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Non insulin therapy of Diabetes Mellitus

This document discusses several types of non-insulin pharmacological therapies for diabetes mellitus, including biguanides, sulfonylureas, meglitinides, and thiazolidinediones. It provides details on the mechanisms of action, efficacy, side effects, dosing and administration of metformin and sulfonylureas as first-line treatment options. The document also summarizes the mechanisms and characteristics of other non-insulin therapies such as meglitinides and thiazolidinediones.

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NON INSULIN THERAPY OF DM
• NON INSULIN THERAPY PHARMACOLOGICAL NON PHARMACOLOGICAL
PHARMACOLOGICAL 7 TYPES OF NON-INSULIN THERAPY AVAILABLE FOR TREATMENT OF DIABETES MELLITUS • Insulin secretagogues (sulfonylureas, meglitinides, GLP-1 agonists, DPP4 antagonist), • biguanides, • thiazolidinediones, • α-glucosidase inhibitors, • incretin-based therapies, • an amylin analog, and • a bile acid binding sequestrant.
Biguanides • Two biguanide antidiabetics, ------phenformin and metformin----introduced in the 1950s. • Higher risk of lactic acidosis---phenformin was withdrawn in many countries and has been banned in India since 2003. MOA • Reduces hepatic glucose production and improves peripheral glucose utilization- Primary action • Metformin activates AMP-dependent protein kinase and enters cells through organic cation transporters(polymorphisms of these may influence the response to metformin).
BIGUANIDE
• Metformin increases the activity of the AMP-dependent protein kinase (AMPK) • AMPK is activated by phosphorylation when cellular energy stores are reduced (i.e., lower concentrations of ATP and phosphocreatine). • Activated AMPK stimulates fatty acid oxidation, glucose uptake, and nonoxidative metabolism, and it reduces lipogenesis and gluconeogenesis. • The net result of these actions is increased glycogen storage in skeletal muscle, lower rates of hepatic glucose production, increased insulin sensitivity, and lower blood glucose levels.
• Consistent with this, metformin has been shown to inhibit cellular respiration by specific actions on mitochondrial complex I. • Metformin has little effect on blood glucose in normoglycemic states and does not affect the release of insulin or other islet hormones and rarely causes hypoglycemia.
Absorption, Distribution, and Elimination • Absorbed primarily from the small intestine. • excreted unchanged in the urine • t1/2 in the circulation of ~2 hours. • Metformin is available as an immediate-release form, and treatment is best started with low doses and titrated over days to weeks to minimize side effects. • An extended-release form is available and may have fewer gastrointestinal side effects (diarrhea, anorexia, nausea, metallic taste)
• The currently recommended dosing is 0.5-1.0 g (500- 1000mg)once or twice daily, with a maximum dose of 2550 mg; there is no advantage of thrice-daily administration. • Metformin has been used as a treatment for infertility in women with the polycystic ovarian syndrome. • Metformin reduces fasting plasma glucose (FPG) and insulin levels, improves the lipid profile, and promotes modest weight loss.
• Because of its relatively slow onset of action and gastrointestinal symptoms with higher doses---- the initial dose should be low and then escalated every 2–3 weeks based on SMBG measurements. • Metformin is effective as monotherapy and can be used in combination with other oral agents or with insulin.
SIDE EFFECTS • The most common side effects of metformin are gastrointestinal- nausea, indigestion, abdominal cramps or bloating, diarrhea, or some combination of these. • The major toxicity of metformin, lactic acidosis, is very rare and can be prevented by careful patient selection. • Vitamin B12 levels are ~30% lower during metformin CONTRAINDICATION • FDA recently revised the label for metformin to reflect its safety in patients with eGFR >= 30 mL/min/1.73 m2.(ADA 18) • The National Institute for Health and Clinical Excellence in the United Kingdom suggests that metformin be used at a GFR >30 mL/min, with a reduced dose when the GFR is <45 mL/min. • any form of acidosis, • unstable congestive heart failure (CHF), • liver disease, or • severe hypoxemia.
INSULIN SECRETAGOGUES: • Insulin secretagogues—agents that affect the ATP-sensitive K+ channel • Eg- sufonylureas, meglitinides, GLP-1 agonists, and inhibitors of dipeptidyl peptidase-4 (DPP-4) SULFONYL UREA A. Insulin Release from Pancreatic Beta Cells-beta-cell inward rectifier ATP-sensitive potassium channel. B. Reduction of Serum Glucagon Concentrations-involve indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit alpha-cell secretion.
