INTRODUCTION
Metformin is widely used as the antidiabetic drug of choice for people with type 2 diabetes mellitus (T2DM), but it also may have benefits in protecting against cardiovascular disease as well as stroke and dementia. Metformin has pleiotropic benefits beyond diabetes management. It is the most widely prescribed oral drug for diabetes worldwide and evidence-based research supports that it can reduce cardiovascular mortality. It may also increase survival in cancer patients and reduce the risk of dementia and stroke in patients who have diabetes. It seems to have outperformed the other oral antidiabetic agents in terms of its varied benefits for patients beyond the glycemic control.
In a study conducted by Cheng et al.1 on 14,856 randomly selected patients with diabetes from a Taiwan National Health Research Institute database, two cohorts were analyzed if metformin was used in the prescription. They followed these patients for 4 years for stroke incidence. As a result, 701 (17.5%) of 3,999 diabetic patients had stroke in nonmetformin group, whereas in metformin group only 994 (9.2%) of 10,857 patients had stroke. On statistical analysis showed the stroke hazard ratio for metformin was 0.383. Hazard ratio was still 0.468 even after adjusting for the patients’ age, gender, hypertension, atrial fibrillation, hyperlipidemia, coronary artery disease (CAD), and medications. Metformin had more protective effect in the patients with higher risk of stroke.
Zaki et al.2 in a study in Malaysia have shown that metformin use among patients of T2DM and dyslipidemia significantly improves the clinical outcomes.
CASE PRESENTATION
Metformin therapy may have nonglycemic benefits by offering protection against cardiovascular disease, stroke, and dementia.2
- A 45-year-old male sedentary worker, presented with history of diabetes for last 4 years. His body mass index (BMI) is 26.8, fasting blood sugar (FBS) 145 mg/dL, postprandial (PP) 203 mg/dL, glycated hemoglobin (HbA1c) 7.9%
- He was already on metformin 500 mg/day in divided doses
- He was a known hypertensive having blood pressure (BP) 146/90 mmHg on ramipril 5 mg/day
- He had been smoking about 12–14 cigarettes/day for 10 years
- He had acanthosis nigricans on nape of neck
- His laboratory tests: Kidney profile is normal, urine microalbuminuria 110 mg/L
- Lipids: Total cholesterol 236 mg/dL, low density lipoprotein (LDL) 136 mg/dL, high density lipoprotein (HDL) 33 mg/dL, triglycerides (TGs) 336 mg/dL, very low density lipoprotein (VLDL) 67 mg/dL
- Strong family history of CAD—father, uncle, and cousin. Father is diabetic for 20 years. Mother died of stroke at 55 years, was hypertensive, diabetic.
- Examination reveals an obese, hypertensive, signs of insulin resistance. Foot examination is unremarkable—monofilament normal, pedal vessels normal, fundus normal
- Summarizing: 45-years-old young diabetic, sedentary, obese, hypertensive, dyslipidemic, smoker, microalbuminuria +ve, has strong family history of cardiovascular disease—CAD/stroke
- His laboratory tests were—creatinine 0.8 mg/dL, dyslipidemia, microabuminuria, HbA1c 7.9%.
Management and Outcome
This patient has the Elements of Diabetes Care Scoring Scale 10, has microvascular and early macrovascular complications, comorbidities, strong family history of cardiovascular risk, so requires immediate lifestyle modification (LM), good glycemic control—HbA1c about 7% to reduce his cardiovascular risk.
- His glycemic control is poor, metformin increased to extended-release (SR) 1 g BD after meals. Atorvastatin 10 mg/day added, ramipril increased to 10 mg/day
- He has been counseled to stop smoking, strictly follow 1,400 kcal diabetic low fat diet
- He has been motivated to go for brisk walk 40 min/day, with a target to loose gradually about 5–6 kg weight over 6 months
- Three months later patient's FBS 112 mg/dL, PPBS 162 mg/dL, HbA1c 7.1%, BP 138/84 mmHg. Patient lost 3 kg, repeat lipids—cholesterol 186 mg/dL, LDL 109 mg/dL, HDL 35 mg/dL, TGs 210 mg/dL, VLDL 42 mg/dL
- Now he had a feeling of well-being and was motivated to continue exercise, diet, and LM
- He had stopped smoking on perusal.
DISCUSSION
Metformin has been extensively used in the management of T2DM. A number of properties combined, including cost-effectiveness, safety, weight neutrality, low risk of hypoglycemia, and cardiovascular protection moved metformin to the forefront of diabetes management and is now accepted as the standard first-line therapy. Although other classes of glucose lowering medications were introduced to clinical practice in the recent times, none of such therapies has as yet demonstrated superiority to metformin to justify being considered as a first-line therapeutic option.
The use of metformin has extended in the last 2 decades to include diabetes prevention, gestational diabetes mellitus, cardiovascular protection, hypertension, polycystic ovary syndrome, obesity, hirsutism, and thyroid abnormalities. To add to the array of indications of metformin, there is accumulating evidence from observational studies to suggest a possible role for metformin in cancer prevention and in the management of nonalcoholic fatty liver disease. Of late, researchers have also highlighted the neuroprotective effects of metformin as well as its beneficial effects on lipid profiles. Recent studies have demonstrated that metformin reduces the risk of stroke in patients.
