Metformin and cholesterol -
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Antipsychotics can cause numerous side effects, including weight gain and metabolic abnormalities. The off-label use of the type 2 diabetes medication metformin may be able to help patients who are unable to switch to a lower-risk antipsychotic. Despite the great benefit that second-generation antipsychotics can offer patients with schizophrenia and other psychiatric disorders, taking them can lead to serious side effects for some patients, including a high risk of weight gain and metabolic abnormalities.
To help minimize this risk, experts advise that clinicians discuss the importance of healthy eating and regular exercise with patients before prescribing antipsychotics; monitor any changes in weight, blood pressure, or fasting plasma glucose and lipid levels after initiating therapy; and, if significant changes are detected, consider switching patients to a lower-risk antipsychotic.
If switching antipsychotics is not an option, a growing body of literature suggests that the off-label use of metformin—approved for the treatment of type 2 diabetes—may be able to reduce antipsychotic-induced weight gain and insulin resistance.
A study published last month in Molecular Psychiatry also suggests that the medication may reduce low-density lipoprotein cholesterol LDL-C , which is a primary target of cardiovascular disease reduction.
Christoph Correll, M. As described in Molecular Psychiatry , a team of researchers from the United States and China pooled data from two randomized, placebo-controlled trials, including patients from China aged 18 to 40 who developed dyslipidemia within a year of taking clozapine, olanzapine, risperidone, or sulpiride for the treatment of a first episode of schizophrenia.
Sulpiride has not been approved for use in the United States. After 24 weeks of treatment, Of those who had dyslipidemia defined by LDL-C at baseline, 64 percent of patients who took metformin restored their LDL-C to below the normal level compared with Despite these findings, Correll advised that clinicians hold off on prescribing metformin to patients initiating antipsychotic treatment until they know whether significant weight gain will be an issue.
It is advised that patients take metformin with food to reduce the gastrointestinal side effects of the medication, which include nausea, vomiting, diarrhea, and abdominal pain. Inhibition of this pathway leads to inhibition of promoter activity of the insulin gene and to a decrease of insulin secretion [ ].
Insulin secretion may also be impaired via direct statin induced inhibition of mitochondrial oxidative phosphorylation at complex III [ ]. The resulting decrease in ATP synthesis may induce inhibition of insulin secretion via the cascade described above.
One of the mechanisms of an increased insulin resistance could be the effect on the glucose transporter GLUT-4 located in adipose tissue and muscle. Atorvastatin treatment was shown to reduce the surface expression of GLUT-4 in mice adipocytes by inhibiting isoprenylation via inhibition of the mevalonate pathway [ ].
Mevalonate is an important intermediate in cholesterol synthesis and hence also for the synthesis of isoprenoid intermediates Ras and Rho proteins important in cell proliferation. These are involved in intracellular mobilization and localization of proteins.
Statin treatment may cause inactivation of Ras and Rho molecules so that activation and membrane translocalization of GLUT-4 is inhibited. Experiments in mouse adipocytes confirmed that GLUT-4 located on the plasma membrane moved to the cytosol during atorvastatin treatment [ ].
This may result in an increased insulin resistance. In conclusion, statin treatment may lead to a decreased insulin secretion in the β cell via several mechanisms. However, these effects are up to now mainly seen in animal in vitro studies and so it remains elusive whether these results can be translated to humans.
In addition, it should also be kept in mind that 10 years of statin treatment in patients caused an increased BMI 1. It is not clear whether the patients that developed T2DM on statin treatment increased their BMI excessively.
This is in contrast with metformin. Metformin treated mice showed a decreased weight gain which was related to the increased energy consuming conversion of glucose to lactate in the intestinal wall [ ]. In diabetic rats — g it was shown that after 2 weeks metformin—atorvastatin combination therapy mg metformin and 20 mg atorvastatin per 70 kg body weight , glucose-lowering effects, lipid-lowering effects, reduction of oxidative stress, and positive effects on cardiovascular hypertrophy occurred [ ].
The reduction of oxidative stress and protection of the liver observed by studying the liver histology and blood measurement, e.
