Diabetic Nephropathy Medication
- Author: Vecihi Batuman, MD, FACP, FASN; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
Major therapeutic interventions include near-normal blood glucose control, antihypertensive treatment, and restriction of dietary proteins. Drug classes employed include hormones (ie, insulin), sulfonylureas, biguanides, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-adrenergic blocking agents, calcium channel blockers, and diuretics.
Hormones stimulate proper use of glucose by cells and reduce blood sugar levels. Based on their duration of action, several types of insulin are available.
The structure of insulin was established in 1960, leading to complete synthesis by 1963. Human insulin was approved by the US Food and Drug Administration (FDA) in 1982. Bovine, porcine, and recombinant human insulin preparations are currently available for use in diabetes treatment worldwide; however, insulin derived from bovine tissue is no longer available in the US market as of 1999 because of FDA concerns over transmission of bovine spongiform encephalopathy. Regular insulin has a rapid onset of action of 0.5-1 hours and duration of action of 4-6 hours. The peak effects are seen within 2-4 hours.
Insulin aspart has a short onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin aspart is FDA approved for use in insulin pumps.
Insulin glulisine has a rapid onset of action of 5-15 minutes and a short duration of action of 3-5 hours. The peak effect occurs within 30-90 minutes. Insulin glulisine is FDA approved for use in insulin pumps.
Insulin lispro has a rapid onset of action of 5-15 minutes and a short duration of action of 4 hours.
Insulin glargine is a long-acting insulin that has an onset of action of 4-8 hours and a duration of action of 24 hours. The peak effects occur within 16-18 hours.
Insulin NPH is an intermediate-acting insulin that has an onset of action of 3-4 hours and a duration of action of 16-24 hours. The peak effect of insulin NPH occurs within 8-14 hours.
Sulfonylureas act primarily by stimulating release of insulin from beta cells. Extrapancreatic actions include increasing the number of insulin receptors and enhancing insulin-mediated glucose transport independent of increased insulin binding. The use of oral agents has decreased because more emphasis is placed on better control as a means of slowing the development of late complications.
Sulfonylureas are indicated for some patients with relatively mild disease. Commonly used sulfonylureas include chlorpropamide, tolazamide, tolbutamide, glyburide, and glipizide.
Chlorpropamide is a first-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Tolazamide is a first-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Tolbutamide is a first-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Glyburide is a second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Glipizide is a second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.
Biguanides are useful in patients with type 2 diabetes mellitus (DM) who are not responsive to diet and exercise. They are usually added as an adjunctive agent in patients whose disease is not controlled by maximal doses of sulfonylureas. Occasionally, they may be prescribed as monotherapy in diabetic patients who are obese.
Metformin reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in peripheral tissues (muscle and adipocytes). It is a major drug used in obesity and type 2 DM. In contrast to sulfonylureas, metformin does not cause hypoglycemia.
Thiazolidinedione derivatives are active only in the presence of insulin. They are approved for use in patients who are obese, have type 2 DM, and whose diabetes is poorly controlled on insulin. Some physicians administer thiazolidinedione derivatives as add-on agents in patients with type 2 DM who are on maximal doses of other oral agents.
Pioglitazone improves target cell response to insulin without increasing insulin secretion from the pancreas. It decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, liver and adipose tissue.
Rosiglitazone is used to treat type 2 diabetes associated with insulin resistance and has an effect on the stimulation of glucose uptake in skeletal muscle and adipose tissue.
Angiotensin-converting enzyme inhibitors
All of these agents except fosinopril are excreted primarily by the kidney. They have similar actions and adverse effects, including severe hypotension, acute renal failure (especially in bilateral renal artery stenosis), hyperkalemia, dry cough (sometimes accompanied by wheezing), and angioedema. Cough and angioedema are believed to be mediated by bradykinin.
Captopril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Enalapril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion.
Lisinopril is a competitive inhibitor of ACE. It reduces angiotensin II levels, decreasing aldosterone secretion
Angiotensin receptor blockers
ARBs are specific and selective angiotensin II receptor antagonists. Compared with ACE inhibitors, ARBs are associated with a lower incidence of drug-induced cough, rash, and/or taste disturbances.
Losartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce more complete inhibition of the renin-angiotensin system than ACE inhibitors do, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema.
Valsartan produces direct antagonism of angiotensin II receptors. It may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.
Irbesartan is used to treat diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/d) in patients with type 2 diabetes and hypertension. It reduces the rate nephropathy progression. It blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor.
Beta-adrenergic blocking agents
Beta-adrenergic blocking agents affect blood pressure via multiple mechanisms. Actions include a negative chronotropic effect that decreases heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the central nervous system, and suppression of renin release from kidneys.
Metoprolol is used to treat hypertension. It is a beta-adrenergic blocking agent that affects blood pressure via multiple mechanisms. Actions include negative a chronotropic effect that decreases the heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, reduction of sympathetic outflow from the CNS, and suppression of renin release from the kidneys. During intravenous administration, carefully monitor blood pressure, heart rate, and ECG.
Atenolol is used to treat hypertension. It selectively blocks beta1-receptors, with little or no affect on beta 2 types. It is also used to improve and preserve hemodynamic status by acting on myocardial contractility, reducing congestion, and decreasing myocardial energy expenditure.
Labetalol is a beta-adrenergic blocking agent that reduces blood pressure via multiple mechanisms. Actions include a negative chronotropic effect that decreases the heart rate at rest and after exercise, a negative inotropic effect that decreases cardiac output, a reduction of sympathetic outflow from the CNS, and suppression of renin release from the kidneys.
