Discussing Type II Diabetes - Article Example

Please just send a message if you need to change anything. Thanks! PHARMACOLOGY- TYPE II DIABETES A RISK FACTOR FOR CARDIOVASCULAR DISEASE Abstract This paper reviewed 10 pharmacology related articles discussing Type II diabetes as a risk factor for cardiovascular disease. These include discussing background information about potential receptors, method used in the study, the result, and comparison of articles based on beneficial effects. The most common method used are Animal Laboratory Experiment followed by Review of Clinical Trials. Treatment is mostly based on the ability of drugs to activate receptors that would improve insulin resistance, control diabetes, reduce blood pressure, and maintain glucose levels. Aglycone genistein, Lorcaserin, Kinin, Mipomersen, Candersartan, and Pioglitazone seems a useful agent for Type II diabetes treatment and improving risks of vascular disease. However, their side effects needs further investigation particularly those associated with toxicity and cardiac growth. Table of Contents Contents Contents 3 1. Introduction Type II diabetes is more common than Type I as result of study conducted by suggest that it accounts to 90-95% of all patients with diabetes. It is caused by numerous factors such as diet, obesity, visceral fat, sedentary life, genetic and it can lead to different microvascular and macrovascular complications such as neuropathy (nerve damage), retinopathy (disease in the retina of the eye), coronary artery disease, stroke, and peripheral vascular disease (narrowing and hardening of the arteries). The following sections review and compare 10 different articles regarding Type II diabetes as a risk factor for cardiovascular disease. These include description of drugs in relation to its use of receptors, method of research, test procedures, results, comparative table showing important differences between articles, and summary of critical points found by this article review. 2. Article Review 2.1 Effects of aglycone genistein in a rat experimental model of postmenopausal metabolic syndrome by Background Metabolic syndrome consists of risk factors such as obesity, hypertension, and insulin resistance that increases the risk of Type 2 diabetes and cardiovascular disease . An isoflavone or organic compound in soybean, Genistein has been shown to be a potentially useful insulinotropic agent with satisfactory anti-diabetic effect in experimental animals and patients . This article described the investigation conducted on the potential of genistein aglycone in reducing cardiovascular risk among postmenopausal women who according to is higher due to low estrogen level that decrease blood flow and reduced ability of estrogen to protect the pancreatic beta cells in Type 2 diabetics . Method and Test Conducted Experimental study is conducted using 80 female rats under normal conditions. Initially, they were fed with foods low in soy protein content and tap water. After 4 weeks, these rats were divided into eight groups where 4 groups received (through oral gavages) human equivalent dose of 54mg genistein aglycone or ~4.8mg/kg for a 250g rat daily for a month. In contrast, the other 4 groups through a vehicle received 5gcarboxymethylcellulose, 5 ml benzyl alcohol, 9g NaCL, 4ml Tween 80 in 100ml distilled water. Rats body weight and food intake were monitored weekly and tested for glucose tolerance at the end of the experiment. The rats were then anesthetized with 50mg/kg sodium pentobarbital and blood samples were taken from mensenteric artery and liver while their uteri were removed for further examination. Results All rat gained weight but those treated with genistein (controlled groups) weigh less in relation to those treated with vehicle. Genistein did not alter uterine weights but increase PPARA or Peroxisome proliferator-activated receptor alpha in controlled groups. Total HDL and LDL cholesterol and triglycerides levels are significantly reduced in controlled groups while other groups showed slight alterations in triglycerides levels and moderate increase in HDL cholesterol. Glucose levels and insulin response is considerably reduced by genistein administration while blood pressure and heart rate decreased throughout the treatment. 