Strong Link Between Statin Drugs and Diabetes

Strong Link Between Statin Drugs and Diabetes

In a study of nearly 26,000 beneficiaries of Tricare, the military health system, cholesterol-lowering drugs statins have been found to increase the risk of developing diabetes. The study, published in the Journal of General Internal Medicine, confirms past findings on the link between the widely prescribed drugs and diabetes risk. The study included only people who at baseline were free of heart disease, diabetes and other severe chronic disease, is among the first to show the connection in a relatively healthy group of people.

The researchers examined patient records for the period between October 2003 and March 2012.

Statin drugs are the all-time leading prescription drugs sold around the world, prescribed by doctors to lower people’s cholesterol levels. While the side effects are a serious concern, there are also concerns that statin drugs have no therapeutic value either. Studies have never conclusively proven that lowering one’s cholesterol levels by medication increases one’s life span. In fact, there is evidence to the contrary, that higher cholesterol levels are associated with longer life spans.

Some eye-opening findings are:

1. Among 3,351 pairs of similar patients-part of the overall study group-those patients on statins were 250 percent more likely than their non-statin-using counterparts to develop diabetes with complications.

2. Statin users were also 14 percent more likely to become overweight or obese after being on the drugs.

3. Higher the dose of any of the statins, the greater the risk of diabetes, diabetes complications, and obesity.

4. About three-quarters of the statin prescriptions in Mansi's data were for simvastatin, sold as Zocor.

Using two different techniques for data analayis, namely a) propensity score matching where out of the total study population, the researchers chose 3,351 statin users and paired them with non-users who were very similar, at baseline, based on array of 42 health and demographic factors. The only substantial difference, from a research standpoint, was the use of statins. This helped the researchers isolate the effects of the drugs, b) looking at the overall comparison between the study's roughly 22,000 nonusers and 4,000 users, and statistically adjusting for certain factors. The researchers found a similar outcome: Users of statins were more than twice as likely to develop diabetes.

The authors conclude as “Diabetes, diabetic complications, and overweight/obesity were more commonly diagnosed among statin-users than similar nonusers in a healthy cohort of adults. This study demonstrates that short-term clinical trials might not fully describe the risk/benefit of long-term statin use for primary prevention.”

Article citation: Mansi, I.; et. al. Statins and New-Onset Diabetes Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults. Journal of General Internal Medicine, 2015; DOI: 10.1007/s11606-015-3335-1

Patients Using Statins Especially Simvastatin Have Lower Cancer-Specific Mortality Rates

Patients Using Statins Especially Simvastatin Have Lower Cancer-Specific Mortality Rates

A population-based cohort study to investigate whether statin users had reduced risk of lung cancer-specific mortality has provided evidence that lung cancer patient who used statins, and particularly simvastatin, have reduced rates of cancer-specific mortality.

Newly diagnosed lung cancer patients (~14000), from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate HRs for cancer-specific mortality and 95% confidence intervals (CI) by statin use before and after diagnosis, and to adjust these HRs for potential confounders.

Following are the findings:

1. In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.89; 95% CI, 0.78-1.02; P = 0.09).

2. Associations were more marked after 12 prescriptions (adjusted HR, 0.81; 95% CI, 0.67-0.98; P = 0.03) and when lipophilic statins were investigated (adjusted HR, 0.81; 95% CI, 0.70-0.94; P = 0.01), but were attenuated in some sensitivity analyses.

3. In 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.88; 95% CI, 0.83–0.93; P less than 0.001).

The authors conclude as “there was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality”. They also suggest conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients.

Article citation:  Cardwell, C. R.; et. al. Statin Use and Survival from Lung Cancer: A Population-Based Cohort Study. Cancer Epidemiol Biomarkers Prev 2015, 24(5), 833–841.

PCSK9 Inhibitors as Cholesterol Drugs

PCSK9 Inhibitors as Cholesterol Drugs

What is PCSK9?

Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme that in humans is encoded by the PCSK9 gene. PCSK9 has medical significance because it acts in cholesterol homeostasis. Drugs that block PCSK9 can lower low-density lipoprotein cholesterol (LDL-C), and are beginning Phase III clinical trials to assess their safety and efficacy in humans, and to determine if they can improve outcomes in heart disease.

PCSK9 Inhibitors

Two PCSK9 inhibitors, alirocumab and evolocumab, are in late-stage clinical development, because of their ability to lower LDL-C in patients for whom other treatments have been ineffective. Both of them are as the name suggest, -umab or monoclonal antibodies.