Calcium channel blockers
Calcium channel blockers inhibit the influx of extracellular calcium across myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits contractile processes of myocardial smooth muscle cells, resulting in dilation of coronary and systemic arteries and improved oxygen delivery to myocardial tissue. In addition, total peripheral resistance, systemic blood pressure, and afterload are decreased.
Calcium channel blockers provide control of hypertension associated with less impairment of function of the ischemic kidney. Calcium channel blockers may have beneficial long-term effects, but this remains uncertain. During depolarization, these agents inhibit calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. Amlodipine is longer acting.
Diltiazem is a nondihydropyridine calcium channel blocker. It relaxes the vascular smooth muscle, causing a decrease in peripheral vascular resistance and leading to antihypertensive effects.
Verapamil is a nondihydropyridine calcium channel blocker. It inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes.
Nifedipine is a dihydropyridine calcium channel blocker. It relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. In addition, it decreases peripheral resistance, systemic blood pressure, and afterload.
Amlodipine is a dihydropyridine calcium channel blockers that has antianginal and antihypertensive effects. It inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle.
Furosemide and bumetanide are loop diuretics that appear primarily to inhibit reabsorption of sodium and chloride in the ascending limb of the loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Following administration, renal vasodilation occurs, renal vascular resistance decreases, and renal blood flow is enhanced.
Hydrochlorothiazide is a thiazide diuretic that inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water and potassium and hydrogen ions.
Furosemide is a loop diuretic that increases the excretion of water by interfering with the chloride-binding co-transport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. It increases renal blood flow without increasing the filtration rate. The onset of action generally is within 1 hour. It increases potassium, sodium, calcium, and magnesium excretion.
This is a thiazide diuretic that inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions. Diuretics are used only as an as an adjunct to other medications.
Bumetanide increases the excretion of water by interfering with the chloride-binding co-transport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.
Direct Renin Inhibitors
This is the newest class of antihypertensive drugs. They act by disrupting the renin-angiotensin-aldosterone system feedback loop.
Aliskiren is a direct renin inhibitor that decreases plasma renin activity and inhibits the conversion of angiotensinogen to angiotensin I (as a result, also decreasing angiotensin II) and thereby disrupts the renin-angiotensin-aldosterone system feedback loop. It is indicated for hypertension as monotherapy or in combination with other antihypertensive drugs.
Antidiabetics, Dipeptyl Peptidase-IV Inhibitors
The dipeptidyl peptidase (DPP)–4 inhibitors (ie, gliptins) are a new class of antidiabetic agents that can be used in type 2 diabetes. They decrease the breakdown of the incretin hormones, such as glucagonlike peptide 1 (GLP-1). GLP-1 is secreted by the GI tract in response to food intake and leads to insulin secretion in a glucose-dependent manner, while also decreasing glucagon release. GLP-1 also slows gastric emptying.
Sitagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Sitagliptin is indicated for diabetes type 2 as monotherapy or combined with metformin or a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist (eg, thiazolidinediones).
Linagliptin increases and prolongs incretin hormone activity, which are inactivated by DPP-4 enzyme Incretins regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic β cells and reducing glucagon secretion from pancreatic α cells.
Saxagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 DM.
Alogliptin slows inactivation of incretin hormones (eg, GLP-1, GIP), thereby reducing fasting and postprandial glucose concentrations in a glucose-dependent manner
Antidiabetics, Alpha-Glucosidase Inhibitors
Alpha-glucosidase inhibitors decrease the breakdown of oligosaccharides and disaccharides in the small intestine, slowing the absorption of glucose after a meal.
Acarbose delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose. It inhibits the metabolism of sucrose to glucose and fructose.
Miglitol delays glucose absorption in the small intestine and lowers postprandial hyperglycemia.
Antidiabetics, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors
Agents in this category inhibit renal glucose absorption in the proximal tubule, the site in the kidney where approximately 90% of glucose reabsorption occurs. This leads to increased excretion of glucose in the urine.
Canagliflozin is a selective sodium-glucose transporter-2 (SGLT2) inhibitor. SGLT-2 inhibition 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.
Antidiabetics, Glucagon-like Peptide-1 Agonists
These drugs act in the satiety center and reduce appetite, thus helping with weight loss. These drugs promote insulin release, delay glucagon release, and slow gastric emptying and are less likely to cause hypoglycemia.
Exenatide is an incretin mimetic agent that mimics glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins. It improves glycemic control in patients with type 2 DM by enhancing glucose-dependent insulin secretion by pancreatic βcells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The drug's 39–amino acid sequence partially overlaps that of the human incretin, GLP-1. It is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin or a sulfonylurea but have not achieved glycemic control.
Liraglutide is an incretin mimetic analog of human GLP-1; it acts as a GLP-1 receptor agonist to increase insulin secretion in the presence of elevated blood glucose; it delays gastric emptying to decrease postprandial glucose, and it also decreases glucagon secretion.
These agents are amylin analogs; amylin is co-secreted by βcells with insulin and is deficient in diabetes. Its levels parallel insulin levels, and its actions are complementary to insulin in regulating plasma glucose concentration. Amylin slows gastric emptying, reduces postprandial glucagon, and can suppress appetite.
Pramlintide is a synthetic analog of human amylin, a naturally occurring hormone made in pancreas βcells. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake due to centrally mediated appetite modulation. It is indicated to treat type 1 or type 2 diabetes in combination with insulin. It is administered before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. Pramlintide helps achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, Hgb A1C levels) compared with insulin alone. Additionally, less insulin use and reduction in body weight is also observed.
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