Summary

These notes provide an overview of diabetes, its causes, and treatments. They include information on various types of diabetes, the role of the pancreas, and insulin's function. The document also details different drugs used to treat the condition.

Full Transcript

2024/10/04 DIABETES Dr Sarentha Chetty BPharm, MSc, PhD CONTENTS Introduction Diabetes The Pancreas Drugs used in the treatment of diabetes Mechanism of Action Adverse effects Drug interactions ...

2024/10/04 DIABETES Dr Sarentha Chetty BPharm, MSc, PhD CONTENTS Introduction Diabetes The Pancreas Drugs used in the treatment of diabetes Mechanism of Action Adverse effects Drug interactions 2024/10/04 INTRODUCTION Chronic, metabolic disease - elevated levels of blood glucose Over time -serious damage to the heart, blood vessels, eyes, kidneys, nerves Type 2 diabetes Most common Usually adult onset When the body becomes resistant to insulin or doesn't make enough insulin Type 1 diabetes Juvenile diabetes or insulin-dependent diabetes Chronic condition where the pancreas produces little or no insulin by itself DIABETES FACTS ± 537 million adults are living with diabetes Projected to rise to 643 million by 2030 and 783 million by 2045 3 in 4 adults with diabetes live in low- and middle-income countries Over 90% have type 2 diabetes Driven by socio-economic, demographic, environmental, and genetic factors Key contributors to the rise in type 2 diabetes include: Urbanization An ageing population Decreasing levels of physical activity Increasing overweight and obesity prevalence 2024/10/04 THE PANCREAS ± 1 million islets of Langerhans cells Homones produced: Insulin - storage and anabolic hormone of the body Glucagon: Hyperglycemic factor that raise blood glucose by using stored hepatic glycogen INSULIN Secreted by the β-cells of the islets of Langerhans Stimuli - release insulin from storage Stimulants: Sugars, amino acids, Glucagon-like polypeptide 1 (GLP1), glucose dependent insulinotropic polypeptide (GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and β-adrenergic sympathetic activity Incretins Glucagon-like insulinotropic peptide (GIP) and glucagon-like peptide (GLP-1) - hormones released from the gut in response to food They ↑ insulin release by a direct action on pancreatic β-cells Their action is terminated by dipeptidyl peptidase (DPP-4) 2024/10/04 INSULIN RELEASE Continuous basal secretion with surges at feeding times The β-cells possess K+ channels that are regulated by intracellular adenosine triphosphate (ATP) - (KATP channels) When blood glucose ↑, more glucose enters the β-cells and its metabolism results in ↑ intracellular ATP, which closes the KATP channels The resulting depolarization of the β-cell initiates an influx of Ca2+ ions through voltage-sensitive Ca2+ channels This triggers insulin release. One model of control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. In the resting cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases, potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secretagogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same mechanism. Citation: Chapter 41 Pancreatic Hormones & Glucose-Lowering Drugs, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281754092 Accessed: May 20, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved 2024/10/04 Insulin receptors Insulin binds to insulin receptors in the cell membranes → increase in glucose uptake by the muscle, liver and adipose tissue. Membrane-spanning glycoproteins consisting of two α-subunits and two β-subunits linked covalently by disulphide bonds Insulin binds to the α-subunit of the receptors which activates the tyrosine kinase activity of the β-subunit and initiates a complex chain of reactions Schematic diagram of the insulin receptor heterodimer in the activated state. IRS, insulin receptor substrate; MAP, mitogen-activated protein; P, phosphate; Tyr, tyrosine. Citation: Chapter 41 Pancreatic Hormones & Glucose-Lowering Drugs, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281754092 Accessed: May 20, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved How insulin works https://www.youtube.com/watch?v=HJGjNTJgf48 2024/10/04 TYPE 1 DIABETES Severe or absolute insulin deficiency Type 1 diabetes is further subdivided into Immune mediated (type 1a) and idiopathic causes (type 1b) Type 1a - most common form Patients < 30 years at the time of diagnosis, but onset can occur at any age. 10–15% of patients have a positive family history Most patients have one or more circulating antibodies to: Glutamic acid decarboxylase 65 (GAD 65) Insulin autoantibody Tyrosine phosphatase IA2 (ICA 512) Zinc transporter 8 (ZnT8) These antibodies - diagnosis of type 1a diabetes and can also be used to screen family members at risk for developing the disease. Most type 1 diabetes patients with acute symptomatic presentation have significant beta cell loss and insulin therapy is essential to control glucose levels and to prevent ketosis. 