invention, reducing the risk of developing or preventing new onset of diabetes means a reduction in the number of physician diagnosed cases of diabetes or prediabetes; as measured by the HbA1c levels.

The beneficial effects in reversing glycemic profiles from diabetic to prediabetic and prediabetic to normoglycemic range can be monitored by various blood parameters like blood Glucose and HbA1c levels.

Thus the present invention provides a method for treatment of cardiovascular disease comprising administration of hydroxychloroquine or its enantiomer or a pharmaceutically acceptable salt thereof along with Statin (s) therapy for prophylaxis against onset of Diabetes Mellitus in individuals prescribed statin therapy. The statin therapy, according to the present invention refers to is administration of statins selected from, but not limited to, atorvastatin, simvastatin, pravastatin, rosuvastatin, compactin, fluvastatin, dalvastatin, lovastatin, pitavastatin or mixtures thereof and their pharmaceutically acceptable salts, the more preferred statin being Atorvastatin , Simvastatin or Pravastatin.

The chemical structure of hydroxycholorquine (formula I) is given below. It possesses a chiral centre at carbon represented with an asterisk and thus it can represent in racemic, R-, and S-enantiomeric forms or their mixtures thereof. The present invention comprises of all its enantiomeric forms, mixtures, and racemates thereof. Hydroxycholoroquine or its enantiomer can be used in its free base form or an acid addition salt form, and salt may be selected from, but are not limited to, sulphate, phosphate as well as other pharmaceutically acceptable forms thereof.

Formula I

In a preferred embodiment, the present invention relates to a method of prophylaxis and/or treatment of new onset of pre-diabetes in normoglycemic individuals or diabetes mellitus induced by Statin in a subject in need of statin therapy or likely to receive statin therapy comprising administration of a therapeutically effective amount of Hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof.

In another embodiment, the present invention relates to a method of reversal of the condition induced by Statin therapy in subjects who are prediabetic or diabetic comprising administering a therapeutically effective amount of Hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof. Accordingly, the treatment comprises reversal from diabetic to prediabetic or prediabetic to normoglycemic condition or relative decrease in HbA1c levels.

The invention discloses a method for preventing, delaying the development of diabetes or reducing the risk of development of diabetes in individuals with Cardiovascular Disease as a result of a subject receiving a statin, regardless of the indication for the statin, the subject being naïve to statin therapy, comprising administering a therapeutically effective amount of Hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof.

In yet another embodiment, the present invention relates to a method for prevention or delay of onset or progression of diabetes in dyslipidemic patients receiving statin therapy or likely to receive statin therapy comprising administering a therapeutically effective amount of hydroxychloroquine or its enantiomers or a pharmaceutically acceptable salt thereof along with statin.
In another embodiment, the present invention discloses a method for treatment of atherosclerotic cardiovascular disease (ASCVD) and statin induced diabetes comprising administering a therapeutically effective amount of hydroxychloroquine or its enantiomers or a pharmaceutically acceptable salt thereof.

In an embodiment, the present invention relates to a method for maintaining and or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and or insulin resistance, in a patient in need thereof comprising administering a therapeutically effective amount of hydroxychloroquine or its enantiomers or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention comprises administration of hydroxychloroquine or its enantiomers or a pharmaceutically acceptable salt thereof to patients in need of Statin therapy or likely to be prescribed statin therapy, to avert the risk of hyperinsulinemia and or insulin resistance involved in statin therapy.

In another embodiment, the present invention relates to a pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for prophylaxis and/or treatment of onset of pre-diabetes in normoglycemic individuals or diabetes mellitus induced by Statin in a subject in need of statin therapy or likely to be prescribed statin therapy.

In an embodiment, the present invention relates to a pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for prevention or delay of onset or progression of diabetes in individuals with Cardiovascular Disease receiving statin therapy or likely to receive statin therapy.

In yet another aspect, the invention relates to a pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for prevention or delay of onset or progression of diabetes in dyslipidemic patients receiving statin therapy or likely to receive statin therapy.

The invention further relates to a pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof for treating a patient at a risk of developing atherosclerotic cardiovascular disease (ASCVD) and statin induced diabetes.

The pharmaceutical composition comprising of a combination of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salt, solvate, or a prodrug thereof may be administered to a person undergoing statin therapy or in need of a Statin therapy to prevent or delay Statin induced Diabetes.

In an embodiment, the present invention relates to a pharmaceutical composition comprising Hydroxychloroquine or its enantiomers or its salts thereof and a statin in the manufacture of a medicament for treating the ischemic complications of established or end-stage diabetes unrelated to preventing the occurrence of diabetes or treating the condition itself.

Typically a combination of hydroxychloroquine or its enantiomers and their salts thereof and a statin can be administered once or twice a day for short term or long term treatment to a patient at a risk of developing atherosclerotic cardiovascular disease (ASCVD) and statin induced diabetes. Herein statin is selected from, but not limited to, atorvastatin, simvastatin, pravastatin, rosuvastatin, compactin, fluvastatin, dalvastatin, lovastatin, pitavastatin or mixtures thereof and their pharmaceutically acceptable salts, the more preferred statins being Atorvastatin, Simvastatin or Pravastatin. Long term treatment refers to an extended period of time, typically longer than two weeks, and includes any length of time whereby the individual/subject (mammal) exhibits improvement in disease conditions/symptoms. This dosage formulation is beneficial for prophylactic treatment of individuals who are identified to develop ASCVD or pre-diabetic symptoms.

