Rosiglitazones are Red, Pioglitazones are Blue… Metformin, Thiazolidinediones, Pramlintide, SGLT2 Inhibitors

2.2 – “Rosiglitazones are Red, Pioglitazone Pioglitazoness Thiazolidinedi Thiazolidinediones, ones, Pramlint Pramlintide, ide, SGLT2 inh inhibitors ibitors are Blue…”: Metformi Metformin, n, • Drugs that lower glucose levels by a variety of means can be used in Type 2 diabetes (2nd grade); require functional β cells. Unlike the sulfonylureas, meglitinides, & GLP analogs, these drugs act outside the pancreas →↓serum glucose • Metformin (kneeling kid reciting metaphors) o First line oral agent for T2DM. o Decreases serum glucose by poorly understood mechanisms. The only biguanide used clinically. ▪ Inhibits mitochondrial glycerophosphate dehydrogenase, the first step in hepatic gluconeogenesis, decreasing glucose production (girl eating candy, but distracted by serenade so is not taking candy out of liver-shaped bag) ▪ Activates AMP-activated protein kinase (AMPK) (AMP Kandy), decreasing liver gluconeogenesis (friend stopping candy release from bag). ▪ Increasing peripheral insulin sensitivity, resulting in increased peripheral glucose uptake & utilization, by enhancing glucose mediated insulin utilization (“Inside” notice on mailbox) ▪ Decreased intestinal glucose absorption. o Excreted by kidney as active drug (kidney shaped lunch tray) o ↓ risk of hypoglycemia o Adverse effects ▪ Lactic acidosis d/t lactate inability to enter gluconeogenesis(spilled sour milk). Rare. More likely to occur in conditions of renal failure or tissue hypoxia (kidney shaped lunch tray is broken). ▪ GI adverse effects anorexia, nausea/V, diarrhea (girl looks sick) ▪ Can cause modest weight reduction or stabilization (thin physique). • Thiazolidinediones (aka glitazones) o Include rosiglitazone, pioglitazone (“Roses are red” card filled with glitter) o Oral agents. Because these drugs affect gene transcription, take days to weeks for improvements. o Increase glucose utilization & decrease glucose production in adipose tissue, liver, & muscle. o Thiazolidinediones are ligands of peroxisome proliferator-activated receptor γ (PPAR-γ) (PPAR-γ on kid’s shirt). PPAR-γ receptors are intracellular nuclear receptors found in muscle, fat, & liver; part of the steroid & thyroid family of intranuclear receptors. ▪ Regulated genes include those affecting lipid & glucose metabolism, insulin signal transduction, adipocyte differentiation. ▪ One of the more important genes: adiponectin, which is low in patients with T2DM, obesity (turtleneck). Increases insulin sensitivity & fatty acid oxidation; increases differentiation & number of adipocytes (elevated donut jar). ▪ Increased availability of adipocytes increases triglyceride storage combined with increased fatty acid oxidation → ↓circulating TG levels ▪ Upregulate GLUT4 in peripheral tissue →↑glucose uptake (door to mailbox) o Adverse effects ▪ Weight gain d/t increased triglyceride storage — a little “extra glit in your zone” (fat kid) • May be exacerbated when coadministered with sulfonylurea ▪ ↑sodium resorption can cause fluid retention & peripheral edema (kid wearing baggy sweatpants • Contraindicated in HF d/t risk of exacerbation (balloon!) in ▪ Increased risk of atypical extremity fractures in women d/t decreased bone mineral density (fractured chair leg). Exact mechanism unknown, possibly d/t ↓osteoblast activity • Amylin analogues (twins Amy & Lynn) o Pramlintide o Analog of endogenous islet amyloid peptide (i.e. amylin) usually present in insulin secretory granules. ▪ Decreases glucagon secretion (glucagon packets) ▪ slows gastric emptying (closed stomach shaped water cooler) ▪ Appetite suppressant o Used for glycemic control. Can be used to manage postprandial hyperglycemia in either T1DM or T2DM (peaked cupcakes). Injected immediately before eating o Adverse effects ▪ Can cause hypoglycemia (knocking over candy jar) ▪ GI SSx (n/v, anorexia) (kid is nauseated) • Alpha-glucosidase inhibitors o Include acarbose & miglitol (box of A-carb wigglers in corner) o Intestinal α-glucosidase normally converts disaccharides in the intestines into absorbable monosaccharides. Blocking this enzyme decreases absorption of dietary sugars at the intestinal brush border, delaying carbohydrate absorption (“Monosaccharide FREE” box label; brush border flags; delayed access to wiggles) o Can be used to blunt postprandial serum glucose spike by as much as 30-50% (peaky cupcakes). Can be administered regularly through the day. o Side effects generally limit use. GI adverse effects (diarrhea, flatulence, abdominal pain, etc.) result from fermentation of undigested carbs by gut bacteria (leaky bathroom) • SGLT2 inhibitors o Include canagliflozin, dapagliflozin (flossing). Are the newest class. o Sodium-glucose cotransporter 2 (SGLT2) is a low affinity, high capacity transporter responsible for resorbing 90% of glucose in the PCT (Salty Glucose peanuts; pro-cart track poster). Inhibition causes significant glucose loss in the urine. o 2nd or 3rd line for diabetes management. Usually added to existing oral regimen o Side effects are mostly d/t glucosuria: ▪ UTI (bladder cup) ▪ Yeast infections (snowball in the crotch) ▪ Increased osmotic diuresis can cause symptomatic hypotension in some patients, especially elderly & those on diuresis (kid diuresing pants & falling over) ▪ Contraindicated in renal insufficiency d/t ↓ efficacy, ↑ risk of Adverse effects (cracked kidney tray)