Metformin as a Lipoprotective Drug
Diabetes is a CAD risk equivalent which is the leading cause of morbidity and mortality in this population. Diabetics carry two- to fourfold increased risk of cardiovascular, peripheral vascular, and cerebrovascular disease. Diabetic dyslipidemia characterized by hypertriglyceridemia; low levels of HDL cholesterol; PP lipemia; and small, dense LDL cholesterol particles has been seen in many epidemiological studies. Metformin with statins and thiazolidinediones has been found to be useful for the treatment of diabetic dyslipidemia.
Metformin increases adipocyte (fat cell) and muscle insulin receptors. It only increases insulin sensitivity but does not increase insulin secretion, so will not induce hypoglycemia. Metformin thus reduces insulin levels by improving insulin sensitivity in peripheral tissues thus restoring glucose and insulin to physiological levels resulting in weight loss and decrease in the body's total fat content. Reduction in HbA1c has been shown to decrease total cholesterol, TGs, and LDL cholesterol.4
Metformin use among patients of T2DM and dyslipidemia has been shown to significantly improve the clinical outcomes by Zaki et al.2 in a study in Malaysia.
Mourao-Junior et al.3 documented that in 57 T2DM patients with metabolic syndrome on insulin before and 6 months after addition of metformin that there was improvement in lipid profile other than the impact on glycemic control, BP. Total cholesterol (229.0 ± 29.5 to 214.2 ± 25.0 mg/dL) (P <0.05), BMI (30.7 ± 5.4 to 29.0 ± 4.0 kg/m2), waist circumference (WC) (124.6 ± 11.7 to 117.3 ± 9.3 cm), and daily dose of insulin reduced significantly.
Total cholesterol reduced independently of the reductions of A1c (9.65 ± 1.03 to 8.18 ± 1.01%) and BMI. The reduction of BMI and WC did not interfere with the improvement of A1c (Table 1).
Ginsberg and Grant et al.4,5 in agreement with Junior have shown reduced total cholesterol levels, while few other studies have shown improvement in of total cholesterol and TG and increase of HDL cholesterol. DeFronzo et al.6 also documented improvement in the lipid profile with metformin even in nondiabetic patients.
Wulffele et al.7 in a meta-analysis of 41 studies to showed effects of metformin on BP and lipid profile but documented only total cholesterol reduction.
Another study by Grant et al.5 have shown reduction in TGs in the high-dose group from 2.89 to 2.26 mmol/L, relative to placebo (P <0.05) over 6 months. With 1,500 mg metformin, TGs came down from 3.2 to 2.15 mmol/L, but was not statistically significant compared with placebo (P = 0.06). Cholesterol fell from 5.9 to 5.6 mmol/L (P <0.008) compared to placebo, in the high-dose group but nonsignificantly with the lower dose of metformin.
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Buse et al.8 analyzed 37 trials and documented reduced TG levels with metformin, related to glycemic control. Another meta-analysis of 24 trials with metformin has shown a modest reduction in LDL, independent of glycemic control. However, metformin was not associated with improvement in HDL when the results of 29 trials were collectively analyzed. Twenty nine trials compared the effect of metformin monotherapy versus oral antidiabetic drug treatment revealed metformin reduced LDL more effectively than sulfonylureas and also had a favorable effect on weight7,9 (Table 2).
Protective Effect of Lipid Accumulation in Metabolic Syndrome
Metformin reduces lipid accumulation in macrophages by repressing forkhead box protein O1 (FOXO1)-mediated fatty acid-binding protein 4 (FABP4) transcription so may be an important therapeutic agent treating atherosclerosis in metabolic syndrome. Metformin reduces lipid accumulation in adipocytes also. Metformin significantly reduced palmitic acid (PA)-induced intracellular lipid accumulation in macrophages. 6Metformin improved expression of carnitine palmitoyltransferase I and reduced the expression of FABP4 responsible for PA-induced lipid accumulation. Metformin modulates FABP4 expression at the transcriptional level. Moreover, forkhead transcription factor FOXO1 has been identified as a positive regulator of FABP4 expression. Inhibiting FOXO1 expression with FOXO1 siRNA significantly reduces basal and PA-induced FABP4 expression. Metformin decreased FABP4 expression by promoting FOXO1 nuclear exclusion and subsequently restricting its activity.10
Metformin Reduces the Risk of Myocardial Infarction
Type 2 diabetes mellitus is associated with higher cardiovascular morbidity and mortality which is a major concern. Diabetes is a CAD risk equivalent with risk of myocardial infarction (MI) as high as in a nondiabetic who already had a coronary event. Tight glycemic control has proven to reduce microvascular complications but not so convincingly macrovascular (Box 1).