The composition of hydroxychloroquine for administration can be manufactured as single dosage form or along with statins in combination with pharmaceutical carriers or diluents. For oral use, suitable pharmaceutical carriers include inert diluents or fillers thereby forming oral dosage forms such as tablets, powders, capsules, syrups or suspensions and the composition may be administered as a single dose in alternation or a fixed dose combination. Hydroxychloroquine or its enantiomers and their salts thereof can be added to existing therapeutic regime of patients receiving statin therapy or can be incorporated in drug regime of those who are likely to be prescribed statin therapy.

The dosage can be delivered to the subject using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, transdermal, subcutaneous and intravenous injections. A preferred mode of administration is by oral route.

The quantity of each substance to be administered will vary depending upon the statin used, subject to be treated, severity of disease or condition being treated, body weight and age of the subject, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The method for oral administration may comprise hydroxychloroquine, or its pharmaceutical salt for an average adult, in a quantity ranging from 50 mg to 500 mg calculated based on the weight of hydroxychloroquine free base, more preferably a dose of 100 to 400 mg may be administered as a daily dose. The statin, for example, atorvastatin, for an average adult patient the recommended dose range is 10 mg to 80 mg.

Accordingly, a daily dosage of 100 mg to 500 mg of hydroxychloroquine free base and 10 mg to 80 mg of atorvastatin or the corresponding dosage of the respective salt, solvate, or a prodrug thereof, may be conveniently administered to a patient in need thereof.

The quantity of hydroxychloroquine or its pharmaceutically acceptable salts and statins in the composition may be fixed in range from 50 mg to 500 mg calculated based on the weight of hydroxychloroquine free base, more preferably a dose of 100 to 400 mg may be administered as a daily dose and the statin for example, atorvastatin as calcium salt may be used in range of 10 to 80 mg, for oral use, respectively.

The present combination drugs or their pharmaceutically acceptable salts, solvate or prodrugs thereof can be delivered to the subject using a wide variety of routes or modes of administration. Suitable routes of administration include, but are not limited to, oral, rectal, transmucosal, intestinal and parenteral administration, including intramuscular, transdermal, subcutaneous and intravenous injections. A preferred mode of administration is by oral route.

The method of the present invention comprises simultaneous, separate, sequential, including in alternation, or combined administration of effective amounts of the above active compounds and/or co-treatment with other medications, in a ratio which provides a therapeutically beneficial effect.

In an embodiment, the present invention provides novel composition(s) or kit or co-pack/combi-pack comprising of hydroxychloroquine or its pharmaceutically acceptable salts, solvates or prodrugs thereof and statin for simultaneous, separate, sequential, including in alternation, or combined use, especially in the prevention, delaying the development of diabetes or reducing the risk of development of diabetes as a result of a subject receiving a statin, regardless of the indication for the statin, the subject being naive to therapy with the statin; treating the ischemic complications of established or end-stage diabetes unrelated to preventing the occurrence of diabetes or treating the condition itself.

The fixed dose formulation of the present invention is preferably in the form of tablets or capsules, wherein tablets/capsules can be prepared in immediate release, modified/controlled release, extended or in sustained release form. Dosage form may be, for example, but not limited to, a multilayer tablet, a two-layer tablet, or capsules or sachets containing the active ingredients in separate granulates or beads, either granulate or bead, optionally being coated with a protective coating or an enteric-coating.

For example, tablets containing variety of excipients such as disintegrants like starch, complex silicates together with binding agents such as poly vinyl pyrrolidone, sucrose, gelatin and acacia. Lubricants such as magnesium silicate/stearate, sodium lauryl sulfate and talc are often used in tableting purposes. Solid compositions of the present invention can also be filled into soft and hard gelatin capsules.

For soft gelatin capsule, the composition may be solubilized in suitable vegetable or edible oil such as sunflower oil, corn oil, peanut oil or any other suitable oil.

In an embodiment, the present invention relates to of pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salt thereof useful for maintaining and or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and or insulin resistance, in a patient in need thereof.

In another embodiment, the present invention relates to the pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salt thereof used for prevention or delay of prediabetic condition in normoglycemic individuals or diabetic condition in prediabetic individuals.

In another embodiment, the present invention relates to the pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salt thereof useful for preventing, delaying the development of diabetes or reducing the risk of development of diabetes in individuals with cardiovascular disease receiving statin therapy.

In yet another embodiment, the present invention relates to the pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salt thereof useful for prevention or delay of onset or progression of diabetes in dyslipidemic patients receiving statin therapy or likely to receive statin therapy.

The present invention relates to the pharmaceutical composition comprising of hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salt thereof useful for treatment of atherosclerotic cardiovascular disease (ASCVD) and statin induced diabetes.

The invention in yet another embodiment relates to pharmaceutical composition comprising hydroxychloroquine or its enantiomers or its pharmaceutically acceptable salts thereof useful for maintaining and or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and or insulin resistance, in a patient in need thereof.