2024/10/04 Inactivity or total absence of insulin Results in ↓ glucose uptake by insulin-sensitive tissues Lipolysis and muscle proteolysis result in weight loss and weakness Blood levels of free fatty acids and glycerol rise Excess acetyl-CoA is produced in the liver and converted to acetoacetic acid, which is then either reduced to β-hydroxybutyric acid or decarboxylated to acetone These ‘ketone bodies’ accumulate in the blood, causing an acidosis (ketoacidosis) SIGNS AND SYMPTOMS OF DIABETIC KETOACIDOSIS 2024/10/04 TYPE II DIABETES Tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion Circulating endogenous insulin is sufficient to prevent ketoacidosis, but is inadequate to prevent hyperglycemia Initially patients controlled with diet, exercise, and non-insulin glucose lowering drugs Some patients have progressive beta cell failure and eventually may also need insulin therapy. GESTATIONAL DIABETES MELLITUS (GDM) Defined as any abnormality in glucose levels noted for the first time during pregnancy During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester Risk assessment for diabetes is suggested starting at the first prenatal visit 2024/10/04 OTHER SPECIFIC TYPES OF DIABETES MELLITUS The “other” designation refers to multiple other specific causes of an elevated blood glucose: Pancreatectomy, pancreatitis, non-pancreatic diseases Drug therapy, etc. For a detailed list the reader is referred to the American Diabetes Association report, 2014. LABORATORY FINDINGS 2024/10/04  Plasma or Serum Glucose ≥ 126 mg/dL (7 mmol/L) on more than one occasion after at least 8 hours of fasting is diagnostic of diabetes mellitus 100–125 mg/dL (5.6–6.9 mmol/L) - associated with increased risk of diabetes (impaired fasting glucose tolerance) Hemoglobin A1c Measurements When plasma glucose levels - normal range, about 4–6% of hemoglobin A has one or both of the N terminal valines of their beta chains irreversibly glycated by glucose—referred to as hemoglobin1c (HbA1c) The HbA1c fraction is abnormally elevated in people with diabetes with chronic hyperglycemia RBCs - lifespan of up to 120 days, the HbA1c value reflects plasma glucose levels over the preceding 8–12 weeks. Oral Glucose Tolerance Test If either HbA1c level is < 6.5% or the fasting plasma glucose level is 42 hours Degludec - once a day to achieve a stable basal coverages. 2024/10/04 5. INSULIN ICODEC* Basal insulin analog given once a week The lysine at B29 of the insulin is conjugated to 1,20 icosanedioic acid (C20) There are three amino acid substitutions (A14E, B16H and B25H) The C20 di-acid group results in strong, reversible binding to albumin thus delaying SC absorption The amino acid substitutions attenuate insulin receptor affinity and ↑ resistance to degradation. Extent and duration of action of various types of insulin as indicated by the glucose infusion rates (mg/kg/min) required to maintain a constant glucose concentration. The durations of action shown are typical of an average dose of 0.2–0.3 U/kg. The durations of regular and NPH insulin increase considerably when dosage is increased. Citation: Chapter 41 Pancreatic Hormones & Glucose-Lowering Drugs, Vanderah TW. Katzung’s Basic & Clinical Pharmacology, 16th Edition; 2024. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3382&sectionid=281754092 Accessed: May 20, 2024 Copyright © 2024 McGraw-Hill Education. All rights reserved 2024/10/04 6. MIXTURES OF INSULINS Intermediate-acting isophane insulins require several hrs to reach adequate therapeutic levels Patients usually require supplements of rapid or short-acting insulin before meals For convenience, these can be mixed together in the same syringe before injection The regular insulin or rapidly acting insulin analog is withdrawn first, then the NPH insulin, and then the mixture is injected immediately. Stable premixed insulins (70% isophane and 30% regular) are available Premixed preparations of rapidly acting insulin analogs (lispro, aspart) and isophane are not stable because of exchange of the rapidly acting insulin analog for the human regular insulin in the protamine complex 2024/10/04 To remedy this problem, intermediate insulins composed of NPL complexes of protamine with the rapidly acting insulin analogs were developed (neutral protamine lispro [NPL]; aspart protamine). Premixed combinations of NPL and insulin lispro are now available for clinical use (Humalog Mix 75/25 and Humalog Mix 50/50) These mixtures - more rapid onset of glucose lowering activity compared with 70% NPH/30% regular human insulin mixture Can be given within 15 minutes before or after starting a meal A similar 70% insulin aspart protamine/30% insulin aspart (NovoLog Mix 70/30) is now available The main advantages of these new mixtures are: (1) Can be given within 15 minutes of starting a meal (2) More effective in achieving glucose targets with the postprandial glucose rise after a carbohydrate rich meal Insulin glargine and insulin detemir cannot be mixed in the same syringe with other insulins. INSULIN DELIVERY SYSTEMS A. Insulin Syringes and Needles B. Insulin Pens C. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps) D. Closed Loop Systems Algorithms have been devised to use glucose data from the CGM systems to automatically deliver insulin by CSII pump. These closed loop systems (“artificial pancreas”) have been shown to reduce night-time hypoglycemia and lower HbA1c levels E. Inhaled Insulin 2024/10/04 ADVERSE EFFECTS A. IMMUNOPATHOLOGY OF INSULIN THERAPY Five molecular classes of insulin antibodies may be produced in patients during the course of insulin therapy: IgA, IgD, IgE, IgG, IgM. 1. Insulin allergy Rare, immediate type hypersensitivity Local or systemic urticaria results from histamine release from tissue mast cells sensitized by anti-insulin IgE antibodies Severe cases -anaphylaxis Sensitivity is often to non-insulin protein contaminants Human and analog insulins have markedly reduced the incidence of insulin allergy, especially local reactions. 2. Immune insulin resistance A low titer of circulating IgG anti-insulin Antibodies that neutralize the action of insulin Rarely -the titer of insulin antibodies leads to insulin resistance May be associated with other systemic autoimmune processes such as lupus erythematosus B. Hypoglycaemia Caused by insulin overdose or inadequate calorific intake When severe →coma and death Patient requires treatment with glucose (intravenously if unconscious). 2024/10/04 C. LIPODYSTROPHY AT INJECTION SITES Animal insulin preparations sometimes led to atrophy of subcutaneous fatty tissue at the site of injection Human and analog insulin preparations of neutral pH, this type of immune complication is almost never seen Hypertrophy of subcutaneous fatty tissue remains a problem if insulin is injected repeatedly at the same site Rotate sites to prevent MEDICATIONS FOR TREATMENT OF TYPE 2 DIABETES 2024/10/04 ANTI-DIABETIC AGENTS (1) Agents that bind to the sulfonylurea receptor and stimulate insulin secretion (sulfonylureas, meglitinides, D-phenylalanine derivatives) (2) Agents that lower glucose levels by their actions on liver, muscle, and adipose tissue (biguanides, thiazolidinediones) (3) Agents that principally slow the intestinal absorption of glucose (α-glucosidase inhibitors) (4) Agents that mimic incretin effect or prolong incretin action (GLP1 receptor agonists, glucose dependent insulinotropic polypeptide [GIP]/GLP1 receptor agonists, dipeptidyl peptidase 4 [DPP4] inhibitors) (5) agents that inhibit the reabsorption of glucose in the kidney (sodium glucose co-transporter inhibitors [SGLTs]) (6) agents that act by other or ill-defined mechanisms (pramlintide, bromocriptine, colesevelam). 2024/10/04 DRUGS THAT PRIMARILY STIMULATE INSULIN RELEASE BY BINDING TO THE SULFONYLUREA RECEPTOR: A. SULFONYLUREAS ↑ insulin release from the pancreas Bind to sulfonylurea receptor that is associated with a beta cell inward rectifier ATP sensitive potassium channel Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of insulin Drug is metabolized by the liver and excreted via kidney Newer ones partly excreted via bile SULFONYLUREAS FIRST GENERATION SULFONYLUREAS Tolbutamide Rapidly metabolized in the liver Duration of effect is relatively short (6–10 hours) Half-life of 4–5 hours Short half-life and inactivation by the liver Relatively safe in the elderly and in patients with renal impairment 2024/10/04 SECOND GENERATION SULFONYLUREAS Glibencamide, glipizide, gliclazide, and glimepiride 100–200 times more potent than tolbutamide Adverse Effects: Hypoglycemia Weight gain Some sulfonamides (sulfisoxazole) and oral azole antifungal medications - inhibit tolbutamide metabolism →prolonged hypoglycemia. Glibencamide - occasionally cause flushing after ethanol ingestion B. MEGLITINIDE ANALOGS Repaglinide Binds and closes the ATP-dependent potassium channel on beta cells →insulin release Mechanism of action similar to sulfonylurea so concurrent use is contraindicated Peaks 1 hour, duration (4–7 hrs) Hepatic clearance by CYP3A4 2024/10/04 Due to rapid onset → indicated for use in controlling postprandial glucose excursions Should be taken just before each meal Risk of hypoglycemia if meal is delayed/skipped/contains inadequate carbohydrate Can be used in patients with renal impairment and in the elderly Monotherapy or as combination therapy C. D-PHENYLALANINE DERIVATIVE Nateglinide Stimulates insulin release from beta cells through closure of the ATP- sensitive K+ channel Absorption (20 minutes), peak concentration < 1 hr, metabolized in the liver by CYP2C9 and CYP3A4, half-life (1 hr) Overall duration of action about 4 hr Taken before the meal and reduces the postprandial rise in blood glucose Efficacious when given alone or in combination with non-secretagogue oral agents (such as metformin) Adverse effect: Hypoglycemia Can be used in patients with renal impairment and in the elderly. 