CRP, TNF-α, IL-6, protein carbonyl levels was also seen in T2DM rats treated with metformin and atorvastatin [ , ].
These positive effects and the fact that a great number of patients are treated with Metformin — statin combination therapy led to the design of a metformin—atorvastatin combination tablet used as a single daily dose [ , ].
There is only a minor chance for toxic drug interactions when metformin and statin are administered together because metformin is not metabolised and most statins are metabolised via the cytochrome P system [ ]. Patients with T2DM are often taking metformin and statins together to control CVD risk as well as glucose metabolism [ 82 ].
Since metformin shows beneficial effects on both dyslipidemia and glycemic control and has been shown to reduce CVD risk while statins may have an added beneficial effect on CVD risk, combined treatment with both drugs seems a good option.
As far as we have been able to discern no randomised clinical trials have been carried out to establish whether combination therapy is superior to monotherapy when focusing on CVD risk.
Ethical considerations maybe prohibitive in this respect but perhaps subgroup analysis in ongoing studies such as the DDPOS may provide an answer. Studies aiming at optimal dosing of both drugs have not been performed. Clinical studies on the effects of metformin and statin combination therapy have been carried out but for different purposes [ 82 , , , , , , , ].
Each of these studies had different objectives and included different patients groups, i. either with T2DM, dyslipidemia, treated different doses , untreated, or newly diagnosed T2DM.
This precludes comparing these studies to arrive at overall results of metformin statin combination therapy. These studies are now discussed briefly to obtain knowledge about the overall effects on glucose and lipid metabolism in T2DM patients with dyslipidemia Table 5.
Atorvastatin 20 mg showed to attenuate the glucose- and HbA1c-lowering effect in combination with and mg metformin. This may complicate analysis of the obtained changes on the glucose and lipid metabolism. However, it could be used for hypothesis-generation rather than making rigid decisions, considering the lack of multiple dose dependent combination studies.
The effects of metformin on lipid homeostasis as discussed in this review article, indicate that lipid metabolism is positively affected in the intestine and liver leading to decreased plasma triglycerides, LDL-C, and total cholesterol.
Metformins effects on lipid metabolism seem to be localized to the intestine. Statins mainly act on plasma cholesterol levels via activation of the LDL-receptor suggesting that combination therapy should show an additional effect on plasma lipids.
However, the data in Table 5 give little indication for an added beneficial effect of both drugs on lipid parameters.
Dedicated studies are required to further investigate the effects of both drugs by combination therapy in humans. Metformin has been shown to exert a significant influence on the composition of the gut microbiota. Interestingly, statins showed such effects as well, particularly in studies with mice and rats [ , ].
Statins were able to decrease the production of butyrate which may relate to the development of new onset T2DM [ ].
Atorvastatin given to hypercholesterolemic patients restored anti-inflammatory bacteria [ ]. In T2DM patients with non-alcoholic fatty liver disease NAFLD beneficial use of combination therapy seems indicated since statin therapy associates negatively with non-alcoholic steatohepatitis and significant fibrosis while a safe use of metformin in patients with T2DM and NAFLD was demonstrated [ ].
Combination therapy consisting of metformin and statin treatment is frequently prescribed to women with an endocrine disorder called polycystic ovary syndrome PCOS. PCOS increases the risk of T2DM and cardiovascular morbidity as it is associated with abnormal increased lipid levels, insulin resistance, systemic inflammation and endothelial dysfunction [ ].
Meta-analysis showed that combined statin-metformin therapy in women with PCOS resulted in improved lipid and inflammation markers but it did not improve insulin sensitivity [ ].
Additional studies are recommended to confirm these results. Combination therapy could also be considered for T2DM patients with diabetic retinopathy.
Diabetic retinopathy DR is a microvascular complication of diabetes caused by hyperglycemia and hyperosmolarity. Leakage and accumulation of fluid in the macula is known as macular edema and results in severe vision loss in DR patients. The use of statins in T2DM patients and pre-existing DR showed a protective effect against development of diabetic macular edema [ ].
