Antidiabetics and insulin

Antidiabetics and insulin: Following agents are used in the treatment of diabetes mellitus.

1. Metformin (biguanide): It decreases hepatic gluconeogenesis, intestinal glucose absorption, improves insulin sensitivity by increasing the peripheral glucose uptake and utilization, improves glucose tolerance and lowers both basal and postprandial plasma glucose. It does not typically cause hypoglycemia or hyperinsulinemia. Metformin inhibits mitochondrial glycerophosphate dehydrogenase enzyme, increases HDL and decreases LDL levels. It is used in type 2 diabetics and pre-diabetics to lower HbA1c levels. Adverse effects include lactic acidosis, metallic taste in mouth, vit B12 deficiency, nausea, vomiting, diarrhea, abdominal pain, muscle cramps and mental status changes. High risk groups include elderly, renal or cardiac insufficiency. Metformin should be discontinued before surgery or administration of contrast media to prevent lactic acidosis.
2. Thiazolidinediones (rosiglitazone, pioglitazone): They activate transcription factor PPAR gamma or peroxisome proliferator activated receptor gamma, which results in increased transcription of genes involved in glucose and lipid metabolism. Peripheral glucose utilization is increased and hepatic gluconeogenesis is decreased. It reduces triglycerides, LDL and increases HDL levels and does not cause hypoglycemia. Adverse effects include weight gain, edema, fluid retention, heart failure and osteoporosis. It is contraindicated in liver failure and in bladder cancer( pioglitazone).
3. Sulfonylureas (glyburide, glipizide): They block ATP sensitive K+ channels on the pancreatic beta cells causing depolarization, calcium influx and insulin secretion. Hence they are also called as insulin secretagogues. They are useless if insulin stores are absent like in Type 1 DM. They increase insulin sensitivity and decrease hepatic gluconeogenesis. They may cause hypoglycemia, weight gain, neutropenia, hemolytic anemia, skin allergies and alcohol intolerance. They are contraindicated in sulfa allergies, advanced renal or hepatic failure. Caution should be used while co-prescribing with beta blockers which may mask the effects of hypoglycemia like tachycardia and tremors.
4. Meglitinides (repaglinide, nateglinide): They are analogues of sulfonylureas and increase insulin secretion from the pancreatic beta cells by blocking K+ channels. Adverse effects include weight gain, hypoglycemia and hepatotoxicity.
5. Incretin mimetics or GLP 1 receptor agonists (exenatide, liraglutide, albiglutide and dulaglutide): GLP 1, an incretin, is normally degraded by the enzyme DPP 4. Incretin mimetic drugs are resistant to degradation by DPP 4. They bind to GLP 1 receptor and increase insulin secretion, decrease glucagon secretion and slow gastric emptying. It causes weight loss. Adverse effects include GI upset, pancreatitis and rarely, pancreatic cancer.
6. DPP 4 (dipeptidyl peptidase) inhibitors or gliptins (sitagliptin, saxagliptin): Enhance the effect of incretins (GLP 1 and GIP), by inhibiting DPP 4 enzyme. Increase insulin secretion, decrease glucagon secretion and delay gastric emptying. Adverse effects include GI upset, diarrhea, constipation, nasopharyngitis, URTI, arthralgia, headache, dizziness, pancreatitis and acute renal failure.
7. SGLT 2 inhibitors (gliflozins like dapagliflozin, empagliflozin and canagliflozin): They inhibit SGLT 2 or sodium dependent glucose cotransporter in the proximal tubule of the kidney and decreases renal glucose reabsorption, causing glycosuria and polyuria. It promotes weight loss. Adverse effects include UTIs, vulvovaginitis, balanitis, dehydration and diabetic ketoacidosis.
8. Alpha glucosidase inhibitors (acarbose, miglitol): They inhibit the enzyme alpha glucosidase that breaks down glucose, and decrease glucose absorption. Adverse effects include gas, bloating, flatulence, abdominal discomfort and diarrhea. It should not be used in IBD and malabsorption syndromes.
9. Amylin analogue (pramlintide): It slows gastric emptying by activation of amylin receptors in the nucleus accumbens and dorsal vagal nucleus, acts on the hypothalamus to decrease appetite and decreases glucagon secretion from the pancreas. It leads to decreased postprandial rise in blood glucose. It causes weight loss. Adverse effects include hypoglycemia.

Insulin types

*Prevent ketoacidosis , hepatic gluconeogenesis and fasting hyperglycemia

Insulin mixtures are also available like NPH plus regular; Protamine plus Lispro and Protamine plus Aspart in varying ratios. Adverse effects of insulin include hypoglycemia, weight gain, hypersensitivity (especially with protamine insulin) like erythema, pruritus, anaphylaxis, development of antibodies to insulin and increased risk of cancers. Lipodystrophy is seen following long term use of insulin injections, it includes atrophy or hypertrophy. Lipoatrophy is an immune-mediated condition resulting in loss of fat at insulin injection sites. Lipohypertrophy is a common, non-immunological side effect of insulin resulting from insulin’s trophic effects following repeated injections of insulin into the same subcutaneous site. Patients should be advised not to inject insulin at sites of lipohypertrophy as insulin is absorbed less from those sites. Insulin is the mainstay of therapy of DM type 1 and is used in DM type 2 when blood sugars can no longer be controlled with oral antidiabetic drugs. Insulin pump or continuous subcutaneous insulin infusion therapy uses rapid acting insulin and is of use in severely diabetic individuals.