2024/10/04 DRUGS THAT PRIMARILY LOWER GLUCOSE LEVELS BY THEIR ACTIONS ON THE LIVER, MUSCLE, & ADIPOSE TISSUE: A. BIGUANIDES Metformin ↓ hepatic glucose production and acts peripherally to ↑glucose uptake ↑hepatic adenosine monophosphate-activated protein kinase activity, which ↓hepatic gluconeogenesis and lipogenesis Half-life of 1.5–3 hrs Not bound to plasma proteins, not metabolized, and is excreted by the kidneys as the active compound As it does not ↑insulin release, rarely causes hypoglycaemia. Due to its blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid In patients with renal insufficiency, the biguanide accumulates and ↑the risk of lactic acidosis Appears to be a dose-related complication Safely used (eGFR) between 60 and 45 mL/min per 1.73 m2 Cautiously - eGFR between 45 and 30 mL/min per 1.73 m2 Contraindicated if the eGFR is less than 30 mL/min per 1.73 m2 Patients with decompensated liver failure should not take ↑ risk of lactic acidosis. 2024/10/04 METFORMIN: CLINICAL USES First-line drug for patients who are obese  cardiovascular mortality and improves longevity. Used in combination with non-insulin agents (oral and injectable) and insulin in patients with type 2 diabetes in whom monotherapy is inadequate Adverse effects: Most common: Gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), occurring in up to 20% of patients Dose-related, occurs mainly at onset, and are often transient Take with food or use of an extended release formulation can ameliorate the symptoms Interferes with absorption of vitamin B12 intrinsic factor complex in the terminal ileum, causing vitamin B12 deficiency after a number of years Periodic screening for vitamin B12 deficiency should be considered Rare- Lactic acidosis More likely: In conditions of tissue hypoxia when ↑production of lactic acid In renal failure when there is ↓ clearance of metformin (kidney, liver, or cardiorespiratory insufficiency; alcoholism) 2024/10/04 B. THIAZOLIDINEDIONES Bind to the peroxisome proliferator activated receptor gamma (PPARγ) PPAR receptors are found in muscle, fat, and liver PPARγ receptors modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, and adipocyte and other tissue differentiation ↑glucose transporter expression (GLUT 1 and GLUT 4)  insulin sensitivity,  hepatic glucose production, and  glucose uptake in the peripheral tissues. ↓ free fatty acid levels Clinical effect is to lower insulin requirements (improve insulin sensitivity) Rosiglitazone: Withdrawn in SA (2011) due to increased risk of CVS events (MI, stroke) Pioglitazone : Some PPAR-α as well as PPARγ activity Absorption ↓ with concomitant use of bile acid sequestrants Metabolized by CYP2C8 and CYP3A4 to active metabolites Pioglitazone ↓ levels of ethinyl estradiol estrogen, additional methods of contraception are advised Effective as monotherapy and combination therapy 2024/10/04 ADVERSE EFFECTS A meta-analysis RCTs with rosiglitazone suggested an ↑ risk of angina pectoris or myocardial infarction As a result, rosiglitazone was suspended in Europe and severely restricted in the United States. A subsequent large prospective clinical trial (the RECORD study) failed to confirm the metaanalysis findings. While the US lifted restrictions, rosiglitazone (Avandia) has been discontinued by the manufacturer. The drug remains unavailable in Europe and several other countries Fluid retention - 3–4% on thiazolidinedione monotherapy Occurs more frequently (10–15%) on concomitant insulin therapy Heart failure can occur Macular edema is a rare adverse effect Loss of bone mineral density and ↑atypical extremity bone fractures in women This is postulated to be due to decreased osteoblast formation Anemia Weight gain occurs, especially when used in combination with a sulfonylurea or insulin Not recommended for use in patients with active liver disease Liver function tests should be performed prior to initiation of treatment and periodically thereafter. 2024/10/04 DRUGS THAT AFFECT ABSORPTION OF GLUCOSE α-glucosidase inhibitors Competitively inhibit the intestinal α-glucosidase enzymes and reduce post-meal glucose excursions by delaying the digestion and absorption of starch and disaccharides Acarbose and miglitol Potent inhibitors of glucoamylase, α-amylase, and sucrase The drug is not metabolized and is cleared by the kidney. It should not be used in renal failure. ADVERSE EFFECTS Flatulence, diarrhea, and abdominal pain due to undigested carbohydrate in the colon that - fermented into short-chain fatty acids, releasing gas Adverse effects tend to diminish with ongoing use Chronic exposure to carbohydrate induces the expression of α- glucosidase in the jejunum and ileum, ↑distal small intestine glucose absorption and minimizing the passage of carbohydrate into the colon Hypoglycemia may occur with concurrent insulin secretagogue treatment Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown may be blocked An increase in hepatic aminotransferases has been noted in clinical trials 2024/10/04 DRUGS THAT MIMIC INCRETIN EFFECT OR PROLONG INCRETIN ACTION Oral glucose causes a release of gut hormones (“incretins”) GLP1 and glucose-dependent insulinotropic peptide (GIP), that amplify the glucose-induced insulin secretion Glucagon-like peptide 1 agonists (GLP-1 agonists): Activate GLP-1 β-cell receptors and increase insulin release. The GLP1 effect is glucose-dependent →insulin release is more when glucose levels are elevated Why? GLP1 has a lower risk for hypoglycemia than the sulfonylureas Other effects: It suppresses glucagon secretion, delays gastric emptying Patients with type 2 diabetes on GLP1 therapy are less hungry Unclear whether this is mainly related to the deceleration of gastric emptying or whether there is a CNS effect as well. Used in type 2 diabetes because - good glucose-lowering activity without causing hypoglycaemia and their ability to cause weight loss Subcutaneous injection May cause nausea and vomiting GIP, like GLP1, potentiates glucose-dependent insulin secretion. 