Vitamin D, K2 Plus Empagliflozin Combination in Type Two Diabetes Mellitus

Empagliflozin:

Generally, Sodium-glucose co-transporter-2 inhibitors (SGLT2i), have important benefits for older people, such as a low risk of hypoglycemia, reduction of cardiovascular and renal risk, and an insulin-independent mechanism, allowing its use in disease of any duration. Advantages include lack of hypoglycemia as a side effect, and mild reduction in blood pressure and body weight.

The SGLT2i class is well-tolerated, though some caution is also suggested, including adjustment of concomitant therapies, such as insulin and antihypertensives, especially loop diuretics.

The 2022 latest guidelines by the American Diabetes Association recommend that if insulin is used in adults with type 2 diabetes, it is recommended that, for better efficacy and durability of treatment effect, combination therapy be employed using a glucagonlike peptide 1 receptor agonist and consideration may be given to combined therapy employing a sodium-glucose cotransporter 2 inhibitor and a glucagon-like peptide 1 receptor agonist, both with demonstrated cardiovascular benefit, "for additive reduction in the risk of adverse cardiovascular and kidney events" in patients "with type 2 diabetes and established atherosclerotic cardiovascular disease or multiple risk factors for atherosclerotic cardiovascular disease". Moreover, among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), sodiumglucose cotransporter-2 (SGLT2) inhibitors or glucacon-like peptide 1 (GLP-1) receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management. The same guidelines recommend that among patients with ASCVD in whom heart failure coexists or is of special concern, SGLT2 inhibitors are recommended and patients who are unable to maintain glycemic targets on basal insulin in combination with oral medications can have treatment intensified with GLP-1 receptor agonists, SGLT2 inhibitors, or prandial insulin.

Conclusively, it is recommended that a sodium-glucose cotransporter-2 (SGLT2) inhibitor or glucagonlike peptide-1 receptor agonist (GLP-1 RA) with demonstrated cardiovascular disease benefit be administered to patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), indicators of high ASCVD risk, established kidney disease, or heart failure.

VITAMIN D3:

This section focuses on seven diseases, conditions, and interventions in which vitamin D might be involved: bone health and osteoporosis, cancer, cardiovascular disease (CVD), depression, multiple sclerosis (MS), type 2 diabetes, and weight loss.

Among postmenopausal women and older men, many clinical trials have shown that supplements of both vitamin D and calcium result in small increases in bone mineral density throughout the skeleton. They also help reduce fracture rates in institutionalized older people.

Laboratory and animal studies suggest that vitamin D might inhibit carcinogenesis and slow tumor progression by, for example, promoting cell differentiation and inhibiting metastasis. Vitamin D might also have anti-inflammatory, immunomodulatory, proapoptotic, and antiangiogenic effects. Observational studies and clinical trials provide mixed evidence on whether vitamin D intakes or serum levels affect cancer incidence, progression, or mortality risk.

Vitamin D helps regulate the renin-angiotensin-aldosterone system (and thereby blood pressure), vascular cell growth, and inflammatory and fibrotic pathways. Vitamin D deficiency is associated with vascular dysfunction, arterial stiffening, left ventricular hypertrophy, and hyperlipidemia. For these reasons, vitamin D has been linked to heart health and risk of CVD.

Vitamin D is involved in various brain processes, and vitamin D receptors are present on neurons and glia in areas of the brain thought to be involved in the pathophysiology of depression.

Many epidemiological and genetic studies have shown an association between Multiple Sclerosis (MS) and low 25(OH)D levels before and after the disease begins. Observational studies suggest that adequate vitamin D levels might reduce the risk of contracting MS and, once MS is present, decrease the risk of relapse and slow the disease's progression.

Vitamin D plays a role in glucose metabolism. It stimulates insulin secretion via the vitamin D receptor on pancreatic beta cells and reduces peripheral insulin resistance through vitamin D receptors in the muscles and liver. Vitamin D might be involved in the pathophysiology of type 2 diabetes through its effects on glucose metabolism and insulin signaling as well as its ability to reduce inflammation and improve pancreatic beta-cell function.

Low vitamin D status appears to be associated with type 2 diabetes and most other insulin resistance disorders reported to date.In persons with prediabetes, vitamin D supplementation reduces the risk of T2DM and increases the reversion rate of prediabetes to normoglycemia. The benefit of the prevention of T2DM could be limited to nonobese subjects.

Moreover, Vitamin D, among many benefits, has positive outcomes on hemoglobin A1c (HbA1c) control. It aids in insulin secretion and sensitivity. The clinical significance of Vitamin D administration in DM II from a glucose homeostasis perspective, and complications such as nephropathy, neuropathy, and retinopathy. Vitamin D had a clinical positive impact on glucose level, particularly on hemoglobin A1c (HbA1c) reduction, alleviation of diabetic neuropathy and nephropathy symptoms, and hyperglycemia induced oxidative stress on the retinal cells.

Observational studies indicate that greater body weights are associated with lower vitamin D status, and obese individuals frequently have marginal or deficient circulating 25(OH)D levels.

VITAMIN K2:

Type 2 diabetic patients are at high risk of bone fractures even if their bone mineral density is normal or high. This is likely explained by poor bone quality and extraskeletal factors. Vitamin K(2) stimulates γ-carboxylation of osteocalcin and can increase bone formation through steroid and xenobiotic receptors. study showed that vitamin K(2) administration in a type 2 diabetic had the following skeletal benefits: increased serum osteocalcin, improved collagen cross-link profiles, and increased bone strength. These new findings suggesting a possible beneficial effect of vitamin K(2) supplementation on bone quality in type 2 diabetes.

Micronutrients are gaining acceptance as an important nutritional therapy for the prevention and/or management of diabetes and its associated health risks. Although a very small quantity of micronutrients are required for specific functions in our bodies, moderate deficiencies can lead to serious health issues. Impaired insulin sensitivity and glucose intolerance play a major role in the development of diabetic pathophysiology. Vitamin K is well known for its function in blood coagulation. Moreover, several human studies reported the beneficial role of vitamin K supplementation in improving insulin sensitivity and glucose tolerance, preventing insulin resistance, and reducing the risk of type 2 diabetes (T2 D). Both animal and human studies have suggested that vitamin K-dependent protein (osteocalcin [OC]), regulation of adipokine levels, antiinflammatory properties, and lipid-lowering effects may mediate the beneficial function of vitamin K in insulin sensitivity and glucose tolerance.

Studies showed vitamin K2 intake reduced 7% T2DM risk with each 10-μg increment.

• Vitamin K2 has a more significant effect than vitamin K1 on T2DM.
• Vitamin K2 increased insulin sensitivity via osteocalcin metabolism. . Vitamin K2 improved IR via anti-inflammatory property and lipid-lowering effects.
• Vitamin K2 suppresses inflammation via inactivating NF-κB signalling pathway.
• Vitamin K2 supplementation decreases fat accumulation and serum triglycerides.

An important strategy for controlling T2DM is the use of vitamin supplements. vitamin K supplementation can effectively improve clinical features of diabetes. Vitamin K has different forms, including vitamin K1 (phylloquinone), vitamin K2 (menaquinone or MK) and vitamin K3 (synthetic form named menadione). Differences in the chemical structure of K1 (phylloquinone) and K2 (menaquinone) have led to differences in their uptake and bioavailability. Adsorption, bioavailability and the half-life of K2 is higher than K1. Another study suggested that vitamin K supplementation in T2DM results in improved glycemic status, including: FBS, HbA1C, FI and HOMA-IR. Vitamin K supplementation may also help with body weight maintenance.