• All of these agents, however, have the potential to cause profound and persistent hypoglycemia, especially in elderly individuals. • Hypoglycemia is usually related to ----- i. delayed meals, ii. increased physical activity, iii. alcohol intake, or iv. renal insufficiency.
SULFONYLUREAS • Differ by substitutions at the para position on the benzene ring and at one nitrogen residue of the urea moiety. • The first generation sulfonylureas (tolbutamide, tolazamide, and chlorpropamide) • First-generation sulfonylureas (chlorpropamide, tolazamide, tolbutamide) have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions, and are no longer used.
• The second, more potent generation of hypoglycemic sulfonylureas includes glyburide , glipizide and glimepiride. • Second-generation sulfonylureas have a more rapid onset of action and better coverage of the postprandial glucose rise, but the shorter half-life of some agents may require more than once-a-day dosing. • Glimepiride and glipizide can be given in a single daily dose and are preferred over glyburide, especially in the elderly. • These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years) who have residual endogenous insulin production. • Insulin Secretagogues are generally well tolerated.
• Sulfonylureas reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1- to 2-week intervals based on SMBG. • Because of their short half-life, these agents are given with each meal or immediately before to reduce meal-related glucose excursions. • with chronic therapy, though, the insulin release is more sustained.
• The usual starting dosage is 2.5 mg/day. • given as a single dose in the morning. • Glyburide is metabolized in the liver into products with very low hypoglycemic activity.
• Sulfonylureas may also reduce hepatic clearance of insulin, further increasing plasma insulin levels. • In the initial months of sulfonylurea treatment, fasting plasma insulin levels and insulin responses to oral glucose challenges are increased. • The absence of acute stimulatory effects of sulfonylureas on insulin secretion during chronic treatment is attributed to down regulation of cell surface receptors for sulfonylureas on the pancreatic β cell. • If chronic sulfonylurea therapy is discontinued, pancreatic β cell response to acute administration of the drug is restored.
Absorption, Distribution, and Elimination. • absorbed from the GI tract. • bound to protein- (90-99%) • half-lives are short (3-5 hours), • their hypoglycemic effects are evident for 12- 24 hours-once daily dosing.
Adverse Effects and Drug Interactions. • sulfonylureas may cause hypoglycemic reactions, including coma. • Because of the long t1/2 of some sulfonylureas, it may be necessary to monitor or treat elderly hypoglycemic patients for 24- 48 hours with an intravenous glucose infusion in the in-patient setting.
• Less frequent side effects of sulfonylureas include nausea and vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, and dermatological reactions. • Glyburide, but not glimepiride, interacts with the sulfonylurea receptor in these nonislet sites and may be associated with increased cardiovascular risk.--- A related isoform of ATP-sensitive potassium channels is present in the myocardium and the brain. • But studies have not shown an increased cardiac mortality with glyburide or other agents in this class.
• Other adverse effects include a hyperemic flush after alcohol ingestion in genetically predisposed patients and dilutional hyponatremia. • Hematologic toxicity (transient leukopenia, thrombocytopenia) occurs in less than 1% of patients. • Weight gain, a common side effect of sulfonylurea therapy, results from the increased insulin levels and improvement in glycemic control.
DRUG INTERACTION • Some drugs (sulfonamides, clofibrate, and salicylates) displace the sulfonylureas from binding proteins, thereby transiently increasing the concentration of free drug. Other drugs may ----decrease the glucose-lowering effect of sulfonylureas by • increased hepatic metabolism, • increased renal excretion, or • inhibiting insulin secretion • Eg- β-blockers, Ca2+ channel blockers, cholestyramine, diazoxide, estrogens, hydantoins, isoniazid, nicotinic acid, phenothiazines, rifampin, sympathomimetics, thiazide diuretics, and urinary alkalinizers.
Contraindications • type 1 diabetes, • pregnancy, • lactation, • Significant hepatic or renal insufficiency. • They should be used with caution in patients with cardiovascular disease or in elderly patients, in whom hypoglycemia would be especially dangerous.
