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Diabetes drugs (Hypoglycaemic agents (Sodium glucose co-transporter 2…

- - - - Metformin increases the density of insulin receptors at the tissues (GLUT4), decreases hepatic glucose production (gluconeogenesis), decreases intestinal glucose absorption and improving muscular glucose absorption. It does not affect insulin secretion. Metformin improves glucose tolerance, lowers both basal and postprandial plasma glucose.
      - Used with caution in patients with lactic acidosis, hepatic disease, renal problems, and cardiovascular problems. Does not result in hyperinsulinemia or hypoglycaemia. Helps with weight loss and in improving lipid levels
        Common SE: N/V, flatulence, anorexia
        Metformin is CONTRAINDICATED in patients with:
        
        Renal dysfunction
        
        Acute or chronic metabolic acidosis, eg DKA
        
        +/- Low BMI/Anorexia
        
        Lactate accumulates in the liver with metformin administration because lactate is a substrate for hepatic gluconeogenesis, a process that metformin inhibits. In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs. Given impaired kidney function, clearance of metformin and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup.
    - - They act to increase insulin-dependent glucose disposal and decrease insulin resistance in the periphery and liver without increasing insulin production. Exact mechanism remains unclear. Primary mechanism of action is via the activation of the nuclear transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ)
        
        PPAR-γ ligands are known to regulate glucose metabolism, adipogenesis, and improve insulin sensitivity at adipose tissues, liver and skeletal muscles. Stimulation of these receptors may result in increased production of GLUT1 and GLUT 4, and enhances tissue sensitivity to insulin.
      - Side Effects – Weight gain, peripheral edema, increased risk of heart failure (fluid retention) and bone fractures
        Contraindication in risk of heart failure, osteoporosis
  - - - MOA
        Principal target of sulfonylureas is the pancreatic β-cell ATP-sensitive potassium (KATP) channel, which plays a major role in controlling the β-cell membrane potential. Sulfonyureas (SU) bind to the SU receptor proteins, subunits of the KATP channels. Drug binding inhibits KATP channel mediated K+ efflux, triggering a calcium-dependent exocytosis of insulin granules from the pancreatic β-cells.
      - Avoid if:
        
        Sulfa allergy
        
        CKD except for glipizide
        
        Dose reduction to prevent hypoglycemia if:
        
        Poor oral intake
        
        CKD or rising Cr
        
        Liver failure
      - Benefits
        Glipizide can be used in CKD due to inactive metabolites since hepatic metabolism, unlike metformin
        Cons
        Risk of hypoglycemia
        Nil CVS benefits
      - Glipizide vs Gliclazide
        Both do not decrease hypoglycemia risk
        
        Glipizide (short acting) may have less incidence of hypoglycemia due to accumulation but it increases risk of hypo due to tall peaks and deep troughs since short acting
        
        Gliclazide (long acting) avoids tall peaks and deep trough but increases risk of hypo due to long DOA
        
        Glipizide 1st choice for CKD
        Gliclazide 1st choice for frail elderly which avoids peaks and troughs since frail elderly may have less reserves (if CKD use Glipizide)
      - 1st gen
        Tolbutamide (Should not be used anymore)
        
        Effect of 1st GEN sulfonylureas on ATP-dependent potassium channels on cardiac cells > MACE effects > no reduction in CVS mortality independent of glucose control as compared to metformin
      - 2nd gen
        
        More specific to pancreatic beta cells
        
        Glipizide: Short acting, 2-4hrs, inactive metabolites
        Gliclazide: Intermediate acting, 10hrs, inactive metabolites
        Glimipiride (AVOID since active metabolites): Intermediate, 5-8hrs, active metabolites
        Glibenclamide aka Glyburide (AVOID since high risk of hypo): Long-acting, >24hrs, active metabolites
    - - Meglitinides bind and close the ATP-dependent potassium (KATP) channels on the pancreatic beta cells in a glucose-dependent manner stimulating insulin release. This action is mediated through a unique binding site on the SUR1 of the beta cell that differs from sulfonylureas’ site of action.
        
        Used with caution in patients with hepatic impairment.
        Insulin release is glucose-dependent and diminishes at low glucose concentrations, hence reducing the risk of hypoglycaemia as compared to sulfonylureas
  - - - enzyme that degrades GLP-1 and GIP
        
        Increase insulin release, decrease glucagon release
    - - better than GIP agonist as it induces satiety, delayed gastric emptying, suppresses glucagon release better
      - Increases insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.
- - - - Substitution or addition of amino acids that result in changes to the charge and/or conformation of the insulin molecule at physiological pH.
        Prevent formation of dimers, resulting in rapid absorption of monomers from the subcutaneous tissue at the time of injection.
      - The shorter duration of action of these rapid-acting insulin analogues may also lead to a lower incidence of hypoglycaemia
    - - Regular insulin is structurally similar to endogenous human insulin. It consists of dissolved zinc-insulin crystals (soluble, unmodified insulin) which self aggregate in the subcutaneous tissue and results in a delayed onset of action of 30 to 60 minutes (crystalline zinc insulin).
      - 30 minutes prior to meals
      - Regular insulin acts almost instantly when injected intravenously (hospital setting only, not home setting), most effective for patients with severe hyperglycemia, DKA
    - - Combination of recombinant human insulin with protamine which results in crystal formation. It has a cloudy appearance
        When injected subcutaneously, precipitated crystals of NPH insulin are released slowly resulting in a longer duration of action compared to regular insulin.
      - NPH typically requires twice a day dosing
    - - Virtually no plasma peak, and act for about 18-24 hours, hence allowing once-daily administration as background insulin.
      - Glargine is formulated at an acidic pH 4. At physiological pH 7.4, it forms aggregates that slowly release insulin over time.
      - Detemir has a C14 fatty acid side chain, which not only increases self- association into hexamers and di-hexamers, but also allows reversible binding of insulin detemir to albumin present in all tissue and in the circulation. Albumin binding contributes almost as much to the prolongation of action of insulin detemir, as does the di-hexameric self-association.
      - lower intra-subject variation and reduced risk of hypoglycaemia compared with (NPH) insulin.
      - These long-acting insulins can’t be mixed in the same syringe with other insulins – affect pharmacokinetics due to pH differences