2.2 Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution by Background Previous studies in both human and animal obesity suggest that CB1 or blockade of the cannabinoid receptor 1 that is part of the endocannabinoid system and present in the brain, liver, and muscle tissue can reduce weight of Type II diabetics . However, the link between obesity and CNR1 (a CB1 receptor gene variant) is not clear thus further investigation is required. This article investigated if CNR1 variants such as rs806381, rs10485179, and rs1049353 are actually responsible in obesity reduction and fat distribution. Method and Test Conducted A population-based study, the investigation carried out a survey and evaluated a sample of 3000 men with age ranging from 20 to 29 using questionnaires. However, only 2042 responded and out of this number, only 783 expressed their willingness to participate in clinical follow-up that include taking blood samples, glucose levels, examination and kidney and endocrine functions, and others. The questionnaires include demographics, life style factors, and participants medical history such as pharmacological treatments and physical examination. Total body fat mass was measured using dual x-ray densitometer while MRI evaluated abdominal and femoral FM. Biological materials collected in clinical follow-up were stored at negative 80 degrees centigrade and examined using hexokinase-based method for plasma glucose and homogenous enzymatic end point colourimetric for serum cholesterol, low-density lipoprotein, and high-density cholesterol. For measuring serum triglycerides, an enzymatic end point colourimetric method was applied while a non-competitive immunoflourometric assays estimated the serum insulin. The study also conducted genotyping and evaluated genotypes of CNR1 from blood samples using TaqMan assays while statistical analysis were performed using STATA v.10. Results None of the CNR1 variants is directly associated with TBFM or BMI. However, abdominal FM is highly associated with rs806381 polymorphism while visceral and intermuscular FM is linked to rs1049353. Similarly, there is no evidence linking variants polymorphisms to TBFM and insulin resistance. 2.3 Lorcaserin: a selective serotonin receptor (5-HT2C) agonist for the treatment of obesity by Background A selective serotonin receptor or 5-HT2C, Lorcaserin is used in chronic weight management as it does not only reduce weight of obese patients but reduce risks associated with Type II diabetes and cardiovascular diseases. However, its effect on risk associated with adverse cardiac events such as heart attack and stroke is not yet clear. This article investigated the effects of Lorcaserin through review of three phase-3 clinical trials such as BLOOM or Behavioral modification and Lorcaserin for Overweight and Obesity Management, BLOOM:DM with Diabetes Mellitus, and BLOSSOM or Behavioral modification and Lorcaserin Second Study for Obesity Management. Method and Test Conducted BLOOM is a 2-year randomized clinical trial with 3, 182 patients who are mostly obese and with at least one diabetes mellitus related cardiovascular disorder such as hypertension and dyslipidemia. These patients were divided into two groups, one for placebo and the other for Lorcaserin treatment. In BLOSSOM, which is a 1-year double blind clinical trial, 4,008 patients who possess similar characteristics as in BLOOM were given 10mg of Lorcaserin BID and QD. BLOOM-DM on the other hand is more specific as aside from the lower number patients studied (604 only), participants are those with BMI higher than or equal to 27 kg/m2 and inadequately controlled Type 2 diabetes and treated with metformin or sulfonylurea. Results In BLOOM, 47.5% of those in the Lorcaserin group and 20.3% of those receiving placebo lost 5% of their body weight in year 1. However, 67.9% of patients who continue to receive Lorcaserin maintained their baseline weight compared to 50.3% of those receiving placebo. In contrast, patients receiving Lorcaserin 10mg BID (47.2%) and QD (40.2%) in BLOSSOM lost 5% of baseline body weight, which is significantly more compared to 25% in the placebo group. However, compared to 6.7% of those in the placebo group, 8.6% of patients receiving Lorcaserin discontinued their treatment prematurely due to undesirable reactions such as headache, dizziness, fatigue, and others. 2.4 Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study by Background Activation of serotonin 2C receptor can result to increase satiety, decreased hunger, and subsequent reduction in food intake . Unlike article, Lorcaserin, a small molecule agonist of 5HT2C receptor is viewed as a potential agent not only for weight loss but for regulating glucose tolerance and hepatic insulin sensitivity . This article evaluates the safety and efficacy of Lorcaserin in reducing weight for Type II diabetes patients and in particular verifies the result of BLOOM-DM. Method and Test Conducted The method used in this study is a 1-year randomized, double-blind, placebo-controlled trial. Patients with Type 2 diabetes mellitus, treated with metformin or SFU, 18 to 65 years of age, with BMI between 27-45 kg/m2, had HbA and can participate in moderate intensity exercises are considered. Patients were randomly selected in 1:1:1 ratio and received 10mg of Lorcaserin BID in the morning and placebo in the evening. Lifestyle modification program was administered