MEGLITINIDE Repaglinide.- • Repaglinide (PRANDIN) is an oral insulin secretagogue of the meglitinide class. • benzoic acid derivative • The drug is absorbed rapidly from the GI tract, and peak blood levels are obtained within 1 hour. • The t1/2 is ~1 hour. • Repaglinide is metabolized primarily by the liver (CYP3A4) to inactive derivatives
• the major side effect of repaglinide is hypoglycemia. Nateglinide.— • derived from d-phenylalanine. • Nateglinide promotes a more rapid but less sustained secretion of insulin than other available oral antidiabetic agents. • Nateglinide is approved by the FDA for use in type 2 diabetes. • It is most effective when administered in a dose of 120 mg, 1-10 minutes before a meal.
THIAZOLIDINEDIONES- • Thiazolidinediones (Tzds) act to decrease insulin resistance. • Tzds are ligands of peroxisome proliferator-activated receptor gamma (PPAR-), part of the steroid and thyroid superfamily of nuclear receptors. • The PPAR-γ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues (fat,muscle). • PPAR-γ receptors modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation.
• Rosiglitazone and pioglitazone -----once daily. • The starting dose of rosiglitazone is 4 mg and should not exceed 8 mg daily. • The starting dose of pioglitazone is 15-30 mg, up to a maximum of 45 mg daily. • Thiazolidinediones have proven effects to enhance insulin action on liver, adipose tissue, and skeletal muscle. • average reductions in A1C of 0.5-1.4%.
Adverse Effects and Drug Interactions. • The most common adverse effects of the thiazolidinediones are weight gain (2–3 kg), and edema. • A small reduction in the hematocrit, and a mild increase in plasma volume. • Edema attributable to thiazolidinedione treatment occurs in up to 10% of patients. • The use of insulin with thiazolidinedione treatment roughly doubles the incidence of edema and amount of weight gain, compared with either drug alone. • Macular edema has been reported in patients using both rosiglitazone and pioglitazone- diabetic patients taking thiazolidinediones should be observed for visual changes.
• Increased incidence of congestive heart failure.- This has generally been attributed to the effect of the drugs to cause plasma volume expansion in type 2 diabetic patients who have significantly increased risk for heart failure. ----monitoring for signs and symptoms of congestive heart failure is important, especially when insulin is also used. • Thiazolidinediones should not be used in patients with moderate to severe heart failure, and they should be discontinued in those who develop clinically apparent heart failure while being treated. • Recent evidence suggests that rosiglitazone, but not pioglitazone, increases the risk of cardiovascular events. • Treatment with thiazolidinediones can increase the risk of bone fracture in women. • Associated with a small but consistent reduction in the hematocrit.
INCRETINS There are two main incretin hormones in humans, GIP GLP-1 • Both hormones are secreted by endocrine cells that are located in the epithelium of the small intestine. • Incretin hormone release is regulated in a similar way to other digestive tract hormones. • Incretins are released after eating. • An increase in glucose acts as the trigger for hormone secretion. • Glucose in the small intestine stimulates incretin release. • Incretins are carried through the circulation to their target tissue: the pancreatic beta cells-----stimulation of beta cells causes them to secrete more insulin .
They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. In addition, they inhibit glucagon release from the alpha cells of the islets of Langerhans.
• GLP 1 ANALOGUE-
• GLP-1-Based Agents • GIP is not effective for stimulating insulin release and lowering blood glucose in persons with type 2 diabetes, whereas GLP-1 is effective. • Given intravenously to diabetic subjects in supraphysiologic amounts, GLP- 1 stimulates insulin secretion, inhibits glucagon release, delays gastric emptying, reduces food intake, and normalizes fasting and postprandial insulin secretion. • The insulinotropic effect of GLP-1 is glucose dependent in that insulin secretion at fasting glucose concentrations, even with high levels of circulating GLP-1, is minimal. • GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-4), with a plasma t1/2 of 1-2 minutes; thus, the natural peptide, itself, is not a useful therapeutic agent.
• Exenatide- associated with improved glycemic control, as reflected in an ~1% decrease in HbA1C, and weight loss that averaged 2.5-4 kg. • Liraglutide- The fatty acid side chain permits binding to albumin and other plasma proteins and accounts for an extended t1/2 permitting once a day administration.
• Mechanism of Action. • All GLP-1 receptor agonists share a common mechanism, activation of the GLP-1 receptor. • GLP-1 receptors are expressed by β cells, cells in the peripheral and central nervous system, the heart vasculature, kidney, lung, and GI mucosa. • Binding of agonists to the GLP-1 receptor ----stimulate insulin release.