The safety, efficacy and additive & synergistic effect of the combination of hydroxychloroquine with a statin in primary dyslipidemia is established by the following experiments.

PHARMACOLOGICAL EVALUATION:
In this study we compared the efficacy in terms of potency of combination of hydroxychloroquine with statin against statin alone for example, atorvastatin. The biochemical parameters monitored & compared were serum LDL cholesterol, non-HDL cholesterol, total cholesterol, fasting blood glucose, high sensitivity C- reactive protein (hsCRP) and HbA1c levels.

Study design:
Experimental study on fixed dose combination of Hydroxychloroquine with Atorvastatin
This double blind, double dummy, randomized, parallel group, comparative, multicentric, Phase III study was conducted at 13 centers in India. Eligible patients who received prior statin therapy were directly enrolled in the study. Patients, who gave consent for participation in study and were treatment naïve, were put on placebo washout with controlled diet (step I/step II diet) for four weeks. Patients visited the clinic for minimum of 4 times (Week -4, Week -3, Week -2 and Week -1) during placebo washout period. Eligible patients who received prior statin therapy and those who completed washout period were randomized in one of the two treatment arms for next 24 weeks. Patients from one arm received Atorvastatin 10 mg, OD and another arm received fixed dose combination tablet (Atorvastatin 10 mg with Hydroxychloroquine 200 mg), OD during the entire treatment period.

During the treatment phase, patients were required to visit the clinic at baseline/randomization visit Week 0, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24 (end of the study visit). During the treatment phase, patients were evaluated for efficacy parameters (LDL-C, TC, and Non HDL-C) at all the visits post randomization. However the HbA1c and FBG levels were determined at baseline visit, at Week 12 and Week 24, while hsCRP was performed only at baseline visit and end of therapy (Week 24).

Total 1358 patients were screened, out of which 940 patients were ineligible for participation in the study. Of the remaining 418 patients, 235 treatment naïve patients satisfying the eligibility criteria were put on placebo washout for 4 weeks and 183 patients receiving prior statin therapy were directly enrolled in the study. Of the 235 patients put on placebo washout, 145 patients were found eligible for enrollment in the study. Thus, a total of 328 eligible patients were enrolled on the study and randomized to receive Atorvastatin 10 mg monotherapy (n=167) or fixed-dose combination of Atorvastatin 10 mg + Hydroxychloroquine 200 mg (n=161). All patients were advised controlled diet (step I/step II diet) throughout the study period. Two hundred and thirty four patients (119 from monotherapy group and 115 from combination group) completed the study duration of 24 weeks. Statistical analysis was performed on the modified ITT population i.e. patients completing at least 12 weeks of study treatment without any protocol violation and on per protocol (PP) population which included all patients who completed the study as per protocol without any protocol violation. The mITT population included total 134 patients from atorvastatin alone group and 127 patients from combination of hydroxychloroquine and atorvastatin group. While per protocol population included 119 patients from atorvastatin alone group and 115 patients from combination group.

Baseline parameters did not differ significantly between the groups. For mITT (Table 1) and per-protocol (Table 2) population, at Week-12 and Week-24 of therapy, both the treatment groups showed a significant fall in the mean LDL-C levels (p< 0.0001). The mean LDL-C levels at Week-12 (100.59 ± 31.30 mg/dL vs 91.33 ± 33.94 mg/dL; p= 0.023) and Week-24 (106.60 ± 35.49 mg/dL vs 94.85 ± 31.49 mg/dL; p= 0.005) were significantly low in combination treated patients in mITT population. Similar finding was observed in PP population as well.

TC and non-HDL-C levels significantly reduced at Week-12 and Week-24 from baseline in patients from both the treatment groups (p< 0.0001). The mean level of TC at Week 12 (174.07 ± 36.66 mg/dL vs 162.43 ± 37.02 mg/dL; p= 0.011) and Week 24 (178.13 ± 38.85 mg/dL vs 165.38 ± 37.57 mg/dL; p= 0.008) was significantly low in combination treated patients for mITT population (Table 1). Similar finding was observed in PP population as well (Table 2).

The mean level of non-HDL was also significantly low in favor of Atorvastatin + HCQ combination group at Week-12 (126.96 ± 35.86 mg/dL vs 115.92 ± 37.70 mg/dL; p= 0.016) and Week-24 (131.75 ± 38.29 mg/dL vs 119.51 ± 37.23 mg/dL; p= 0.009) from baseline for mITT population (Table 1). Similar finding was observed for PP population as well (Table 2).

Mean HbA1c levels reduced from baseline at Week 24 in combination treated patients (p= 0.062), whereas mean HbA1c levels significantly raised from baseline in monotherapy treated patients (p= 0.010) in mITT population. The change in HbA1c at Week 24 from baseline was significant in favour of combination group (0.22 vs -0.13; p= 0.002) (Table 3). FBG levels also significantly reduced at Week 24 from baseline in combination treated patients (p= 0.028) as against significant rise in monotherapy treated patients (p= 0.029). The mean FBG level at Week 24 was significantly low in favour of combination group (118.85 ± 42.88 mg/dL vs 108.72 ± 28.20 mg/dL; p= 0.026) (Table 3). Similar finding was observed for PP population as well (Table 4).