2024/10/04 GLP1 - rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and by other enzymes such as endopeptidase and is also cleared by the kidney. The native peptide therefore cannot be used therapeutically. One approach to this problem was to develop metabolically stable analogs or derivatives of GLP1 Not subject to the same enzymatic degradation or renal clearance GLP1 receptor agonists—dulaglutide, exenatide (and exenatide XR), liraglutide, lixisenatide, and semaglutide The other approach was to develop inhibitors of DPP4 and prolong the action of endogenously released GLP1 and GIP. ADVERSE EFFECTS GLP1 receptor agonist: nausea, vomiting, and diarrhea More frequent at the higher doses All may risk of pancreatitis Patients on these drugs should be counseled to seek immediate medical care if they experience unexplained persistent severe abdominal pain Cases of renal impairment and acute renal injury reported with exenatide Both exenatide and liraglutide stimulate thyroidal C cell (parafollicular) tumors in rodents Should not be used in persons with a past medical or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome type 2. 2024/10/04 ORAL DIPEPTIDYL PEPTIDASE 4 INHIBITORS (DPP- 4 INHIBITORS) Vildagliptin, ologliptan, sitagliptin DPP4 inhibitors ↓ glucose levels by ↓ the inactivation of endogenous GLP-1 Given orally Less potent than GLP-1 agonists and do not cause weight loss Sitagliptin Dosage adjustment is recommended: Renal impairment Drug interactions with strong inhibitors or inducers of CYP3A4/5 such as ketoconazole, some anticonvulsants, rifampin, and rifabutin. ADVERSE EFFECTS Main adverse effect -predisposition to nasopharyngitis or upper respiratory tract infection Hypersensitivity reactions: anaphylaxis, angioedema, and Stevens Johnson syndrome The frequency of pancreatitis is unclear Rare cases of hepatic dysfunction, including hepatitis, reported with vildagliptin Liver fuction tests - recommended quarterly during the first year of use Saxagliptin may increase the risk of heart failure The FDA has issued a warning that the DPP4 inhibitors can occasionally cause joint pains 2024/10/04 SODIUM GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS Glucose is freely filtered by the renal glomeruli and is reabsorbed in the proximal tubules by sodium glucose transporters (SGLTs). Accounts for 90% of glucose reabsorption Inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes Canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin The SGLT2 inhibitors have also shown benefit in reducing the progression of albuminuria Efficacy is  in chronic kidney disease. Can also increase creatinine and decrease eGFR, especially in patients with kidney impairment Use is generally not recommended in patients with eGFR less than 45 mL/min/1.73 m2 (for glycemic control) Contraindicated in patients with eGFR less than 30 mL/min/1.73 m 2. 2024/10/04 ADVERSE EFFECTS Major adverse effects: ↑ incidence of genital mycotic infections and UTIs Reports -pyelonephritis and septicemia requiring hospitalization Cases of necrotizing fasciitis of the perineum (Fournier gangrene) reported Glycosuria can cause intravascular volume contraction and hypotension. Canagliflozin and empagliflozin caused a modest increase in LDL cholesterol levels (4–8%) In clinical trials -dapagliflozin had higher rates of breast cancer (nine cases vs none in comparator arms) and bladder cancer (nine cases vs one in placebo arm) Canagliflozin - reported to cause a ↓ in bone mineral density at the lumbar spine Cases of euglycemic diabetic ketoacidosis have been reported with off-label use of SGLT2 inhibitors in patients with type 1 diabetes Patients with type1 diabetes are taught to give less insulin if their glucose levels are not elevated. Because patients with type 1 taking an SGLT2 inhibitor may have normal glucose levels, they may either withhold or reduce their insulin doses to such a degree can induce ketoacidosis SGLT2 inhibitors should not be used in patients with type 1 diabetes and in those patients labelled as having type 2 diabetes but who are very insulin deficient and prone to ketosis. 