including counseling sessions, moderate exercises, and self-monitoring of blood glucose BID. The study also performed echocardiography and statistical analysis of sample size, population, and efficacy analysis. Results Most patients receiving Lorcaserin BID or 66% and Locarcaserin QD or 78.9% completed the study while discontinuation is mostly attributed to adverse event caused by Lorcaserin. Patients taking Lorcaserin BID and QD lost an average of 5% body weight that becomes more evident after two weeks of trial. In week 52, patients in the Lorcaserin group decreased their hip circumference significantly compared to the placebo group. Similar, there is a noticeable decrease in Mean HbA1c among Lorcaserin patients (50% in BID and 52.2% in QD) while insulin resistance dropped significantly. 2.5 Selective kinin receptor agonist as cardioprotective agents in myocardial ischemia and diabetes by Background Cardiac ischemia, a complication of coronary heart disease and usually caused by diabetes, according to this article is the leading cause of death in diabetic patients. Since the kallikrein-kinin system contributes to myocardial protection in ischemia, activated kinin receptors may have therapeutic effect that can prevent cardiac ischemia because it trigger release of numerous of endothelial mediators responsible for smooth muscle relaxation, fibrinolysis, and inhibition of platelet aggregation. More importantly, B2R, a receptor subtype that usually activated by kinins is induced in high glucose-induced situations and therefore essential in diabetes treatment and ischemia prevention . Method and Test Conducted The study performed a laboratory experiment using ten week-old mice housed with a 12h light/dark cycle and has free access to food and water. The first group was injected streptozotocin 5 times a day to induce diabetes (diabetes induction in animals) while the other received vehicle representing the non-diabetic group. The mice were anesthetized by sodium pentobarbital before the catherer is inserted into the left carotid artery for blood pressure and heart rate recording. The study also performed myocardial IR injury procedure to verify the effect of kinin receptor agonist on IR injury and statistical analysis using one-way ANOVA to assess the effect of ischemia-reperfusion and agonist treatment on infarct size and signaling pathways and effects of diabetes on receptor mRNA level. Results Kinin receptor agonist activated the reperfusion ischemia salvage kinases and inhibition of GSK-3β. Diabetes has no effect on B2R mRNA level while B1Rand B2R are not affected by ischemia-reperfusion. B1R has strong cardioprotective effect in diabetic mice by activating PI3-kinase and MAPK pathway. 2.6 Peroxisome proliferator-activated receptor β stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin by Background PPARβ is a potential drug for regulating lipoprotein and glucose metabolism and lately , it came to be recognized as treatment for metabolic syndrome and associated cardio vascular disease. This is because PPARβ activation improves insulin responses, increase oxidative metabolism, burns fatty acid, reduce fat mass, normalized adipokine secretion, and mimic the beneficial effect of physical exercise. However, its effect on cardiac growth and vascularization are still not clear particularly PPARβ agonist GW0742 and GW501516. Method and Test Conducted The study conducted animal laboratory test using ten-week old male mice injected with GW0742 or GW5015156 dissolved in DMSO at 1 mg/kg once a day. It also performed histological and immunohistochemical analysis, terminal deoxynucleotidyl transferase dUTP nick end labeling of apoptotic cells, echocardiography, statiscal analysis in ANOVA and Mann-Whitney test, cell culture and transient transfection experiments, chromatin immunoprecipitation and electrophoretic mobility shift assays. Results PPARβ activation result to rapid induction of cardiac growth with increased calcineurin expression and induced rapid cardiac angiogenesis. It can directly activate calcineurin and its growth promoting effect is limited to the heart. PPARβ stimulation is similar to physical exercise as mice running time and distance increase by around 70% thus beneficial to obesity treatment. 