Other Antidiabetics

Thiazolidinediones bind PPAR-γ, a ligand-activated nuclear transcription factor. The genes it controls in muscle, fat and liver regulate glucose metabolism, fatty-acid storage and adipocyte differentiation; they include lipoprotein lipase, glucokinase and the GLUT4 transporter. PPAR-γ activation raises adiponectin, an adipocyte cytokine that increases insulin sensitivity, and opposes TNF-α in fat cells. The result is less insulin resistance in the periphery and liver: more insulin-dependent glucose disposal and less hepatic glucose output.

Pioglitazone needs endogenous insulin and is not an insulin secretagogue, so it is not used in type 1 diabetes or ketoacidosis and does not cause hypoglycemia on its own. Because it works by changing gene expression, its maximal glucose-lowering effect takes 6 weeks to 6 months. Pioglitazone is both a PPAR-γ and a PPAR-α agonist; triglycerides fall and HDL rises, with no consistent change in LDL, and there is no conclusive evidence of macrovascular benefit.

TZDs cause dose-related fluid retention, worse with insulin. PPAR-γ in the collecting tubules induces epithelial sodium channel expression and increases sodium reabsorption — the same site where aldosterone acts. Retained fluid can cause or worsen heart failure, which is pioglitazone’s boxed warning: it is not recommended in symptomatic heart failure, and starting it in NYHA class III or IV is contraindicated. Weight gain comes from fluid and from fat: adipocytes carry the most PPAR-γ, and TZDs mature preadipocytes into adipocytes, with the gain mainly subcutaneous rather than visceral.

Fractures are more frequent in women, mostly non-vertebral in the distal limbs; PPAR-γ activation is thought to divert osteoblast precursors toward adipocytes. Pioglitazone may increase the risk of bladder cancer — study results are inconsistent — so it is not used with active bladder cancer. The first TZD, troglitazone, was withdrawn for hepatotoxicity; pioglitazone has rare postmarketing reports of hepatic failure, so liver tests are checked before and during treatment. Rosiglitazone, the other TZD, carries a higher risk of heart failure and death than pioglitazone; its sales were restricted from 2011 to 2013 over heart-attack concerns, and the restriction was then lifted.

Dietary starch is broken down by pancreatic α-amylase into oligosaccharides in the intestinal lumen; membrane-bound α-glucosidases at the brush border then split oligosaccharides and disaccharides into glucose and other monosaccharides. Acarbose competitively and reversibly inhibits both α-amylase and the brush-border enzymes; miglitol inhibits the brush-border α-glucosidases. Carbohydrate absorption is delayed and the post-meal glucose rise is smaller, without any increase in insulin secretion, so on their own they do not cause hypoglycemia. They are taken with the first bite of each main meal, because they act only on carbohydrate eaten then.

Acarbose does not inhibit lactase, so it does not cause lactose intolerance. The carbohydrate left undigested reaches the colon, where bacteria ferment it into gas — hence flatulence, diarrhea and abdominal discomfort. Because the drugs block the splitting of sucrose into glucose and fructose, a low caused by an added sulfonylurea or insulin must be treated with glucose (dextrose). Acarbose is barely absorbed and is metabolized in the gut; miglitol is absorbed and excreted by the kidneys.

Repaglinide and nateglinide close ATP-dependent potassium channels on β cells; the cell depolarizes, calcium channels open, and the calcium influx releases insulin — the same channel sulfonylureas close (Sulfonylureas page), which is why the two are not combined. Their action needs functioning β cells, and their insulin release is glucose-dependent and diminishes at low glucose. What sets them apart is time: repaglinide is rapidly absorbed with a half-life under an hour, and nateglinide’s half-life is about 1.5 hours, so they suit post-meal glucose spikes and are taken just before meals.

The rule that follows is to skip the dose when a meal is skipped; otherwise hypoglycemia can result. Repaglinide is metabolized by CYP2C8 and CYP3A4, so gemfibrozil (contraindicated) and clopidogrel (avoid) — both CYP2C8 inhibitors — raise its exposure several-fold. It is inactivated and excreted by the liver, and it has been used in chronic kidney disease. Nateglinide is metabolized mainly by CYP2C9.

Amylin is stored with insulin in β-cell secretory granules and co-secreted with it in response to food; in type 1 and type 2 diabetes the secretion of both is reduced. Amylin slows gastric emptying without changing overall nutrient absorption, suppresses glucagon secretion (which insulin alone does not normalize), lowering hepatic glucose output, and reduces food intake through central effects on appetite. Pramlintide, an amylin analog, does the same: slower gastric emptying, a smaller post-meal glucagon rise, and more satiety.

Pramlintide is used with mealtime insulin, in type 1 or type 2 diabetes, when insulin alone has not achieved control. Alone it does not cause hypoglycemia, but with insulin it raises the risk of severe hypoglycemia — its boxed warning — especially in type 1 diabetes, within 3 hours of an injection, so the mealtime insulin dose is reduced when it is started. Hypoglycemia unawareness and gastroparesis are contraindications, and because it slows the stomach, time-critical oral drugs are given 1 hour before or 2 hours after it.