2024/10/04 OTHER GLUCOSE LOWERING DRUGS Pramlintide: islet amyloid polypeptide (IAPP, amylin) analog IAPP is a peptide present in insulin secretory granules and secreted with insulin Physiologically acts as a negative feedback on insulin secretion At pharmacologic doses, IAPP ↓ glucagon secretion, slows gastric emptying by a vagally mediated mechanism, and centrally ↓ appetite. Approved for use in insulin treated type 1 and type 2 patients Major adverse effects: hypoglycemia and GIT symptoms, including nausea, vomiting, and anorexia. Since the drug slows gastric emptying, recovery from hypoglycemia can be problematic because of the delay in absorption of fast acting carbohydrates. Colesevelam hydrochloride: Bile acid sequestrant and cholesterol lowering drug Approved as an antihyperglycemic agent for patients with type 2 diabetes who are taking other glucose lowering medications or have not achieved adequate control with diet and exercise Mechanism of action - unknown but thought to involve an interruption of the enterohepatic circulation and a ↓ in farnesoid X receptor (FXR) activation FXR is a nuclear receptor with multiple effects on cholesterol, glucose, and bile acid metabolism. Bile acids are natural ligands of the FXR Additionally, the drug may impair glucose absorption Adverse effects: gastrointestinal (constipation, indigestion, flatulence) Can exacerbate the hypertriglyceridemia that commonly occurs in patients with type 2 diabetes. 2024/10/04 Bromocriptine Dopamine agonist In randomized placebo controlled studies lowered HbA1c by 0– 0.2% compared with baseline and by 0.4–0.5% compared with placebo. The mechanism by which it lowers glucose levels is not known Main adverse events: nausea, fatigue, dizziness, vomiting, and headache. Colesevelam and bromocriptine have very modest efficacy in lowering glucose levels, and their use in diabetes is questionable. MANAGEMENT OF A PATIENT WITH DIABETES 2024/10/04 MANAGEMENT OF THE PATIENT WITH DIABETES: DIET Well balanced, nutritious diet Individualized macronutrient proportions based on the patient’s eating patterns, preferences, and goals. Limiting carbohydrate intake and substituting some of the calories with monounsaturated fats, such as olive oil, rapeseed (canola) oil, or the oils in nuts and avocados, can lower triglycerides and increase HDL cholesterol. A Mediterranean style eating pattern (a diet supplemented with walnuts, almonds, hazelnuts, and olive oil) - shown to improve glycemic control and lower combined endpoints for cardiovascular events and stroke. Caloric restriction and weight loss are important goals for the obese patient with type 2 diabetes. EDUCATION Informed about the kind of diabetes Rationale for achieving target glucose levels Emphasis on glucose monitoring especially if the patient is on insulin or oral secretagogues that can cause hypoglycemia. Insulin therapy should understand the time action profile of the insulins Know how to determine if the basal insulin dose is correct and how to adjust the rapidly acting insulin dose for carbohydrate content of meals. Insulin adjustments for exercise and infections should be discussed. Should be informed about the signs and symptoms of hypoglycemia. 2024/10/04 Glycemic Targets The American Diabetes Association criteria for acceptable control HbA1c of less than 7% (53 mmol/mol) Pre-meal glucose levels of 90–130mg/dL (5–7.2 mmol/L), and peak postprandial glucose of less than 180 mg/dL (10 mmol/L) HbA1c goals may need to be modified for individuals treated with insulin or insulin secretagogues due to their  risk of hypoglycemia Less stringent glycemic control also for children as well as patients with a history of severe hypoglycemia, significant microvascular and macrovascular disease, other comorbidities (eg, coronary heart disease), and limited life expectancy For the elderly, frail patient an HbA1c close to 8% may be appropriate More stringent glycemic control is appropriate for adult patients with newly diagnosed diabetes, limited comorbidities, and a long life expectancy. TREATMENT Individualized based on the type of diabetes and specific needs A. Type 1 Diabetes Combination of rapid acting insulin analogs and long-acting insulin analogs allow for more physiologic insulin replacement A newly diagnosed patient may require minimal doses of basal and bolus insulins because they still have endogenous insulin production. In patients with longer duration of diabetes, the 24-hour basal insulin needs are usually based on age and body weight. 2024/10/04 B. Type 2 Diabetes Normalization of glucose levels can occur with weight loss and improved insulin sensitivity in the obese patient Combination of caloric restriction and ↑ exercise For selected patients, medical or surgical options should be considered. Orlistat, phentermine/topiramate, naltrexone plus extended release bupropion, high dose liraglutide, and semaglutide are approved weight loss medications for use in combination with diet and exercise Bariatric surgery (RouxenY, gastric banding, gastric sleeve, biliopancreatic diversion/duodenal switch) typically results in significant weight loss and can result in remission of the diabetes. Non obese patients with type 2 diabetes -increased visceral adiposity—the so called metabolically obese, normal weight patient There is less emphasis