Costly than Statins

PCSK9 inhibitors will undoubtedly be a more costly treatment option than the current standard LMT, statins, which are a largely generalized class.

Trials and Results

The clinical trials for each of the PCSK9 inhibitors in development were designed to evaluate the long-term safety and tolerability of evolocumab (OSLER) and alirocumab (ODYSSEY) in high CVD-risk patients with hypercholesterolemia not effectively controlled with their current lipid-modifying therapy (LMT). The clinical trials for both alirocumab and evolucumab were global and included a broad cross-section of subjects-all of whom had difficult-to-treat hypercholesterolemia. The studies cut across all demographic categories, including age, race, nationality and economic status. Each drug lowered LDL-C by about 60% and decreased the rate of CVD events, including heart attack, heart failure leading to hospitalization and death, by about 50%.

Advantages

The advantage of PCSK9 inhibitors is that dosing will only involve a subcutaneous injection either once or twice per month. Patients will receive pre-filled syringes that they can easily administer at home.

Side-Effects

Overall, patients treated with PCSK9 inhibitors had higher rates of nonspecific side effects, such as arthralgia, headache, limb pain and fatigue, compared with placebo-treated patients. There were also more injection-site reactions in subjects treated with PCS9 inhibitors. Moreover, 1% to 1.5 % of patients experienced treatment-related neurocognitive effects, mainly confusion and some memory loss.

Evolocumab (Repatha) is developed by Amgen and Alirocumab (Praluent) is Sanofi and Regeneron product.

Rosuvastatin

Common name: Rosuvastatin; Crestor; R2; S-4522; Rosuvastatin calcium
Trademarks:  Crestor; Zyrova
Molecular Formula: C22H28FN3O6S
CAS Registry Number: 287714-41-4
CAS Name: (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid
Molecular Weight: 481.539
SMILES: CC(C)C1=NC(=NC(C2=CC=C(F)C=C2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(=O)O)N(C)S(C)(=O)=O
InChI Key: BPRHUIZQVSMCRT-VEUZHWNKSA-N
InChI: InChI=1S/C22H28FN3O6S/c1-13(2)20-18(10-9-16(27)11-17(28)12-19(29)30)21(14-5-7-15(23)8-6-14)25-22(24-20)26(3)33(4,31)32/h5-10,13,16-17,27-28H,11-12H2,1-4H3,(H,29,30)/b10-9+/t16-,17-/m1/s1
Activity: Hydroxymethylglutaryl-CoA Reductase Inhibitors; HMG-CoA inhibitor
Status: Launched 2003
Originator: Shionogi/Merck

Rosuvastatin synthesis: EP0521471B1 (also Ref. 2)

Rosuvastatin synthesis: Starting material [EP0521471B1 (also Ref. 2)]

Rosuvastatin synthesis: Starting material [Beilstein J Org Chem 2013, 9, 2265–2319 (also Ref. 4)]

Rosuvastatin synthesis: Side Chain [J Org Chem 1994 59(25), 7849-7854]

Rosuvastatin synthesis: Int J Pharm Biomed Sci 2013, 4(4), 118-121

References:
1. Watanabe, M.; et. al. Pyrimidine derivatives as HMG-CoA reductase inhibitors. EP0521471B1
2. Watanabe, M.; et. al. Synthesis and Biological Activity of Methanesulfonamide Pyrimidine- and N-Methanesulfonyl Pyrrole-Substituted 3,5-Dihydroxy-6-heptenoates, a Novel Series of HMG-CoA Reductase Inhibitors. Bioorg Med Chem 1997, 5(2), 437-444.(Many texts give a wrong citation with BMCL instead of BMC)
3. Baumann, M.; et. al. An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles. Beilstein J Org Chem 2013, 9, 2265-2319.
4. Börner, A.; et. al. A New Approach to the Total Synthesis of Rosuvastatin. Eur J Org Chem 2008, 5, 847-853.
5. Patil, P. B.; et. al. An efficient scalable process for rosuvastatin calcium. Int J Pharm Biomed Sci 2013, 4(4), 118-121.
6. Konoike, T.; et. al. Practical Synthesis of Chiral Synthons for the Preparation of HMG-CoA Reductase Inhibitors. J Org Chem 1994, 59(25), 7849-7854.