Remarkable is that T2DM patients receiving statin therapy in combination with increased levels of cholesterol remnants and triglycerides were associated with slight decreased in left ventricular systolic function. Targeting cholesterol remnants in addition to T2DM patients receiving statins might be beneficial on cardiac function [ ].
From a clinical perspective, it was shown that many patients with T2DM and CVD did not receive lipid lowering therapy while their lipid levels were not in the optimal range [ ].
Increased implementation of guideline recommendations for dyslipidemic T2DM patients is therefore recommended [ ]. Metformin is generally thought to exert its beneficial effects on glucose metabolism mainly in the liver. In line with recent literature on the topic we conclude that the drug acts primarily in the intestine.
This is due to the at least one order of magnitude higher concentrations of metformin in the intestine than in the liver. The drug is certainly not absent in the liver hence parts of its effects may be localized to this organ most probably via its effects on gluconeogenesis.
To treat T2DM and its cardiovascular comorbidity combination therapy of metformins with statins seems well placed and may act as a double-sided sword particularly in the case of statins. This drug increases the risk on T2DM particularly in prediabetic subjects, and cotreatment with metformin might reduce this risk.
However, this hypothesis has not yet been systematically verified. In this review, we have investigated possible sites of interaction of metformin and statins and conclude that they act on largely parallel pathways. Statins reduce plasma cholesterol via activation of LDL-C receptor in the liver and may influence glucose homeostasis primarily by inhibition of insulin secretion in pancreatic β cells.
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Analysis of data from the UKPDS 34 study [2] showed that intensive therapy with metformin significantly reduces diabetes-related end points and deaths, and a meta-analysis of clinical trials found that the drug could also significantly lower total and LDL cholesterol levels [3].
However, its mechanism of action on blood lipids is still not understood. To try to find out more about how a single drug can have an impact on two completely different aspects of the disease, the researchers pulled data on metformin-treated patients with type 2 diabetes who were not using insulin from the Cooperative Health Research in the Region of Augsburg KORA cohort.
This was a large-scale population-based cohort followed between and , and the researchers analysed the genetic and metabolomic profiles of the patients. The team found that patients with type 2 diabetes treated with metformin had lower levels of three cholesterol metabolites along with lower LDL cholesterol levels.
The findings pointed to metformin working via the AMP-activated protein kinase pathway, and will help to learn more about the drug. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.
Metformin and cholesterol Diabetology volume 17 cholwsterol, Article Metformin and cholesterol znd Cite Metfirmin article. Metrics details. Patients with diabetes type 2 have chokesterol increased Antioxidant-Infused Drinks for snd disease and commonly use combination therapy Metformin and cholesterol of Metformln anti-diabetic drug metformin and a cholesterol-lowering statin. However, both drugs act on glucose and lipid metabolism which could lead to adverse effects when used in combination as compared to monotherapy. In this review, the proposed molecular mechanisms of action of statin and metformin therapy in patients with diabetes and dyslipidemia are critically assessed, and a hypothesis for mechanisms underlying interactions between these drugs in combination therapy is developed. Type 2 diabetes mellitus T2DM and cardiovascular diseases are common medical conditions that are often found comorbid with each other. Metformin and cholesterol -
Kong , Heung Man Lee , Linda W. Yu , Chun-Chung Chow , Risa Ozaki , Gary T. Ko , Juliana C. Chan; Low HDL Cholesterol, Metformin Use, and Cancer Risk in Type 2 Diabetes : The Hong Kong Diabetes Registry.
Diabetes Care 1 February ; 34 2 : — The AMP-activated protein kinase AMPK pathway is a master regulator in energy metabolism and may be related to cancer. In type 2 diabetes, low HDL cholesterol predicts cancer, whereas metformin usage is associated with reduced cancer risk. Both metformin and apolipoprotein A1 activate the AMPK signaling pathway.
We hypothesize that the anticancer effects of metformin may be particularly evident in type 2 diabetic patients with low HDL cholesterol. In a consecutive cohort of 2, Chinese type 2 diabetic patients enrolled in the study between and , who were free of cancer and not using metformin at enrollment or during 2.
During 13, person-years of follow-up median 5. The anticancer effect of metformin was most evident in type 2 diabetic patients with low HDL cholesterol.