on weight loss in such patients, but exercise is important. Multiple medications may be required to achieve glycemic control Medical therapy should be initiated with intensive lifestyle interventions (diet and exercise), diabetes self-management education, and metformin. If glycemic targets are no longer achieved with metformin monotherapy, a second agent is added. Options include: Sulfonylureas, repaglinide or nateglinide, pioglitazone, GLP1receptor agonists, dual GIP/GLP1 receptor agonist, DPP4 inhibitors, SGLT2 inhibitors, and insulin Choice of second agent - consider efficacy, hypoglycemic risk, effect on weight, presence of cardiovascular disease or renal disease, adverse effects, and cost 2024/10/04 Sulfonylureas and insulins have increased risk of hypoglycemia. Sulfonylureas, insulin, and pioglitazone cause weight gain. Metformin and DPP4 inhibitors are weight neutral GLP1 and GIP/GLP1 receptor agonists cause weight loss SGLT2 inhibitors cause weight loss GLP1 receptor agonists, SGLT2 inhibitors, pioglitazone - cardiovascular benefits Major risk factors: Metformin - lactic acidosis Pioglitazone: Fracture risk, heart failure, and possible bladder cancer GLP1 receptor agonists: GI side effects and pancreatitis DPP4 inhibitors: Nasopharyngitis, joint pains, and allergic reactions SGLT2 inhibitors: Genital infection, urinary tract infections, and ketoacidosis Agents are expensive except for metformin and sulfonylureas In patients who experience hyperglycemia after a carbohydrate rich meal, a short-acting secretagogue before that meal may be enough to control the glucose levels. Patients with severe insulin resistance may be candidates for pioglitazone. Patients who are very concerned about weight gain may benefit from a trial of a GLP1, a GIP/GLP1 receptor agonist, or an SGLT2 inhibitor, which cause weight loss, or a DPP4 inhibitor, which is weight neutral. Presence of CVD - liraglutide, empagliflozin, and canagliflozin shown to have improved cardiovascular outcomes. The SGLT2 inhibitors should be considered as second choice in those patients with diabetic nephropathy or heart failure. If two agents are inadequate, a third agent is added, although data regarding efficacy of such combined therapy are limited. 2024/10/04 When combination of non-insulin agents (oral medications and injectable GLP1 or GIP/GLP1 receptor agonists) fail to adequately control glucose levels, insulin therapy should be added Night-time intermediate or long-acting insulin to medication regimen may lead to improved fasting glucose levels and adequate control during the day If daytime glucose levels are problematic, pre-mixed insulins before breakfast and dinner may help If such a regimen does not achieve adequate control or leads to unacceptable rates of hypoglycemia, a more intensive basal bolus insulin regimen (long-acting basal insulin) combined with rapid acting analog before meals can be instituted Metformin- shown to be effective when combined with insulin therapy and should be continued Pioglitazone can be used with insulin, but this combination is associated with more weight gain and peripheral and macular edema Cost, complexity, and risk for adverse events should be considered when deciding which drugs to continue once the patient starts on insulin therapy. 2024/10/04 ACUTE COMPLICATIONS OF DIABETES A. Hypoglycemia Most common complication of insulin therapy Oral agents that stimulate insulin secretion (e.g, sulfonylureas, meglitinide, D-phenylalanine analogs) Elderly, renal or liver disease Occurs more frequently with - long-acting sulfonylureas Signs of autonomic hyperactivity— Sympathetic (tachycardia, palpitations, sweating, tremulousness) and Parasympathetic (nausea, hunger)—and may progress to convulsions and coma if untreated. BETA BLOCKERS BB therapy in diabetics may lead to severe hypoglycemic episodes because it blunt the symptoms of hypoglycaemia. Worsen diabetes and dyslipidemia by inhibiting the release of insulin and increasing weight gain. A recent study has shown that in patients with hypertension, BBs can increase the risk of developing diabetes by 22% compared to other antihypertensives, except diuretics 2024/10/04 In patients exposed to frequent hypoglycemic episodes during tight glycemic control, autonomic warning signals of hypoglycemia are less common or even absent. This condition is termed hypoglycemic unawareness When patients lack the early warning signs of low blood glucose, they may not take corrective measures in time In patients with persistent, untreated hypoglycemia, the manifestations of insulin excess may develop—confusion, weakness, bizarre behavior, coma, seizures Hypoglycemic awareness may be restored by preventing frequent hypoglycemic episodes Identification bracelet, necklace, or card in the wallet or purse, as well as some form of rapidly absorbed glucose, should be carried by every diabetic person who is receiving hypoglycemic drug therapy. Hypoglycemia relieved by glucose administration To expedite absorption, simple sugar or glucose should be given, preferably