Antitumour Activity of Simvastatin

Antitumour Activity of Simvastatin

Statins (for ex. Atrovastatin, Simvastatin, etc.), inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are efficient and widely used drugs in the treatment of lipid disorders, especially hypercholesterolemia. In addition to their cholesterol-lowering effects, statins are reported to inhibit tumour cell growth, enhance the effects of chemotherapy  and overcome chemoresistance [1].

It is reported that cancer cells overexpress HMG-CoA reductase [2]. Statins help in inhibition of HMG-CoA reductase in cholesterol synthesis and thereby, also inhibits cell growth [3]. Although it is postulated that statins lead to apoptotic cell death through their inhibition of the mevalonate pathway, few other mechanisms also have been suggested [4].  Statins are reported to inhibit the activation of protein ras [4], influence production of Interleukin-18 (IL-18) [5], and control angiogenesis.

Researchers investigating the potential effects of Simvastatin on Renal cell carcinoma (RCC) cells and mechanisms by which Simvastatin exerted its actions, published the following results [6]:

1. Simvastatin potently suppressed cell growth of A498 and 786-O cells in a time- and dose- dependent manner.  

2. The xenograft model performed in nude mice exhibited reduced tumor growth with simvastatin treatment.

3. The inhibitory effects of Simvastatin on migration and invasion were also observed in vitro.

4. Simvastatin could suppress the proliferation and motility of RCC cells via inhibiting the phosphorylation of AKT, mTOR, and ERK in a time- and dose- dependent manner.

5. Simvastatin could exert the anti-tumor effects by suppressing IL-6-induced phosphorylation of JAK2 and STAT3.

These results suggest that Simvastatin may be a potential therapeutic agent for the treatment of RCC patients.

References:

1. Nishibori, M.; et. al. The antitumour activities of statins. Curr Oncol 2007, 14(6), 246.

2. Hentosh, P.; et. al. Sterol-independent regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in tumor cells. Mol Carcinog 2001, 32, 154-66.

3. Buchwald, H. Cholesterol inhibition, cancer, and chemotherapy. Lancet  1992, 339, 1154-1156.

4. Wong , W. W.; et. al. hmg-coa reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia 2002, 16, 508-19.

5. Takahashi H. K.; et. al. Simvastatin induces interleukin-18 production in human peripheral blood mononuclear cells. Clin Immunol 2005, 116, 211-126.

6. Liu, Z.; et. al. Simvastatin Inhibits Renal Cancer Cell Growth and Metastasis via AKT/mTOR, ERK and JAK2/STAT3 Pathway. PLoS One. 2013, 8(5), e62823.

Simvastatin

Common name: Simvastatin; Synvinolin; MK-733; MK733; MK 733; Zocor
Trademarks:  Zocor
Molecular Formula: C25H38O5 
CAS Registry Number: 79902-63-9
CAS Name: (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl 2,2-dimethylbutanoate
Molecular Weight: 418.566
SMILES: [H][C@]12[C@H](C[C@@H](C)C=C1C=C[C@H](C)[C@@H]2CC[C@@H]1C[C@@H](O)CC(=O)O1)OC(=O)C(C)(C)CC
InChI Key: RYMZZMVNJRMUDD-HGQWONQESA-N
InChI: InChI=1S/C25H38O5/c1-6-25(4,5)24(28)30-21-12-15(2)11-17-8-7-16(3)20(23(17)21)10-9-19-13-18(26)14-22(27)29-19/h7-8,11,15-16,18-21,23,26H,6,9-10,12-14H2,1-5H3/t15-,16-,18+,19+,20-,21-,23-/m0/s1
Activity: CARDIOVASCULAR DRUGS, Treatment of Lipoprotein Disorders, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors
Status: Launched 1992
Originator: Merck

Simvastatin is an active synthetic analogue of Lovastatin. Most of the synthetic processes start with either Lovastatin or it's derivatives. Here are important ones:

Simvastatin semi-synthesis: Org Proc Res Dev 1999, 3(6), 476-479

Simvastatin semi-synthesis: Scheme 1 (J Org Chem 1991, 56(16), 4929-4932) (Not favoured as final yield is only 48%. Moreover, Lovastatin appears as major impurity with the final product)

Simvastatin semi-synthesis: Scheme 2 (J Org Chem 1991, 56(16), 4929-4932) (Yield of 91%; commerically preferred route)

References:

1. Thaper, R. K.; et. al. A Cost-Efficient Synthesis of Simvastatin via High-Conversion Methylation of an Alkoxide Ester Enolate. Org Proc Res Dev 1999, 3(6), 476-479.