A sub-group analysis was performed to compare the HbA1c & FBG in the three groups i.e. Normoglycemic (HbA1c < 5.7% and no use of anti-diabetic medication), pre-diabetic (HbA1c between 5.7% and 6.4%, and no use of anti-diabetic medication), and diabetic (HbA1c =6.5% with or without use of anti-diabetic medication) groups at week 12 and week 24 (Table 5, Fig: 3-8). There was a slight increase in HbA1c at week 12 and week 24 in normoglycemic population but that is not clinically significant as it falls within the normal range. However, HbA1c levels dropped in prediabetic and diabetic patients treated with combination therapy at week 12 & week 24 as compared to monotherapy.

For further analysis, cohort 1 was considered as normoglycemic and cohort 2 was considered as pre-diabetic + diabetic group. The mean HbA1c was comparable between two treatment groups in both the cohorts at baseline. In Cohort 1, patients from both the treatment groups showed a significant rise in HbA1c at week 24. In Cohort 2, patients treated with combination therapy showed a significant decrease in HbA1c (p= 0.030) at Week 24, as against significant rise in monotherapy treated patients (p= 0.029). The mean HbA1c level was significantly low in combination group as compared to monotherapy group (6.95 ± 1.39% vs 6.52 ± 1.07%; p= 0.012) (Table 6).

In addition, a sub-group analysis was performed to compare the TC, TG, LDL, HDL, non HDL in the three groups i.e. Normoglycemic (HbA1c < 5.7% and no use of anti-diabetic medication), pre-diabetic (HbA1c between 5.7% and 6.4%, and no use of anti-diabetic medication), and diabetic (HbA1c =6.5% with or without use of anti-diabetic medication) groups at week 12 and week 24 (Table 7). LDL and TC levels significantly reduced at Week-12 and Week-24 from baseline in patients from all three groups with monotherapy as well as combination therapy. However, the decrease from baseline was more in patients on combination therapy in prediabetic group.

Further a sub-group analysis was performed to assess the development of new onset diabetes in pre-diabetic patients (HbA1c between 5.7% and 6.4% without any anti-diabetic medication). At the end of 24 weeks, 8 patients (15.09%) from Atorvastatin monotherapy group and only 1 patient (1.96%) from Atorvastatin + HCQ combination group developed diabetes (HbA1c =6.5%) (p= 0.034) (Table 8, Fig: 1).

Similar sub-group analysis was performed in diabetic patients (HbA1c = 6.5% with or without use of anti-diabetic medicine) to assess the change in baseline HbA1c. The data is presented in (Table 9, Fig: 2) At the end of 24 weeks of therapy, 7 patients (12.96%) from monotherapy group and 14 patients (23.33%) from combination group reported HbA1c between 5.7% and 6.4% (Table 9).

Table-1: Effect of combination of Hydroxychloroquine+ Atorvastatin on lipid levels of mITT population
Outcome Atorvastatin
(N = 134) Atorvastatin + Hydroxychloroquine
(N = 127) P value
Total Cholesterol (mg/dL)
Baseline 238.81 ± 29.14 233.76 ± 27.47 0.151
Week 12 174.07 ± 36.66 162.43 ± 37.02 0.011
Week 24 178.13 ± 38.85 165.38 ± 37.57 0.008
LDL_C (mg/dL)
Baseline 160.41 ± 22.78 157.38 ± 22.74 0.283
Week 12 100.59 ± 31.30 91.33 ± 33.94 0.023
Week 24 106.60 ± 35.49 94.85 ± 31.49 0.005
Non-HDL_C (mg/dL)
Baseline 192.01 ± 27.13 189.51 ± 26.68 0.454
Week 12 126.96 ± 35.86 115.92 ± 37.70 0.016
Week 24 131.75 ± 38.29 119.51 ± 37.23 0.009
Values presented as mean ± SD, and compared using two sample t test.

Table-2: Effect of combination of hydroxychloroquine+atorvastatin on lipid levels (PP population)
Outcome Atorvastatin
(N = 119) Atorvastatin + Hydroxychloroquine
(N = 115) P value
Total Cholesterol (mg/dL)
Baseline 239.93 ± 29.14 233.99 ± 27.23 0.109
Week 12 172.37 ± 36.35 160.41 ± 35.48 0.012
Week 24 177.24 ± 38.95 164.27 ± 36.63 0.009
LDL_C (mg/dL)
Baseline 160.37 ± 22.87 157.11 ± 22.31 0.270
Week 12 98.50 ± 30.53 89.48 ± 32.79 0.030
Week 24 105.55 ± 35.50 93.96 ± 30.99 0.008
Non-HDL_C (mg/dL)
Baseline 192.50 ± 27.35 189.06 ± 26.52 0.330
Week 12 124.83 ± 35.47 113.40 ± 36.09 0.015
Week 24 130.65 ± 38.51 117.65 ± 35.99 0.008

Values presented as mean ± SD, and compared using two sample t test.