Patients with type 2 diabetes have increased cancer risk, although the risk association of cancer with antidiabetes drugs remains controversial 1. This is in part attributed to heterogeneity in causalities, phenotypes, and treatment responses.
In addition to age and smoking status, abnormal lipids are strong predictors of cancer in type 2 diabetes 2. Our group has reported a V-shaped risk association of HDL cholesterol with cancer, with an optimal level of 1.
Low HDL cholesterol is a common feature of type 2 diabetes 3 and obesity, the latter often considered a linking factor for cancer risk because of insulin resistance 4.
However, apolipoprotein Apo A-I, the main lipoprotein of HDL cholesterol, also can stimulate the phosphorylation of AMP-activated protein kinase AMPK and acetyl-CoA carboxylase ACC to increase glucose uptake in muscle 5 and insulin sensitivity. In this light, the AMPK pathway is considered to be a master switch in sensing and regulating energy metabolism by balancing catabolism lipolysis and anabolism protein and glycogen storage 6.
A large number of factors can activate or inhibit the AMPK signaling pathway, and one of these is the upstream signal, LKB1, a tumor suppressor. In experimental studies, inhibition of the LKB1-AMPK pathway results in tumor formation 7 , whereas metformin activates the LKB1-AMPK pathway and inhibits cancer cell growth 8.
In support of these findings, epidemiological studies have reported reduced cancer risk 9 and associated mortality 10 in type 2 diabetic patients treated with metformin compared with other antidiabetes drugs.
This study argued that the anticancer effects of metformin, if any, would be most evident in patients with low HDL cholesterol. We selected a prospective cohort from the Hong Kong Diabetes Registry enrolled between 1 December and 8 January because drug dispensary data became fully computerized and available for analysis purposes in A detailed description of the Hong Kong Diabetes Registry is available elsewhere 11 — The referral sources of the cohort included general practitioners, community clinics, other specialty clinics, the Prince of Wales Hospital, and other hospitals.
A 4-h assessment of complications and risk factors was performed on an outpatient basis, modified from the European DiabCare protocol Ethical approval was obtained from the Chinese University of Hong Kong Clinical Research Ethics Committee.
This study adhered to the Declaration of Helsinki, and written informed consent was obtained from all patients at the time of assessment, for research purposes. By , 7, diabetic patients were enrolled in the registry since December We sequentially excluded 1 patients with type 1 diabetes or missing data on types of diabetes; 2 45 patients with non-Chinese or unknown nationality; 3 patients with a known history of cancer or receiving cancer treatment at enrollment; 4 patients with missing values on any variables used in the analysis see Table 1 for a list of variables ; and 5 3, patients who used metformin during 2.
The remaining 2, patients were included in the analysis. The cutoff point of 2. Clinical and biochemical characteristics of the study cohort stratified according to occurrence of cancer during follow-up period. Patients attended the center after an 8-h fast and underwent a 4-h structured clinical assessment that included laboratory investigations.
A sterile, random-spot urinary sample was collected to measure albumin-to-creatinine ratio ACR. Total cholesterol, triglycerides, and HDL cholesterol were measured by enzymatic methods on a Hitachi automated analyzer Boehringer Mannheim, Mannheim, Germany using reagent kits supplied by the manufacturer of the analyzer, whereas LDL cholesterol was calculated using the Friedewald equation Drug usage data were extracted from the Hong Kong Hospital Authority Central Computer System, which recorded all drug dispensary data in public hospitals, including the start dates and end dates for each of the drugs of interest.
In Hong Kong, all medications are dispensed on site in both inpatient and outpatient settings. These databases were matched by a unique identification number, the Hong Kong identity card number, which is compulsory for all residents in Hong Kong. A trained team at the Hong Kong Hospital Authority coded all hospital admissions.
All medical admissions of the cohort from enrollment to 30 July were retrieved from the Hong Kong Hospital Authority Central Computer System, which recorded admissions to all public hospitals in Hong Kong.