The United Kingdom Prospective Diabetes Study proved that in obese T2DM patients, metformin reduces the risk of MI better than sulfonylureas or insulin and it has been attributed to pleiotropic effects of metformin. Metformin has shown putative beneficial actions on arterial vessels by improving lipids, inflammation, hemostasis, endothelial, and platelet functions.11
Neuroprotective Role of Metformin
Oxidative damage occurs in pathogenesis of diabetic neuropathy and neurodegenerative diseases. Oral antidiabetic drug, metformin prevents oxidative stress-related cellular death in non-neuronal cell lines. In a study by El-Mir et al.,12 authors pointed the direct neuroprotective effect of metformin, using the etoposide-induced cell death model. The exposure of intact primary neurons to this cytotoxic insult induced permeability transition pore (PTP) opening, the dissipation of mitochondrial membrane potential (Δψm), cytochrome c release, and subsequent death. Importantly, metformin in combination with cyclosporin A (CsA), strongly extenuate the activation of apoptotic cascade.
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In addition, metformin delays CsA-sensitive PTP opening in permeabilized neurons, as a trigger by a calcium overload, probably through its mild inhibitory effect on the respiratory chain complex I. Author concluded that etoposide-induced neuronal death is partly attributable to PTP opening and the disruption of Δψm with the emergence of oxidative stress and metformin inhibits this PTP opening-driven commitment to death. Thus, results proposed that metformin, beyond its antihyperglycemic role, also acts as an effective drug for diabetes-associated neurodegenerative disorders.
Alzheimer's disease, a common neurodegenerative disease, has been labeled type 3 diabetes and is characterized by neuronal insulin resistance and impaired insulin action so there is excessive generation and accumulation of amyloid oligomers, a key factor in the development of alzheimer's disease.
Metformin prevents PTP opening and subsequent cell death in various endothelial cell types exposed to hyperglycemia. Metformin by inhibiting PTP opening and blocking the release of cytochrome c could interrupt the apoptotic cascade in a model of etoposide-induced cell death. Metformin by activating a protein kinase C-CREB binding protein (PKC-CBP) pathway is presumed to promote rodent and human neurogenesis recruiting neural stem cells and enhancing neural function especially spatial memory function.
Metformin has potential neuroprotective effect in vivo so can cross blood brain barrier13 and this has been shown by Liu et al.14 in mice following middle cerebral artery occlusion.
Metformin in an AMP-activated protein kinase-dependent manner downregulates intercellular adhesion molecule-1, which prevents ischemia-induced brain injury by alleviating neutrophil infiltration.
Thus, metformin could be a promising therapeutic agent in stroke therapy.
Thus, metformin can be an important therapeutic agent in diabetes-associated peripheral neuropathy but also in neurodegenerative diseases.13,14
CONCLUSION
Metformin has pleiotropic benefits beyond glycemic control. It is one of the most commonly prescribed oral drug for diabetes worldwide, all guidelines rightly endorsing metformin as first-line antidiabetic drug in T2DM. Evidence supports that it can reduce cardiovascular mortality and can increase survival in cancer patients, and reduce the risk of dementia and stroke in patients who have diabetes. It has outperformed the other oral antidiabetic agents in terms of its varied benefits for patients beyond the glycemic control.8
REFERENCES
- Cheng YY, Leu HB, Chen TJ, et al. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis. 2014;23(2):e99–105.
- Zaki NF, Sulaiman AS, Gillani WS. Clinical evaluation of dyslipidemia among type II diabetic patients at Public Hospital Penang, Malaysia. Int Arch Med. 2010;3:34.
- Mourao-Junior CA, Sa JR, Guedes OM, et al. Effects of metformin on the glycemic control, lipid profile, and arterial blood pressure of type 2 diabetic patients with metabolic syndrome already on insulin. Braz J Med Biol Res. 2006;39(4):489–94.
- Ginsberg H, Plutzky J, Sobel BE. A review of metabolic and cardiovascular effects of oral antidiabetic agents: beyond glucose-level lowering. J Cardiovasc Risk. 1999;6:337–46.
- Grant PJ. The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care. 1996;19:64–6.
- DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333:541–9.
- Wulffele MG, Kooy A, de Zeeuw D, et al. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256:1–14.
- Buse JB, Tan MH, Prince MJ, et al. The effects of oral antihyperglycaemic medications on serum lipid profiles in patients with type 2 diabetes. Diabetes Obes Metab. 2004;6:133–56.
- Saenz A, Fernandez-Esteban I, Mataix A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(3):CD002966.
- Song J. Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4. Biochem Biophys Res Commun. 2010;393(1):89–94.
- Anfossi G, Russo I, Bonomo K, et al. The cardiovascular effects of metformin: further reasons to consider an old drug as a cornerstone in the therapy of type 2 diabetes mellitus. Curr Vasc Pharmacol. 2010;8(3):327–37.
- El-Mir MY, Detaille D, R-Villanueva G, et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci. 2008;34(1):77–87.
- Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6.
- Liu Y, Tang G, Li Y, et al. Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. J Neuroinflammation. 2014;11:177.