Table 3: Effect of combination of Hydroxychloroquine + Atorvastatin on Glycemic Parameters at Week 12 and Week 24 from baseline (mITT population)

Outcome Atorvastatin
(N = 134) Atorvastatin + HCQ (N = 127) P value Difference
(95% CI)
HbA1c, (% )
Baseline* 6.45 ± 0.99 6.54 ± 0.99 0.463 -
Week 12* 6.47 ± 1.16 6.43 ± 1.10 0.794 -
Change† 0.03
(-0.11 to 0.16)
-0.09
(-0.23 to 0.04) 0.220 -0.12
(-0.31 to 0.07)
P-value‡ 0.652 0.132 - -
Week 24* 6.66 ± 1.38 6.40 ± 1.05 0.090 -
Change† 0.22
(0.07 to 0.37)
-0.13
(-0.28 to 0.03) 0.002 -0.35
(-0.56 to -0.13)
P-value‡ 0.010 0.062 - -
FBG (mg/dL)
Baseline* 111.39 ± 31.00 114.90 ± 33.28 0.379 -
Week 12* 112.60 ± 34.98 108.35 ± 37.95 0.347 -
Change from baseline at Week 12† 0.67
(-4.31 to 5.66) -5.83
(-10.97 to -0.70) 0.075 -6.51
(-13.67 to 0.65)
P-value‡ 0.652 0.021 - -
Week 24* 118.85 ± 42.88 108.72 ± 28.20 0.026 -
Change from baseline at Week 24† 6.70
(1.24 to 12.15) -5.17
(-10.79 to 0.46) 0.003 -11.86
(-19.70 to -4.02)
P-value‡ 0.029 0.028 - -
*- Values presented as mean ± SD, and compared using two sample t test, †-Least square mean change from baseline (95% CI) adjusted to its baseline value, ‡-indicates comparison with baseline and paired t test used for comparison, HbA1c - Glycosylated Haemoglobin; FBG- Fasting Blood Glucose.Above analysis performed on modified intention to treat population which comprised of patients who had completed the study at-least till Week 12 without any protocol violation.

Table 4: Effect of combination of Hydroxychloroquine + Atorvastatin Glycemic Parameters at Week 12 and Week 24 from Baseline (Per protocol population)

Outcome Atorvastatin
(N = 119) Atorvastatin + HCQ (N = 115) P value Difference
(95% CI)
HbA1c (% )
Baseline* 6.45 ± 0.97 6.55 ± 1.00 0.473 -
Week 12* 6.46 ± 1.13 6.44 ± 1.11 0.903 -
Change from baseline at Week 12† 0.01
(-0.13 to 0.15) -0.10
(-0.24 to 0.04) 0.292 -0.11
(-0.31 to 0.09)
P-value‡ 0.814 0.135 - -
Week 24* 6.67 ± 1.38 6.40 ± 1.06 0.098 -
Change from baseline at Week 24† 0.22
(0.06 to 0.39) -0.14
(-0.30 to 0.03) 0.003 -0.36
(-0.60 to -0.13)
P-value‡ 0.014 0.063 - -
FBG (mg/dL)
Baseline* 111.15 ± 31.05 115.23 ± 34.28 0.341 -
Week 12* 112.14 ± 34.74 107.76 ± 38.36 0.360 -
Change from baseline at Week 12† 0.35
(-4.94 to 5.64) -6.65
(-12.05 to -1.24) 0.070 -6.99
(-14.56 to 0.58)
P-value‡ 0.728 0.013 - -
Week 24* 119.50 ± 43.65 108.35 ± 27.54 0.021
Change from baseline at Week 24† 7.41
(1.55 to 13.26) -5.69
(-11.68 to 0.29) 0.002 -13.10
(-21.48 to -4.72)
P-value‡ 0.025 0.021 - -
*- Values presented as mean ± SD, and compared using two sample t test; †-Least square mean change from baseline (95% CI) adjusted to its baseline value; ‡-indicates comparison with baseline and paired t test used for comparison; HbA1c - Glycosylated Haemoglobin; FBG- Fasting Blood Glucose.
Above analysis performed on per protocol population which comprised of patients who had completed the study at Week 24 without any protocol violation.

Table 5: Comparison of change in Glycemic level at Week 12 and Week 24 in normoglycemic, prediabetic and diabetic patient populations