2.7 Mipomersen: Pharmacology, Clinical Trials and Its Potential Role in Therapy by Background Mipomersen is a new pharmacologic agent with potential to treat hyperlipidemia or LDL cholesterol levels common in Type 2 diabetic patients. Dyslipidemia is also common in adults with Type 2 diabetes and major risk factor for cardiovascular disease . However, one of the safety concerns with mipomersen is liver toxicity due to significant increase in liver enzymes. This study focuses on mipomersen’s ability as an apolipoprotein B synthesis inhibitor in lowering LDL-C cholesterol concentrations in patients with homozygous familia hypercholesterolaemia. Method and Test Conducted The study conducted a review of clinical trials that include Raal et al.’s study of patients with homozygous familia hypercholesterolaemia, Stein et al.’s study of medication in patients with heterozygous familia hypercholesterolaemia, and Kastelein et al.’s study of mipomersen in patients with mild hyperlipidemia. These trials involved placebo-controlled, double-blined, and randomized phase 3 trial. Results Patients in the first trial taking mipomersen showed an average 25% decrease in LDL-C compared to placebo group with 3% reduction. They also recorded statistically significant reduction in ApoB, total cholesterol, non-HDL cholesterol, Lp (A), triglycerides, and VLDL but no significant effect on Apo A1. Patients in the second trial receiving 200 mg dose of mipomersen showed 30.6% reduction in LDL after 45 days and 34% at day 55. In the third trial, patients receiving mipomersen exhibit decrease in LDL of about 28% while ApoB, total cholesterol, non-HDL cholesterol, Lp (A), triglycerides, VLDL, and ApoA1 decreased considerably during the trial. However, elevated liver enzymes were detected mostly in mipormesen group with 5 out of 12 ratio. 2.8 A Review on Candersartan: Pharmacological and Pharmaceutical Profile by Background Candersartan, an orally active non-peptide tetrazole derivative, is an angitensin II receptor blocker or ARB which is a common treatment for diabetic nephropathy, hypertension, heart failure, and myocardial infarction . This article is a review of previous studies conducted about the beneficial effects of Candersartan particularly in reducing blood pressure, severe and resistant hypertension, and patients intolerant of anti-hypertensive agents from other classes of drugs. Method and Test Conducted The author conducted a review of literature concerning Candesartan. These include evaluation physicochemical properties, mechanism of action, pharmacokinetic and pharmcodynamic profile, Candesartan cilexetic effects in patients with hypertension, heart failure, absorption and distribution, metabolism and excretion, and pharmacodynamics, therapeutic efficacy, dosage and tolerability. Results Results of review suggest that Candersartan cilexetil reduced systolic and diastolic blood pressure but no changes in serum levels of total cholesterol, triglycerides, glucose, and uric acid. The same results were observed in non-insulin dependent Type 2 diabetic patients. Cardersartan also reduced systemic vascular resistance and pulmorary capillary wedge pressure. It has adverse effects such as headache, muscle weakness, hypotension, rash, dry skin, diarrhea, nausea, cough, back pain, fever, and gout. 2.9 Cardioprotective effects of lixisenatide in rat myocardial ischema-reperfusion injury studies by Background Lixisenatide stimulate insulin secretion and inhibits glucagon secretion and gastric emptying. It is a receptor known as GLP1R or Glucagon-like- peptide 1. This article investigated the cardioprotective effects lixisenatide in treatment of ischemia and reperfusion. Method and Test Conducted The effects of lixisenative were investigated using isolated rat hearts subjected to brief ischemia and reperfusion. The study used synthesized Ramipril and lixisenatide freshly dissolved in a sodium acetate buffer. Rats were heparinized and anesthetized for heart removal and examination. Bio markers were assessed using plasma and serum while data from each experiment were analyzed SAS V8.2 for SUN 4 via interface software EverStat V.6.0. ANOVA was used for Gaussian distributions. Results Lixisentatide induced both short and long-term cardioprotection from ischemia and reperfusion. However, its effects are independent of GLP-1 receptor and likely contributed by the direct effects on cardiomyocytes. Moreover, the mechanism concerning lixisenatide mediated cardioprotection was not found and requires further investigation. 2.10 PPAR agonist for the treatment of cardiovascular disease in patients with diabetes by Background PPARs are intracellular receptors located within the cell and within the nucleaus. PPARs act as heterodimers with retinoid X receptor and activated by fatty acids. This activation result to conformational changes, dissociation, and recruitment of different transcription cofactors that affect genes, protein synthesis, and cellular function . This article investigated the effects of PPAR agonists in treating cardiovascular disease particularly in diabetic patients. Method and Test Conducted This study conducted an article review regarding the properties of PPAR isotypes, adverse events associated with PPAR agonists, the result of clinical trial investigating the effects of pioglitazone or mascuvascular outcomes in patients with Type II diabetes, and result of meta-analysis investigating the effects of rosiglitazone in increasing MI and death from cardiovascular causes. Results PPAR agonist have very different and conflicting clinical benefit and adverse event profiles. Pioglitazone contribute to cardioprotection among patients with Type II diabetes while rosiglitazone and muraglitazar are cardiotoxic. 