Absorption, Distribution, Metabolism, Excretion, and Dosing. • Exenatide is given as a subcutaneous injection twice daily, typically before meals. • Exenatide is rapidly absorbed, reaches peak concentrations in ~2 hours, undergoes little metabolism in the circulation, and has a volume of distribution of nearly 30 L. • Clearance of the drug occurs primarily by glomerular filtration, with tubular proteolysis and minimal reabsorption. • Liraglutide is given as a subcutaneous injection once daily. • Peak levels occur in 8-12 hours and the elimination t1/2 is 12-14 hours.
• Adverse Effects and Drug Interactions. • Intravenous or subcutaneous administration of GLP-1 causes nausea and vomiting in a dose-dependent manner • the doses above which GLP-1 causes GI side effects are higher than those needed to regulate blood glucose. • can delay gastric emptying; -----thus exenatide and other drugs of this class should be used with caution with other compounds that affect gastric emptying.-----and they may influence the absorption of other drugs • hypoglycemia associated with GLP-1 agonist treatment is rare. • Some formulations carry a black box warning from the FDA because of an increased risk of thyroid C-cell tumors in rodents and are contraindicated in individuals with medullary carcinoma of the thyroid or multiple endocrine neoplasia.
DPP-4 Inhibitors Mechanism of Action. • DPP-4 is a serine protease that is widely distributed throughout the body, expressed as an ectoenzyme on endothelial cells, on the surface of T-lymphocytes, and in a circulating form. • critical for the inactivation of GLP-1 and GIP Eg- • Sitagliptin • Saxagliptin • Valdagliptin • Alogliptin
• a preferential effect on postprandial blood glucose • Sitagliptin and alogliptin are competitive inhibitors of DPP- 4, whereas vildagliptin and saxagliptin bind the enzyme covalently. • associated with increased insulin secretion, reduced glucagon levels, and improvements in both fasting and postprandial hyperglycemia. • as monotherapy in type 2 diabetic patients, reduced HbA1c levels by an average ~0.8%. • The recommended dose of sitagliptin is 100 mg once daily. The recommended dose of saxagliptin is 5 mg once daily.
Absorption, Distribution, Metabolism, and Excretion. • They are absorbed effectively from the small intestine. • They circulate in primarily in unbound form and are excreted mostly unchanged in the urine. • DPP-4 inhibitors do not bind to albumin • Both sitagliptin and saxagliptin are excreted renally, and lower doses should be used in patients with reduced renal function.
• ADVERSE EFFECTS- • There are no consistent adverse effects that have been noted in clinical trials with any of the DPP-4 inhibitors.
Alpha Glucosidase Inhibitor Mechanism of Action. •α-Glucosidase inhibitors reduce intestinal absorption of starch, dextrin, and disaccharides •by inhibiting the action of α-glucosidase in the intestinal brush border. •Inhibition of this enzyme slows the absorption of carbohydrates from the GI tract and blunts the rate of rise of postprandial plasma glucose. • These drugs also increase the release of the glucoregulatory hormone GLP-1 into the circulation, which may contribute to their glucose-lowering effects.
• Examples • acarbose • miglitol and • voglibose • Both are provided as 25, 50, or 100 mg tablets that are taken before meals. • voglibose was associated with less gastrointestinal side effects and slightly less efficacy for postprandial glucose reduction than acarbose. • Acarbose and miglitol are most effective when given with a starchy, high-fiber diet with restricted amounts of glucose and sucrose.
• α-Glucosidase inhibitors reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion • α-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia. • Simultaneous treatment with bile acid resins and antacids should be avoided. • These agents should not be used in individuals with inflammatory bowel disease, gastroparesis, or a serum creatinine >177 μmol/L (2 mg/dL).
• Absorption, Distribution, Metabolism, Excretion, and Dosing.- minimally absorbed and the small amount of drug reaching the systemic circulation is cleared by the kidney. • Adverse Effects and Drug Interactions.- malabsorption, flatulence, diarrhea, and abdominal bloating.
Bile Acid Binding Resins • Mechanism of Action. • Bile acid metabolism is abnormal in patients with type 2 diabetes • bile acid binding resins lower plasma glucose in diabetic patients. • The mechanism by which bile acid binding and removal from enterohepatic circulation lowers blood glucose has not been established. • Bile acid sequestrants could reduce intestinal glucose absorption, although there is no direct evidence of this. • Bile acids also act as signaling molecules through nuclear receptors, some of which may act as glucose sensors.