2. Tang, Y.; et. al. Efficient Synthesis of Simvastatin by Use of Whole-Cell Biocatalysis. Appl Environ Microbiol 2007, 73(7), 2054-2060.

3. Askin, D.; et. al. Synthesis of synvinolin: extremely high conversion alkylation of an ester enolate. J Org Chem 1991, 56(16), 4929-4932.

4. Todd, P. A.; et. al. Simvastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs 1990, 40(4), 583-607. (activity)

5. Liu, Z.; et. al. Simvastatin Inhibits Renal Cancer Cell Growth and Metastasis via AKT/mTOR, ERK and JAK2/STAT3 Pathway. PLoS One 2013, 8(5), e62823. (antitumor activity)

Atorvastatin

Common name: Atorvastatin calcium, YM-548, CI-981, Prevencor, Tahor, Lipibec, Torvast, Sortis, Lipitor
Tradename: Lipitor (Warner-Lambert); Sortis (Parke-Davis); Torvast (Pfizer); Totalip (Guidotti); Xarator (Parke-Davis)
CAS Registry Number: 125995-03-1 (also see 134523-03-8; 134523-00-5)
CAS Name: 5-(4-Fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1H-pyrrole-3-carboxamide
Molecular Formula: C33H33FN2O4
Molecular Weight: 540.62
SMILES: CC(C)C1=C(C(=O)NC2=CC=CC=C2)C(=C(N1CCC(O)CC(O)CC([O-])=O)C1=CC=C(F)C=C1)C1=CC=CC=C1
InChI Key: XUKUURHRXDUEBC-UHFFFAOYNA-M
InChI: InChI=1/C33H35FN2O5/c1-21(2)31-30(33(41)35-25-11-7-4-8-12-25)29(22-9-5-3-6-10-22)32(23-13-15-24(34)16-14-23)36(31)18-17-26(37)19-27(38)20-28(39)40/h3-16,21,26-27,37-38H,17-20H2,1-2H3,(H,35,41)(H,39,40)/p-1
Activity: CARDIOVASCULAR DRUGS, Treatment of Lipoprotein Disorders, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors
Status: Launched 1996
Originator: Pfizer


Atorvastatin synthesis: EP0409281; US5273995

Atorvastatin synthesis: Contemporary Drug Synthesis, 2004, Wiley Publications (This book as well as many other citations point it as Pfizer's commercial route)

Central Molecule (Tetrahedron Lett 1992, 33, 2283-2284)

Side Chain (Tetrahedron Lett 1992, 33, 2279-2282)

Finally, Atorvastatin

Atorvastatin (lactone) synthesis: J Med Chem 1991, 34(1), 357-66 (Scheme 1) (also Ref. 6)

Atorvastatin ((+)-lactone): J Med Chem 1991, 34(1), 357-66 (Scheme 2) (also Ref. 6)

Atorvastatin Side Chain (J Org Chem 2014, 79(6), 2723-2728)

References:

1. Graul, A.; Castañer, J.; Atorvastatin Calcium. Drugs Fut 1997, 22(9), 956.
2. Roth, B.D.; et. al. Inhibitors of cholesterol biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one inhibitors of HMG-CoA reductase. 2. Effects of introducing substituents at positions three and four of the pyrrole nucleus. J Med Chem 1991, 34(1), 357-66.
3. Radl, S.; et. al.; An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis. Tetrahedron Lett 2002, 43(11), 2087.
4. Roth, B. D. [R-(R*R*)]-2-(4-fluorophenyl)-ß,d-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof. US5273995A, EP0409281B1.
5. Li, J. J.; et. al. Contemporary Drug Synthesis, 2004, Wiley Publications.
6. Roth, B. D. Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis. US4681893A
7. Roth, B. D.; et. al. The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33(17), 2279–2282.
8. Roth, B. D.; et. al. The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33(17), 2283–2284.
9. Krasavin, M.; et. al. An improved kilogram-scale preparation of atorvastatin calcium. Chemistry Central Journal 2015, 9(1), 7. (high-yielding synthesis of atorvastatin calcium salt on 7 kg scale that affords >99.5% product purities)
10. Chen, X.; et. al. Asymmetric Synthesis of the HMG-CoA Reductase Inhibitor Atorvastatin Calcium: An Organocatalytic Anhydride Desymmetrization and Cyanide-Free Side Chain Elongation Approach. J Org Chem 2014, 79(6), 2723-2728 (Cyanide-Free Side Chain Elongation Approach ???)

For more drugs and their synthesis: Synayurajan database