in liquid form. Mild hypoglycemia in a patient who is conscious and able to swallow →dextrose tablets, glucose gel, or any sugar containing beverage or food may be given More severe hypoglycemia resulting in unconsciousness or stupor, the treatment of choice is 1 mg of glucagon injected either subcutaneously or intramuscularly or 3 mg of intranasal glucagon for adults May restore consciousness within 15 minutes to permit ingestion of sugar 2024/10/04 B. DIABETIC COMA 1. Diabetic ketoacidosis DKA) Life-threatening medical emergency caused by inadequate or absent insulin replacement Occurs in type 1 diabetes Infrequent in type 2 diabetes Rarely occurs with type 2 diabetes who have concurrent unusually stressful conditions such as sepsis or pancreatitis or are on high dose steroid therapy. SIGNS AND SYMPTOMS OF DIABETIC KETOACIDOSIS 2024/10/04 DKA more frequent in patients on insulin pumps Poor adherence—either for psychological reasons or because of inadequate education—is one of the most common causes of DKA, particularly when episodes are recurrent Cases of euglycemic diabetic ketoacidosis have been reported with the off-label use of SGLT2 inhibitors in patients with type 1 diabetes and in type 2 patients who are probably quite insulin deficient. Signs and symptoms: nausea, vomiting, abdominal pain, deep slow (Kussmaul) breathing, change in mental status (including coma), elevated blood and urinary ketones and glucose, an arterial blood pH lower than 7.3, and low bicarbonate (15 mmol/L). Treatment: aggressive intravenous hydration and insulin therapy and maintenance of potassium and other electrolyte levels. Fluid and insulin therapy - based on the patient’s individual needs and requires frequent re-evaluation and modification Constant evaluation of hydration and renal status, sodium and potassium levels, and the rate of correction of plasma glucose and plasma osmolality Fluid therapy generally begins with normal saline. Regular human insulin should be used for intravenous therapy with a usual starting dosage of about 0.1 U/kg/h. 2024/10/04 2. HYPEROSMOLAR HYPERGLYCEMIC SYNDROME (HHS) Type 2 diabetes characterized by profound hyperglycemia and dehydration Associated with inadequate oral hydration, especially in elderly patients; with other illnesses; with the use of medication that elevates the blood sugar or causes dehydration, such as phenytoin, steroids, diuretics, and calcium channel blockers; and with peritoneal dialysis and hemodialysis Diagnostic hallmarks: Declining mental status and even seizures, a plasma glucose >600 mg/dL, and a calculated serum osmolality >320 mmol/L Persons with HHS are not acidotic unless DKA is also present. Treatment of HHS: Aggressive rehydration and restoration of glucose and electrolyte homeostasis The rate of correction of these variables must be monitored closely Low dose insulin therapy may be required. 2024/10/04 CHRONIC COMPLICATIONS OF DIABETES Late clinical manifestations of diabetes mellitus include a number of pathologic changes that involve small and large blood vessels, cranial and peripheral nerves, the skin, and the eye Lesions lead to hypertension, end-stage chronic kidney disease, blindness, autonomic and peripheral neuropathy, amputations of the lower extremities, myocardial infarction, and cerebrovascular accidents. These late manifestations correlate with the duration of the diabetic state after the onset of puberty and glycemic control In type 1 diabetes, end stage chronic kidney disease develops in up to 40% of patients, compared with less than 20% of patients with type 2 diabetes Proliferative retinopathy ultimately develops in both types of diabetes but has a slightly higher prevalence in type 1 patients (25% after 15 years’ duration) https://www.endocrine.org/patient-engagement/endocrine-library/diabetes- complications 2024/10/04 In patients with type 1 diabetes, complications from end-stage chronic kidney disease are a major cause of death Patients with type 2 diabetes are more likely to have macrovascular diseases leading to myocardial infarction and stroke as the main causes of death Tobacco use adds significantly to the risk of both microvascular and macrovascular complications in patients with diabetes. 2024/10/04 CASE STUDY A 66-year-old obese Caucasian man presented to an academic Diabetes Center for advice regarding his diabetes treatment. His diabetes was diagnosed 10 years previously on routine testing. He was initially given metformin but when he was no longer achieving his glycemic targets, the metformin was stopped and insulin treatment initiated. The patient was taking 50 units of insulin glargine and an average of 25 units of insulin aspart pre-meals. He had never seen a diabetes educator or a dietitian. He was checking his glucose levels four times a day and smoking half a pack of cigarettes a day. On examination, his weight was 132 kg (BMI 39.5) and blood pressure 145/71, and signs of mild peripheral neuropathy were present. Laboratory tests noted an HbA1c value of 8.1% (normal

Use Quizgecko on...
Browser
Browser