• The only bile acid sequestrant specifically approved for the treatment of type 2 diabetes is colesevelam . • The most common side effects are gastrointestinal (constipation, abdominal pain, and nausea). • Bile acid–binding resins can increase plasma triglycerides and should be used cautiously in patients with a tendency for hypertriglyceridemia. • Bromocriptine A formulation of the dopamine receptor agonist bromocriptine (Cycloset) has been approved by the FDA for the treatment of type 2 DM. However, its role in the treatment of type 2 DM is uncertain.
Sodium-Glucose Co-Transporter 2 Inhibitors (SLGT2) • Inhibits the co- transporter, which is expressed almost exclusively in the proximal convoluted tubule in the kidney. • This inhibits glucose reabsorption,lowers the renal threshold for glucose, and leads to increased urinary glucose excretion. • Due to the increased urinary glucose, urinary or vaginal infections are more common • FDA approved canagliflozin in 2013.
The main driver of benefit may derive from the specific effects of sodium- glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction.
NON PHARMACOLOGICAL TREATMENT
Diabetes Metab Syndr. 2018 Apr 18. pii: S1871-4021(18)30090-0. doi: 10.1016/j.dsx.2018.04.008. [Epub ahead of print] The benefits of yoga practice compared to physical exercise in the management of type 2 Diabetes Mellitus: A systematic review and meta-analysis. Jayawardena R1, Ranasinghe P2, Chathuranga T3, Atapattu PM3, Misra A4. A significant reduction in FBG (15.16 mg/dl), PPBG (28.66 mg/dl), HbA1c (0.39%) and BMI (0.71 kg/m2) was noted in the intervention group ('Yoga') compared to the control group ('Physical Exercise') in the pooled analysis. We did not observe any significant difference between the two groups for lipid parameters, other body composition measures (WC and WHR) and Blood Pressure. In conclusion, our results show that Yoga has beneficial effects on glycaemic control in comparison to physical exercise in T2D ROLE OF YOGA IN TREATMENT OF DIABETES MELLITUS
Cochrane Database Syst Rev. 2017 Dec 4;12:CD003054. doi: 10.1002/14651858.CD003054.pub4. Diet, physical activity or both for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk of developing type 2 diabetes mellitus. Hemmingsen B1, Gimenez-Perez G, Mauricio D, Roqué I Figuls M, Metzendorf MI, Richter B. AUTHORS' CONCLUSIONS: There is no firm evidence that diet alone or physical activity alone compared to standard treatment influences the risk of T2DM and especially its associated complications in people at increased risk of developing T2DM. However, diet plus physical activity reduces or delays the incidence of T2DM in people with IGT. Data are lacking for the effect of diet plus physical activity for people with intermediate hyperglycaemia defined by other glycaemic variables. Most RCTs did not investigate patient-important outcomes.
Complement Ther Clin Pract. 2018 May;31:369-373. doi: 10.1016/j.ctcp.2018.01.003. Epub 2018 Feb 15. Yoga improves quality of life and fall risk-factors in a sample of people with chronic pain and Type 2 Diabetes. Schmid AA1, Atler KE2, Malcolm MP2, Grimm LA2, Klinedinst TC2, Marchant DR3, Marchant TP3, Portz JD4. Data from this small RCT indicates yoga may be therapeutic and may improve multiple outcomes in this seemingly at-risk population.
J Clin Diagn Res. 2017 Sep;11(9):CC10-CC14. doi: 10.7860/JCDR/2017/29307.10633. Epub 2017 Sep 1. Effect of 12 Weeks of Yoga Therapy on Quality of Life and Indian Diabetes Risk Score in Normotensive Indian Young Adult Prediabetics and Diabetics: Randomized Control Trial. Keerthi GS1, Pal P2, Pal GK3, Sahoo JP4, Sridhar MG5, Balachander J6. CONCLUSION: Yoga therapy along with standard treatment for 12 weeks improved QoL and attenuated the diabetes risk among Indian prediabetics and diabetics compared to standard treatment alone. J Clin Diagn Res. 2015 Apr;9(4):CC01-3. doi: 10.7860/JCDR/2015/12666.5744. Epub 2015 Apr 1. Effect of yoga on blood glucose levels in patients with type 2 diabetes mellitus. Chimkode SM1, Kumaran SD2, Kanhere VV3, Shivanna R4. CONCLUSION: The results of the present study demonstrated that the yoga is effective in reducing the blood glucose levels in patients with T2DM.
Non insulin therapy of Diabetes Mellitus