Pharmacological Approach of Type 2 Diabetes Mellitus

Drugs used in treatment of T2 DM

    Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications in type 2 diabetes.

 Drug classes used for the treatment of type 2 diabetes include the following:

·  Biguanides

·   Sulfonylureas

·   Meglitinide derivatives

·    Alpha-glucosidase inhibitors

·   Thiazolidinediones (TZDs)

·  Glucagonlike peptide–1 (GLP-1) agonists 

·   GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonists 

·   Dipeptidyl peptidase IV (DPP-4) inhibitors

·    Selective sodium-glucose transporter–2 (SGLT-2) inhibitors

Biguanides

Metformin is the only biguanide in clinical use and has proved effective and safe. Lactic acidosis during metformin use is very rare and is associated with concurrent comorbidity. Metformin lowers basal and postprandial plasma glucose levels. Metformin works by decreasing hepatic gluconeogenesis. decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Sulfonylureas

  Sulfonylureas (eg, glyburide, glipizide, glimepiride) are insulin secretagogues that stimulate insulin release from pancreatic beta cells and probably have the greatest efficacy for glycemic lowering of any of the oral agents. However, that effect is only short-term and quickly dissipates. Sulfonylureas are indicated for use as adjuncts to diet and exercise in adult patients with type 2 diabetes mellitus. They are generally well-tolerated, with hypoglycemia the most common side effect.

Meglitinide derivatives

Meglitinides (eg, repaglinide, nateglinide) are much shorter-acting insulin secretagogues than the sulfonylureas are, with preprandial dosing potentially achieving more physiologic insulin release and less risk for hypoglycemia.   

Meglitinides may be used in patients who have allergy to sulfonylurea medications.

They have a similar risk for inducing weight gain as sulfonylureas do but possibly carry less risk for hypoglycemia.

Alpha-glucosidase inhibitors

These agents delay sugar absorption and help to prevent postprandial glucose surges. Alpha-glucosidase inhibitors prolong the absorption of carbohydrates, but their induction of flatulence greatly limits their use. They should be titrated slowly to reduce gastrointestinal (GI) intolerance.

Thiazolidinediones

TZDs (eg, pioglitazone   the only TZD currently available) act as insulin sensitizers; thus, they require the presence of insulin to work. They must be taken for 12-16 weeks to achieve maximal effect..They are the only antidiabetic agents that have been shown to slow the progression of diabetes (particularly in early disease).pioglitazone was found to reduce the progression to frank diabetes by 72% in patients with IGT  ^.  However, the drug was associated with significant edema and weight gain. TZDs generally decrease triglyceride levels and increase HDL cholesterol levels. They increase LDL cholesterol, but this increase may involve large, buoyant LDL, which may be less atherogenic.

Glucagon like peptide–1 agonist

GLP-1 agonists (ie, exenatide, liraglutide, albiglutide, dulaglutide and semagutide) mimic the endogenous incretin GLP-1; they stimulate glucose-dependent insulin release, reduce glucagon, and slow gastric emptying so improving glycemic control with significant weight loss without hypoglycemia

Dipeptidyl peptidase IV inhibitors

DPP-4 inhibitors (eg, vildagliptin, sitagliptin, saxagliptin, linagliptin and allogliptin) are a class of drugs that prolong the action of incretin hormones. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). DPP-4 inhibitors can be used as a monotherapy or in combination with metformin or a TZD. They are given once daily and are weight neutral.

Selective sodium-glucose transporter-2 inhibitors

 SGLT-2 inhibition (Canagliflozin, dapagliflozin, empagliflozin and others )    lowers the renal glucose threshold (ie, the plasma glucose concentration that exceeds the maximum glucose reabsorption capacity of the kidney). Lowering the renal glucose threshold results in increased urinary glucose excretion.

   Received FDA approval for the treatment of diabetic kidney disease (DKD) and, in patients with type 2 diabetes and DKD, reduction in the risk of hospitalization for heart failure. prevention of cardiovascular disease–related death in adults with type 2 diabetes who also have cardiovascular disease

Insulin

See insulin in type 1 DM treatment

Indications of insulin in type 2 diabetes

1-        Very high blood glucose   with catabolic state

2-        During pregnancy

3-        Peri operative 

4-        In hospitalized patients

5-        In critically ill patients

6-        Failure of oral medication to keep glycemic control

7-        In patient with   liver or kidney disease