Outcome HbA1c < 5.7% and No diabetic medication HbA1c 5.7% to 6.4% and No diabetic Medication HbA1c > 6.4% or Diabetic Medication taken
Atorvastatin
(N = 27) Atorvastatin
+
HCQ
(N = 16) P value Atorvastatin
(N = 53) Atorvastatin
+
HCQ
(N = 51) P value Atorvastatin
(N = 54) Atorvastatin +
HCQ
(N = 60) P value
Glycemic Parameters
HbA1c (% )
Baseline* 5.35 ± 0.22 5.37 ± 0.23 0.860 5.95 ± 0.20 5.97 ± 0.22 0.591 7.46 ± 0.69 7.31 ± 0.88 0.313
Week 12* 5.58 ± 0.55 5.47 ± 0.24 0.445 5.98 ± 0.43 5.90 ± 0.32 0.321 7.40 ± 1.24 7.14 ± 1.21 0.269
Change from baseline at Week 12† 0.25
(0.07 to 0.43) 0.11
(-0.14 to 0.35) 0.339 0.02
(-0.08 to 0.12) -0.07
(-0.17 to 0.04) 0.234 -0.05
(-0.34 to 0.24) -0.19
(-0.46 to 0.09) 0.491
P-value‡ 0.032 0.140 - 0.691 0.085 - 0.666 0.198
Week 24* 5.50 ± 0.37 5.53 ± 0.25 0.796 6.11 ± 0.50 5.90 ± 0.37 0.016 7.78 ± 1.49 7.06 ± 1.18 0.005
Change from baseline at Week 24† 0.18
(0.08 to 0.28) 0.17
(0.04 to 0.29) 0.867 0.15
(0.04 to 0.26) -0.08
(-0.19 to 0.03) 0.005 0.34
(0.01 to 0.68) -0.29
(-0.61 to 0.03) 0.009
P-value‡ 0.002 0.006 - 0.019 0.088 - 0.123 0.076 -
FBG (mg/dL)
Baseline* 92.15 ± 8.71 97.81 ± 12.30 0.085 96.58 ± 8.34 98.53 ± 14.61 0.404 135.54 ± 36.11 133.69 ± 38.59 0.794
Week 12* 97.30 ± 16.79 88.44 ± 7.55 0.054 96.70 ± 15.57 94.16 ± 12.67 0.364 135.87 ± 42.07 125.72 ± 48.34 0.237
Change from baseline at Week 12† 3.18
(-2.45 to 8.82) -6.06
(-13.45 to 1.33) 0.055 -0.23
(-3.54 to 3.08) -4.01
(-7.39 to -0.64) 0.117 0.78
(-10.28 to 11.8) -7.77
(-18.35 to 2.80) 0.271
P-value‡ 0.185 0.004 0.954 0.007 - 0.957 0.198 -
Week 24* 93.22 ± 7.46 91.31 ± 8.67 0.449 100.89 ± 16.70 96.80 ± 12.86 0.167 149.30 ± 52.07 123.50 ± 33.34 0.002
Change from baseline at Week 24† -0.37
(-3.26 to 2.52) -4.07
(-7.86 to -0.28) 0.130 3.83
(0.07 to 7.59) -1.24
(-5.06 to 2.59) 0.064 14.48
(3.04 to 25.93) -10.18
(-21.13 to 0.77) 0.003
P-value‡ 0.548 0.037 - 0.055 0.372 - 0.093 0.085 -
*- Values presented as mean ± SD, and compared using two sample t test; †-Least square mean change from baseline (95% CI) adjusted to its baseline value, ‡-indicates comparison with baseline and paired t test used for comparison, HbA1c - Glycosylated Haemoglobin; FBG- Fasting Blood Glucose.
Modified intention to treat population comprised of patients who had completed the study at-least till Week 12 without any protocol violation

Table 6: Effect of combination of Hydroxychloroquine (HCQ) + Atorvastatin on HbA1c at Week 24 from Baseline (mITT population)

Outcome Cohort 1: Normoglycemic Cohort 2: Pre diabetic + Diabetic
Atorvastatin
(N = 27) Atorvastatin +HCQ
(N = 16) P value Atorvastatin (N = 107) Atorvastatin + HCQ
(N = 111) P value
Baseline* 5.35 ± 0.22 5.37 ± 0.23 0.860 6.72 ± 0.91 6.70 ± 0.94 0.890
Week 24* 5.50 ± 0.37 5.53 ± 0.25 0.796 6.95 ± 1.39 6.52 ± 1.07 0.012
Change † 0.18
(0.08 to 0.28) 0.17
(0.04 to 0.29) 0.867 0.24
(0.05 to 0.42) -0.18
(-0.36 to 0.00) 0.002
P-value‡ 0.002 0.006 - 0.029 0.030 -
*- Values presented as mean ± SD, and compared using two sample t test; †-Least square mean change from baseline (95% CI) adjusted to its baseline value, ‡-indicates comparison with baseline and paired t test used for comparison, HbA1c - Glycosylated Haemoglobin. Modified intention to treat population comprised of patients who had completed the study at-least till Week 12 without any protocol violation.

