Antidiabetics and insulin

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

1. Metformin (biguanide): Metformin decreases hepatic gluconeogenesis and intestinal glucose absorption. It also improves insulin sensitivity by increasing peripheral glucose uptake and utilization. As a result, it improves glucose tolerance and lowers both basal and postprandial plasma glucose. It does not typically cause hypoglycemia or hyperinsulinemia. Metformin inhibits mitochondrial glycerophosphate dehydrogenase, increases HDL, and decreases LDL levels. It is used in type 2 diabetes and in pre-diabetes to lower HbA1c levels. Adverse effects include lactic acidosis, metallic taste in the mouth, vitamin B12 deficiency, nausea, vomiting, diarrhea, abdominal pain, muscle cramps, and mental status changes. High-risk groups include the elderly and patients with renal or cardiac insufficiency. Metformin should be discontinued before surgery or administration of contrast media to prevent lactic acidosis.
2. Thiazolidinediones (rosiglitazone, pioglitazone): These drugs activate the transcription factor PPAR gamma (peroxisome proliferator-activated receptor gamma). This increases transcription of genes involved in glucose and lipid metabolism. Peripheral glucose utilization increases and hepatic gluconeogenesis decreases. They reduce triglycerides and LDL and increase HDL levels, and they do not cause hypoglycemia. Adverse effects include weight gain, edema, fluid retention, heart failure, and osteoporosis. They are contraindicated in liver failure and in bladder cancer (pioglitazone).
3. Sulfonylureas (glyburide, glipizide): These drugs block ATP-sensitive K+ channels on pancreatic beta cells, causing depolarization, calcium influx, and insulin secretion. For this reason, they are also called insulin secretagogues. They are ineffective if insulin stores are absent (as in type 1 DM). They increase insulin sensitivity and decrease hepatic gluconeogenesis. Adverse effects include hypoglycemia, weight gain, neutropenia, hemolytic anemia, skin allergies, and alcohol intolerance. They are contraindicated in sulfa allergies and in advanced renal or hepatic failure. Use caution when co-prescribing with beta blockers, which may mask signs of hypoglycemia such as tachycardia and tremors.
4. Meglitinides (repaglinide, nateglinide): These drugs are analogues of sulfonylureas. They increase insulin secretion from 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 mimetics are resistant to degradation by DPP 4. They bind to the GLP 1 receptor to increase insulin secretion, decrease glucagon secretion, and slow gastric emptying. They cause weight loss. Adverse effects include GI upset, pancreatitis, and rarely, pancreatic cancer.
6. DPP 4 (dipeptidyl peptidase) inhibitors or gliptins (sitagliptin, saxagliptin): These drugs enhance the effect of incretins (GLP 1 and GIP) by inhibiting the DPP 4 enzyme. They 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): These drugs inhibit SGLT 2 (the sodium-dependent glucose cotransporter) in the proximal tubule of the kidney. This decreases renal glucose reabsorption, causing glycosuria and polyuria. They promote weight loss. Adverse effects include UTIs, vulvovaginitis, balanitis, dehydration, and diabetic ketoacidosis.
8. Alpha glucosidase inhibitors (acarbose, miglitol): These drugs inhibit the enzyme alpha glucosidase, which breaks down glucose, and they decrease glucose absorption. Adverse effects include gas, bloating, flatulence, abdominal discomfort, and diarrhea. They should not be used in IBD and malabsorption syndromes.
9. Amylin analogue (pramlintide): Pramlintide slows gastric emptying by activation of amylin receptors in the nucleus accumbens and dorsal vagal nucleus. It also acts on the hypothalamus to decrease appetite and decreases glucagon secretion from the pancreas. This reduces the 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, such as NPH plus regular; protamine plus lispro; and protamine plus aspart, in varying ratios.

Adverse effects of insulin include hypoglycemia, weight gain, and hypersensitivity (especially with protamine insulin), such as erythema, pruritus, and anaphylaxis. Other adverse effects include development of antibodies to insulin and an increased risk of cancers.

Lipodystrophy can occur with long-term insulin injections and includes atrophy or hypertrophy.

Lipoatrophy is an immune-mediated condition that results in loss of fat at insulin injection sites. Lipohypertrophy is a common, non-immunological side effect caused by insulin’s trophic effects after repeated injections into the same subcutaneous site. Patients should be advised not to inject insulin at sites of lipohypertrophy because insulin is absorbed less from those sites.

Insulin is the mainstay of therapy for type 1 DM. It is also used in type 2 DM when blood sugars can no longer be controlled with oral antidiabetic drugs. An insulin pump (continuous subcutaneous insulin infusion therapy) uses rapid-acting insulin and is used in severely diabetic individuals.