3. Article Comparison Table Article Title Receptor Method Result Beneficial to Type II diabetic Effects of aglycone genistein in a rat experimental model of postmenopausal metabolic syndrome by Aglycone genistein Animal Laboratory Experiment Genistein (controlled groups) weigh less in relation to those treated with vehicle. Genistein did not alter uterine weights but increase PPARA or Peroxisome proliferator-activated receptor alpha in controlled groups. Total HDL and LDL cholesterol and triglycerides levels are significantly reduced in controlled groups while other groups showed slight alterations in triglycerides levels and moderate increase in HDL cholesterol. Glucose levels and insulin response is considerably reduced by genistein administration while blood pressure and heart rate decreased throughout the treatment. Yes Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution by Endocannabinod receptor 1 (CNR1) Population-based survey None of the CNR1 variants is directly associated with TBFM or BMI. However, abdominal FM is highly associated with rs806381 polymorphism while visceral and intermuscular FM is linked to rs1049353. Similarly, there is no evidence linking variants polymorphisms to TBFM and insulin resistance. No Lorcaserin: a selective serotonin receptor (5-HT2C) agonist for the treatment of obesity by Lorcaserin (5-HT2C) Review of Clinical Trials In BLOOM, 47.5% of those in the Lorcaserin group and 20.3% of those receiving placebo lost 5% of their body weight in year 1. However, 67.9% of patients who continue to receive Lorcaserin maintained their baseline weight compared to 50.3% of those receiving placebo. In contrast, patients receiving Lorcaserin 10mg BID (47.2%) and QD (40.2%) in BLOSSOM lost 5% of baseline body weight, which is significantly more compared to 25% in the placebo group. However, compared to 6.7% of those in the placebo group, 8.6% of patients receiving Lorcaserin discontinued their treatment prematurely due to undesirable reactions such as headache, dizziness, fatigue, and others. Yes Randomized Placebo-Controlled Clinical Trial of Lorcaserin for Weight Loss in Type 2 Diabetes Mellitus: The BLOOM-DM Study by Lorcaserin (5-HT2C) Randomized,double blind, placebo-controlled trial Most patients receiving Lorcaserin BID or 66% and Locarcaserin QD or 78.9% completed the study while discontinuation is mostly attributed to adverse event caused by Lorcaserin. Patients taking Lorcaserin BID and QD lost an average of 5% body weight that becomes more evident after two weeks of trial. In week 52, patients in the Lorcaserin group decreased their hip circumference significantly compared to the placebo group. Similar, there is a noticeable decrease in Mean HbA1c among Lorcaserin patients (50% in BID and 52.2% in QD) while insulin resistance dropped significantly. Yes Selective kinin receptor agonist as cardioprotective agents in myocardial ischemia and diabetes by Kinin receptor Animal Laboratory Experiment Kinin receptor agonist activated the reperfusion ischemia salvage kinases and inhibition of GSK-3β. Diabetes has no effect on B2R mRNA level while B1Rand B2R are not affected by ischemia-reperfusion. B1R has strong cardioprotective effect in diabetic mice by activating PI3-kinase and MAPK pathway. Yes Peroxisome proliferator-activated receptor β stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin by PPARβ Animal Laboratory Experiment PPARβ activation result to rapid induction of cardiac growth with increased calcineurin expression and induced rapid cardiac angiogenesis. It can directly activate calcineurin and its growth promoting effect is limited to the heart. PPARβ stimulation is similar to physical exercise as mice running time and distance increase by around 70% thus beneficial to obesity treatment. Yes in obesity management/No to cardiovascular disease Mipomersen: Pharmacology, Clinical Trials and Its Potential Role in Therapy by Mipomersen Review of Clinical Trials Patients in the first trial taking mipomersen showed an average 25% decrease in LDL-C compared to placebo group with 3% reduction. They also recorded statistically significant reduction in ApoB, total cholesterol, non-HDL cholesterol, Lp (A), triglycerides, and VLDL but no significant effect on Apo A1. Patients in the second trial receiving 200 mg dose of mipomersen showed 30.6% reduction in LDL after 45 days and 34% at day 55. In the third trial, patients receiving mipomersen exhibit decrease in LDL of about 28% while ApoB, total cholesterol, non-HDL cholesterol, Lp (A), triglycerides, VLDL, and ApoA1 decreased considerably during the trial. However, elevated liver enzymes were detected mostly in mipormesen group with 5 out of 12 ratio. Yes A Review on Candersartan: Pharmacological and Pharmaceutical Profile by Candersartan Review of Literature Results of review suggest that Candersartan cilexetil reduced systolic and diastolic blood pressure but no changes in serum levels of total cholesterol, triglycerides, glucose, and uric acid. The same results were observed in non-insulin dependent Type 2 diabetic patients. Cardersartan also reduced systemic vascular resistance and pulmorary capillary wedge pressure. It has adverse effects such as headache, muscle weakness, hypotension, rash, dry skin, diarrhea, nausea, cough, back pain, fever, and gout. Yes Cardioprotective effects of lixisenatide in rat myocardial ischema-reperfusion injury studies by Lixisenatide Animal Laboratory Experiment Lixisentatide induced both short and long-term cardioprotection from ischemia and reperfusion. However, its effects are independent of GLP-1 receptor and likely contributed by the direct effects on cardiomyocytes. Moreover, the mechanism concerning lixisenatide mediated cardioprotection was not found and requires further investigation. No PPAR agonist for the treatment of cardiovascular disease in patients with diabetes by Various PPAR agonist Review of Literature PPAR agonist have very different and conflicting clinical benefit and adverse event profiles. Pioglitazone contribute to cardioprotection among patients with Type II diabetes while rosiglitazone and muraglitazar are cardiotoxic Yes to Pioglitazone/No to cardio toxic agents 4. Conclusion In relation to Type II diabetes and cardiovascular disease, aglycone genistein is potentially useful agent in increasing PPARA, reducing cholesterol and triglycerides levels, reducing glucose levels and insulin response, and in decreasing SBP and heart rate among those experiencing metabolic syndrome. Others such as Lorcaserin, Kinin, Mipomersen, Candersatan, PPAR’s pioglitazone are also useful in treating Type II diabetes and associated cardiovascular but their side effects should be further studied. 5. References/Bibliography Aronow, W. S., Fleg, J. L. & Rich, M. W. (2013). Tresch and Aronow's Cardiovascular Disease in the Elderly, Fifth Edition, Taylor & Francis Berkson, D. L. (2010). Safe Hormones Smart Women, iUniverse Bitto, A., Altavilla, D., Bonaiuto, A., Polito, F., Minutoli, L., Di Stefano, V., Giuliani, D., Guarini, S., Arcoraci, V. & Squadrito, F. 2009. Effects of aglycone genistein in a rat experimental model of postmenopausal metabolic syndrome. J Endocrinol, 200, 367-76. Evans, J. & Shelton, D. 2013. Mipomersen: Pharmacology, Clinical Trials and Its Potential Role in Therapy. Advances in Diabetes and Metabolism (1): 2013, 16-20. Frost, M., Nielsen, T. L., Wraae, K., Hagen, C., Piters, E., Beckers, S., De Freitas, F., Brixen, K., Van Hul, W. & Andersen, M. 2010. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution. Eur J Endocrinol, 163, 407-12. Husain, A., S., A., Mitra, M. & Bhasin, P. 2011. A Review on Candersartan: Pharmacological and Pharmaceutical Profile. Journal of Applied Pharmaceutical Science 01(10), 2011, 12-17. Kataria, B. 2012. Lorcaserin: a selective serotonin receptor 5-HT2C agonist for the treatment of obesity. International Journal of Basic & Clinical Pharmacology, 1, 45. O'Neil, P. M., Smith, S. R., Weissman, N. J., Fidler, M. C., Sanchez, M., Zhang, J., Raether, B., Anderson, C. M. & Shanahan, W. R. 2012. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring), 20, 1426-36. Potier, L., Waeckel, L., Vincent, M. P., Chollet, C., Gobeil, F., Jr., Marre, M., Bruneval, P., Richer, C., Roussel, R., Alhenc-Gelas, F. & Bouby, N. 2013. Selective kinin receptor agonists as cardioprotective agents in myocardial ischemia and diabetes. J Pharmacol Exp Ther, 346, 23-30. Preedy, V. R. (2012). Isoflavones: Chemistry, Analysis, Function and Effects, Royal Society of Chemistry Simpson, K. & Bredesen, D. (2006). The Perimenopause and Menopause Workbook: A Comprehensive, Personalized Guide to Hormone Health, New Harbinger Publications Wagner, N., Jehl-Pietri, C., Lopez, P., Murdaca, J., Giordano, C., Schwartz, C., Gounon, P., Hatem, S. N., Grimaldi, P. & Wagner, K. D. 2009. Peroxisome proliferator-activated receptor beta stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin. Cardiovasc Res, 83, 61-71. Wilding, J. 2012. PPAR agonists for the treatment of cardiovascular disease in patients with diabetes. Journal of Diabetes, Obesity, and Metabolisim, 14: 2012, 973-982. Wohlfart, P., Linz, W., Hubschle, T., Linz, D., Huber, J., Hess, S., Crowther, D., Werner, U. & Ruetten, H. 2013. Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies. Journal of Translational Medicine,11(84), 2013, 2-12.  Read More