Table 7: Change in Lipid level at Week 12 and Week 24 from Baseline
Outcome HbA1c < 5.7% and No diabetic Medication HbA1c 5.7% to 6.4% and No diabetic Medication HbA1c > 6.4% with or without Diabetic Medication taken
Atorvastatin
(N = 27) Atorvastatin +
HCQ
(N = 16) P value Atorvastatin
(N = 53) Atorvastatin +
HCQ
(N = 51) P value Atorvastatin
(N = 54) Atorvastatin +
HCQ
(N = 60) P value
TC (mg/dL)
Baseline* 237.74 ± 32.86 224.38 ± 26.70 0.176 243.00 ±32.19 237.75 ± 29.94 0.391 235.24 ± 23.52 232.88 ± 25.15 0.607
Week 12* 175.48 ± 39.26 173.19 ± 37.24 0.851 180.34 ±38.29 158.27 ± 38.64 0.004 167.22 ± 33.02 163.10 ± 35.54 0.524
Change from baseline at Week 12† -59.82
(-73.8 to -48.87) -55.31
(-73.6 to -37.0) 0.697 -60.20
(-71.4 to-49.0) -80.59
(-91.98 to -69.20) 0.013 -67.20
(-76.4 to -58.0) -70.62
(-79.32 to -61.9) 0.594
P-value‡ <0.001 0.001 <0.001 <0.001 <0.001 <0.001
Week 24* 186.15 ± 37.59 173.75 ± 33.93 0.285 181.30 ±42.71 162.47 ± 37.74 0.019 171.00 ± 34.78 165.62 ± 38.57 0.438
Change from baseline at Week 24† -50.86
(-66.19 to -35.5) -51.61
(-71.6 to -31.6) 0.953 -58.18
(-70.2 to -46.1) -76.21
(-88.48 to -63.94) 0.040 -63.61
(-73.7 to -53.5) -64.02
(-73.6 to -54.43) 0.954
P-value‡ <0.001 <0.001 - <0.001 <0.001 - <0.001 <0.001 -
TG (mg/dL)
Baseline* 118.96 ± 56.56 129.31 ±68.47 0.595 161.25 ± 72.78 159.24 ± 75.10 0.890 163.65 ±68.95 171.52 ± 65.12 0.532
Week 12* 126.63 ± 82.89 112.06 ±41.59 0.517 138.36 ± 65.42 114.57 ± 49.64 0.039 133.20 ±57.09 133.33 ± 68.03 0.991
Change from baseline at Week 12† 5.62
(-19.41 to 30.65) -14.04
(-46.6 to 18.5) 0.339 -25.29
(-38.9 to -11.65) -45.38
(-59.3 to -31.48) 0.043 -32.90
(-48.4 to -17.4) -36.16
(-50.8 to -21.5) 0.763
P-value‡ 0.595 0.292 - 0.019 <0.001 - 0.002 <0.001 -
Week 24* 115.26 ± 52.07 105.31 ±44.98 0.529 120.47 ± 51.12 119.82 ± 67.23 0.956 137.35 ±68.27 132.77 ± 70.22 0.725
Change from baseline at Week 24† -6.09
(-22.63 to 10.45) -23.10
(-44.61 to 1.6) 0.213 -40.17
(-54.5 to -25.86) -40.37
(-54.96 to 25.78) 0.984 -23.67
(-41.9 to -5.45) -33.24
(-50.5 to -15.9) 0.452
P-value‡ 0.687 0.182 - <0.001 <0.001 - 0.006 0.001 -
LDL (mg/dL)
Baseline* 164.19 ± 24.25 154.63 ± 25.58 0.228 163.56 ± 25.39 162.68 ± 22.39 0.852 155.42 ± 18.40 153.60 ± 21.72 0.632
Week 12* 102.55 ± 30.53 100.82 ± 36.22 0.868 106.57 ± 33.17 90.30 ± 35.48 0.018 93.75 ± 28.93 89.68 ± 32.11 0.480
Change from baseline at Week 12† -59.27
(-71.8 to -46.7) -57.80
(-74.1 to -41.4) 0.887 -57.32
(-66.8 to -47.8) -72.05
(-81.7 to -62.39) 0.033 -60.81
(-69.0 to -52.6) -64.42
(-72.24 to -56.6) 0.531
P-value‡ <0.001 <0.001 - <0.001 <0.001 - <0.001 <0.001 -
Week 24* 114.64 ± 33.45 102.66 ± 31.39 0.253 111.08 ± 38.55 93.93 ± 32.16 0.016 98.18 ± 32.08 93.56 ± 31.16 0.437
Change from baseline at Week 24† -46.76
(-59.5 to -34.0) -56.70
(-73.4 to -40.0) 0.349 -52.14
(-61.7 to -42.5) -68.18
(-78.0 to -58.39) 0.022 -56.88
(-65.7 to -48.1) -58.81
(-67.1 to -50.47) 0.753
P-value‡ <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
HDL (mg/dL)
Baseline* 49.26 ± 13.43 43.83 ± 10.40 0.173 45.29 ± 13.28 43.46 ± 13.43 0.488 47.06 ± 11.75 45.04 ± 13.06 0.389
Week 12* 48.37 ± 14.79 49.96 ± 8.25 0.696 46.55 ± 13.25 45.65 ± 13.72 0.735 47.05 ± 10.79 46.34 ± 12.14 0.743
Change from baseline at Week 12† -1.06
(-4.44 to 2.31) 6.43
(2.04 to 10.83) 0.010 1.44
(-1.87 to 4.75) 2.04
(-1.34 to 5.41) 0.803 -0.70
(-3.67 to 2.27) 1.58
(-1.24 to 4.40) 0.273
P-value‡ 0.590 0.014 - 0.322 0.303 - 0.992 0.355 -
Week 24* 48.46 ± 13.67 50.03 ± 9.58 0.689 46.13 ± 13.12 45.03 ± 14.24 0.661 45.59 ± 11.69 45.47 ± 13.63 0.959
Change from baseline at Week 24† -0.89
(-4.37 to 2.58) 6.37
(1.83 to 10.91) 0.015 0.84
(-2.21 to 3.89) 1.80
(-1.31 to 4.91) 0.661 -1.84
(-5.36 to 1.67) 0.80
(-2.54 to 4.14) 0.283
P-value‡ 0.615 0.023 - 0.433 0.435 - 0.401 0.802 -
Non HDL (mg/dL)
Baseline* 188.48 ± 27.73 180.55 ± 29.56 0.381 197.7 ± 29.5 194.28 ± 28.07 0.545 188.18 ±23.70 187.84 ± 24.21 0.941
Week 12* 127.11 ± 37.32 123.23 ± 37.37 0.744 133.8 ± 37.7 112.63 ± 40.70 0.007 120.2 ± 32.45 116.76 ± 35.38 0.594
Change from baseline at Week 12† -59.62
(-73.6 to -45.58) -60.28
(-78.6 to -42.0) 0.954 -62.45
(-73.1 to -51.7) -83.19
(-94.10 to -72.3) 0.008 -67.85
(-77.0 to -58.7) -71.22
(-79.9 to -62.5) 0.599
P-value‡ <0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Week 24* 137.69 ± 38.85 123.73 ±32.76 0.235 135.2 ± 41.5 117.44 ± 37.10 0.024 125.4 ± 34.4 120.15 ± 38.87 0.448
Change from baseline at Week 24† -48.80
(-62.8 to -34.75) -60.19
(-78.5 to -41.9) 0.327 -61.27
(-71.9 to -50.7) -78.16
(-88.98 to -67.3) 0.030 -62.67
(-72.2 to -53.1) -67.78
(-76.8 to -58.7) 0.442
P-value‡ <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Table 8: Prediabetic Patients in different HbA1c categories post 24 weeks of Mono/ Combination therapy.
HbA1c at Week 24 Atorvastatin
n (%) (N = 53) Atorvastatin + HCQ
n (%) (N = 51) P value
< 5.7 7 (13.21) 12 (23.53) 0.034
5.7 to 6.4 38 (71.70) 38 (74.51)
= 6.5 8 (15.09) 1 (1.96)
Fisher exact test used for the comparison. Mean HbA1c in patients with HbA1c at week 24 >6.4%-baseline=6.15, week 24=7.03, change=0.88% and p-value=0.002