Additionally, mortality data from the Hong Kong Death Registry during the period were retrieved and cross-checked with hospital discharge status. Hospital discharge principle diagnoses, coded by the International Statistical Classification of Diseases and Related Health Problems 9th Revision ICD-9 , were used to identify cancer events.
The outcome measure of this study was incident cancer fatal or nonfatal: codes — during the follow-up period. We used biological interactions to test whether metformin use was associated with a greater cancer risk reduction in patients with low HDL cholesterol than in those with normal or high HDL cholesterol.
The Statistical Analysis System release 9. Follow-up time was calculated as the period in years from the first enrollment since 1 December to the date of the first cancer event, death, or censoring, whichever came first. We first plotted the full-range association of HDL cholesterol and cancer and further refined cutoff points of HDL cholesterol for cancer risk in the cohort without prevalent metformin users, using restricted cubic spline Cox models Then, we examined the biological interaction for cancer risk between low HDL cholesterol and nonuse of metformin using three measures: 1 relative excess risk caused by interaction RERI ; 2 attributable proportion AP caused by interaction; and 3 the synergy index S A detailed calculation method of additive interaction, including the definition of three indicator variables, an SAS program, and a calculator in Microsoft Excel www.
se , was described by the authors. The RERI is the excess risk attributed to interaction relative to the risk without exposure. AP refers to the attributable proportion of disease, which is caused by the interaction in subjects with both exposures. S is the excess risk from both exposures when there is biological interaction relative to the risk from both exposures without interaction.
A simulation study showed that RERI performed best and AP performed fairly well, but S was problematic in the measure of additivity in the proportional hazard model Use of drugs during follow-up was defined as use of the drugs from enrollment to cancer, death, or censoring date, whichever came first.
By definition, the use of any drugs after the first cancer event was coded as nonuse of these drugs, and any drug users had been given at least one prescription of the drug during follow-up. The total metformin dosage divided by the total number of days during which metformin was prescribed was used as daily metformin dosage.
We also used propensity score to adjust for the likelihood of initiation of metformin during the follow-up period If switching antipsychotics is not an option, a growing body of literature suggests that the off-label use of metformin—approved for the treatment of type 2 diabetes—may be able to reduce antipsychotic-induced weight gain and insulin resistance.
A study published last month in Molecular Psychiatry also suggests that the medication may reduce low-density lipoprotein cholesterol LDL-C , which is a primary target of cardiovascular disease reduction.
Christoph Correll, M. As described in Molecular Psychiatry , a team of researchers from the United States and China pooled data from two randomized, placebo-controlled trials, including patients from China aged 18 to 40 who developed dyslipidemia within a year of taking clozapine, olanzapine, risperidone, or sulpiride for the treatment of a first episode of schizophrenia.
Sulpiride has not been approved for use in the United States. After 24 weeks of treatment, Of those who had dyslipidemia defined by LDL-C at baseline, 64 percent of patients who took metformin restored their LDL-C to below the normal level compared with Despite these findings, Correll advised that clinicians hold off on prescribing metformin to patients initiating antipsychotic treatment until they know whether significant weight gain will be an issue.
It is advised that patients take metformin with food to reduce the gastrointestinal side effects of the medication, which include nausea, vomiting, diarrhea, and abdominal pain. Patients taking metformin are also at a low risk of lactic acidosis.
Another medication that may be able to decrease weight gain in patients taking antipsychotics is topiramate, approved for the treatment of seizure disorders and the prevention of migraine headaches.
While there is some evidence that topiramate can reduce weight gain in patients taking antipsychotic medications, cognitive side effects of the medication have been reported. The research published in Molecular Psychiatry was supported in part by the National Natural Science Foundation of China.
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Cardiovascular Diabetology volume 18Article cholesterlo 54 Cite this Nutrient absorption in the liver. Metrics details. Metformin and cholesterol an increasing global burden of coronary artery disease Metformin and cholesterolcholewterol detection and timely management of risk factors are crucial to reduce morbidity and mortality in such patients. Diabetes mellitus DM is considered an independent risk factor for the development of CAD. Metformin, an anti-diabetic drug, has been shown in pre-clinical and clinical studies, to lower the cardiovascular events in the DM patients.
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