Table 9: Diabetic Patients in different HbA1c categories post 24 weeks of Mono/ Combination therapy
HbA1c at Week 24 Atorvastatin
n (%) (N = 54) Atorvastatin + HCQ n (%)
(N = 60) P value
< 5.7 1 (1.85) 5 (8.33) 0.081
5.7 to 6.4 7 (12.96) 14 (23.33)
= 6.5 46 (85.19) 41 (68.33)
Fisher exact test used for the comparison.

The results show marked reduction in LDL cholesterol, total cholesterol and non-HDL cholesterol. Also at the end of 24 weeks, only 1 patient (1.96%) from Atorvastatin + HCQ combination group developed diabetes (HbA1c =6.5%) as against 8 patients (15.09%) from Atorvastatin monotherapy group; which clearly demonstrates for the first time that the combination therapy of Hydroxychloroquine with statin such as Atorvastatin offers a treatment/therapeutic as well as prophylactic/preventative benefit against onset/development and progression of diabetes in patients receiving statins or in need of statin therapy.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Example 1:

i. Each tablet/capsule contains:
Hydroxychloroquine Sulphate ….. 400 mg
Atorvastatin …. 10mg /80mg
Excipients q.s. ……to make 600 mg tablet/capsule

ii Each tablet/capsule contains:
(S)-, Hydroxychloroquine ….. 200 mg
Atorvastatin …. 10mg /80mg
Excipients q.s. ……to make 400 mg tablet/capsule

iii. Each tablet/capsule contains:
Hydroxychloroquine Sulphate ………..400 mg
Simvastatin ……10mg/ 80mg
Excipients q.s. ……to make 600 mg tablet/capsule

iv. Each tablet/capsule contains:
(S)-, Hydroxychloroquine ……. 200 mg
Simvastatin ……10mg/ 80mg
Excipients q.s. ……to make 400 mg tablet/capsule

v. Each tablet/capsule contains:
Hydroxychloroquine Sulphate ………..400 mg
Rosuvastatin ……10mg/ 80mg
Excipients q.s. ……to make 600 mg tablet/capsule

vi. Each tablet/capsule contains:
(S)-, Hydroxychloroquine ……. 200 mg
Rosuvastatin ……10mg/ 80mg
Excipients q.s. ……to make 400 mg tablet/capsule

vii. Each tablet/capsule contains:
HydroxychloroquineSulphate ………..400 mg
Excipients q.s. ……to make 400 mg tablet/capsule

viii. Each tablet/capsule contains:
(S)-, Hydroxychloroquine ……. 200 mg
Excipients q.s. ……to make 400 mg tablet/capsule

ix. A kit comprising tablet/capsule containing:

Hydroxychloroquine Sulphate ….. 400 mg
Atorvastatin …. 10mg /80mg
Excipients q.s. ……to make 600 mg tablet/capsule

x. A kit comprising tablet/capsule containing
(S)-, Hydroxychloroquine ….. 200 mg
Atorvastatin …. 10mg /80mg
Excipients q.s. ……to make 400 mg tablet/capsule

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein