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Pharmacotherapy of Diabetes Mellitus
The pancreas 2  The pancreas is composed of two major types of tissues; 1. Acini (80%), secrete digestive juices into the duodenum 2. Islets of Langerhans (2%), secrete insulin and glucagon directly into the blood. • These are crucial for normal regulation of glucose, lipid, and protein metabolism • Islets contain three major types of cells, alpha, beta, and delta cells  Pancreas also secretes other hormones with unknown functions [Amylin, somatostatin, and pancreatic polypeptide]
The pancreatic insulin • Produced in response to changes in blood glucose level. • It is a polypeptide containing 51 amino acids arranged in two chains (A and B) linked by disulphide bridge. 7
The pancreas…insulin vs. glucagon 4
• Hyperglycemia results in increased intracellular ATP levels closes the ATP-dependent K channels. • Decreased outward K current through this channel results in depolarization of the β cell and opening voltage–dependent Ca channels. • The resultant influx of Ca triggers the release of insulin The pancreatic insulin 5
Diabetes mellitus 6  Describes a group of chronic metabolic disorders characterized by hyperglycaemia that may result in long term microvascular complications. 🗸 These complications contribute to diabetes being the leading cause of 1. New cases of blindness among adults 2. End-stage renal disease 3. Non-traumatic lower limb amputations. • Macrovascular complications (coronary artery disease, peripheral vascular disease, and stroke)
Epidemiology 7 DM affects 🖙2012: About 29.1(9.3%) million persons in the US. 🖙Financial cost-approximately $245 billion 🖙Direct medical costs -$176 billion 🖙2.3 times higher in the absence of diabetes 🖙Indirect costs secondary to disability, work loss, and premature mortality- $69 billion. 🖙2010: About 3,000 lower extremity amputations
Etiologic classification 8
Pathogenesis: Type 1 DM 9  Loss of insulin secretion results from autoimmune destruction of the insulin-producing β-cells in the pancreas  Individuals may develop; 🗸 Islet cell antibodies (most common) 🗸 More β cells destroyed, compromised glucose metabolism 🖙Reduced insulin release after a glucose load.  About 80% to 95% loss of β-cell function at diagnosis
Pathogenesis…increased diabetic risks 10
Pathogenesis: type 2 diabetes 11  A combination of insulin deficiency, insulin resistance, and other hormonal irregularities, primarily involving glucagon.  Obesity: Visceral fat leads to the release of Bioactive peptides (adipokines), inflammatory mediators, and free fatty acids • Contribute to inflammation, insulin resistance, elevations in blood pressure, dyslipidemia (decreased HDL level, and increased TG and LDL levels), impaired thrombolysis, and further increases in body weight • Contribute to cardio-metabolic risk and cardiovascular disease among patients with type 2 diabetes
Pathogenesis: type 2 diabetes 12  Individuals are characterized by multiple defects: 1. Defects in insulin secretion 2. Insulin resistance involving muscle, liver, and adipocyte 3. Excess glucagon secretion 4. Glucagon-like peptide-1 (GLP-1) deficiency and possibly resistance GLP-1 • Insulinotropic action is glucose dependent Glucose concentrations must be >90 mg/dl to enhance insulin secretion • Suppresses glucagon secretion, slows gastric emptying, and reduces food intake by increasing satiety
Pathogenesis …type 2 diabetes 13  Failure of insulin to normalize plasma glucose, dysglycemia, including prediabetes and diabetes, can ensue  Both β-cell mass and function in the pancreas are reduced.  People will lose ~5% to 7% of β-cell function per year of diabetes.  The reasons • Glucose toxicity • Lipotoxicity • Insulin resistance • Age • Genetics • Incretin deficiency.
Pathogenesis: type 2 diabetes 14  The exact pathogenesis of type 2 is the least understood  Hyperglycemia: due to Glucose utilization by tissues is impaired, hepatic glucose production is increased, and excess glucose accumulates in the circulation Pancreas to produce more insulin in an attempt to overcome insulin resistance Genetic predisposition may play a role • People with type 2 diabetes have a stronger family history of diabetes than those with type 1
Pathogenesis: type 2 diabetes 15  Over time, β-cells lose their ability to respond to elevated glucose concentrations ⚫Leading to increasing loss of glucose control ⚫In patients with severe hyperglycemia, the amount of insulin secreted in response to glucose is diminished and insulin resistance is worsened (glucose toxicity)  Hyperinsulinemia over time leads to down regulation of insulin receptor
Pathogenesis: type 2 diabetes Risk predictor for type 2 DM 16
Classical clinical presentation 17
ADA diagnostic criteria 18
Treatment: General 19  Glycemic control is fundamental to the diabetes management!!!  Goals of Therapy ⚫Short-term Goals Establish and maintain optimum glycemic control No severe or nocturnal hypoglycemia episodes Control symptoms of polydipsia, polyphagia, and polyuria Keeping patients free of urine ketones Achieve optimal control of co-morbidities [hypertension and dyslipidemia]
Treatment… 20 Long-term goals of therapy: Reduce risk for microvascular 🗸 Retinopathy, neuropathy, and nephropathy and Macro vascular complications 🗸 Coronary heart disease, stroke, and peripheral vascular disease Reduce mortality
Pharmacotherapy of DM 3 1 Glycaemic goals Bed time
Non-pharmacologic therapy: 22  Diet: Medical nutrition therapy o Is recommended for all persons with DM and along with activity, is a cornerstone of treatment o Type 1 DM, the focus is on regulating insulin administration with a balanced diet to achieve and maintain a healthy body weight o Type 2 DM often require caloric restriction to promote weight loss, and portion size and frequency are often issues
Non-pharmacologic therapy: 23  Physical activity: o Most patients with DM can benefit from increased activity o Aerobic exercise improves insulin sensitivity and glycemic control in the majority of individuals, and reduces cardiovascular risk factors, contributes to weight loss or maintenance, and improves well-being o Physical activity goals include at least 150 minutes/week of moderate (50%–70% maximal heart rate) intensity exercise
Pharmacologic: type 1DM: Insulin  Pharmacology: stimulates peripheral glucose uptake and inhibits hepatic glucose production  Dosage guidelines: ⚫Insulin is normally injected subcutaneously (SC) ⚫Only regular insulin may be injected intravenously (IV) ⚫The number and size of daily doses, time of administration, and diet and exercise require continuous medical supervision ⚫Insulin is prepared as a 100 Units/mL solution (or suspension) in a 10 mL vial Pramlintide 34
Pharmacologic: type 1DM : Insulin 35 Pramlintide • Approximately 50% of total daily insulin replacement should be basal insulin • The other 50% will be bolus insulin, divided into doses before meals. • Patients may be begun on ≈0.6unit/kg/day with basal insulin and prandial insulin 20% of total dose pre-breakfast, 15% pre- lunch, and 15% pre-supper. • Type 1 DM patients generally require between 0.5 and 1 unit/kg/day. ⚫For those patients who insist on only two injections daily, intermediate-acting insulin and a rapid-acting insulin or regular insulin
Pharmacologic: type 1DM : Insulin • All patients should have extensive education in the recognition and treatment of hypoglycemia. 37 • Many patients experiencing hypoglycemia are tempted to over-treat episodes of hypoglycemia resulting in rebound hyperglycemia afterwards
Pharmacologic: insulin…..Hypoglycemia 27  Treatment: follow the “rule of 15.” • If BG <70 mg/dL • Ingestion of glucose- or carbohydrate containing foods • Consume 15 g of simple carbohydrate (~250 mL orange juice or four glucose tablets)  Retest BG 15 minutes later. • If BG is still <70 mg/dL  May repeat the rule of 15 until BG has normalized.  BG normalized :counsel to eat a meal or snack to prevent recurrent hypoglycaemia  Glucagon : in people unable or unwilling to consume carbohydrates by mouth
Pharmacologic: insulin…..Hypoglycemia 28  Treatment: follow the “rule of 15.”  Glucagon 1mg IM  May take up to 15 minutes to take effect, to mobilise glycogen from the liver  Less effective in  Chronically malnourished (e.g. Alcoholics)  Prolonged period of starvation  Patients prescribed sulphonylurea therapy  Depleted glycogen stores  Severe liver disease and recurrent hypoglycaemia
Insulin action times 4 0 Type of Insulin Onset (Hours) Peak (Hours) Duration (Hours) Maximum Duration (Hours) Appearance Rapid acting Aspart 15–30 min 1–2 3–5 5–6 Clear Lispro 15–30 min 1–2 3–4 4–6 Clear Glulisine 15–30 min 1–2 3–4 5–6 Clear Short-acting Regular 0.5–1.0 2–3 4–6 6–8 Clear Intermediate acting NPH 2–4 4–8 8–12 14–18 Cloudy Long acting Detemir 2 hours — 14–24 24 Clear Glargine 4–5 — 22–24 24 Clear
Acute complications: DKA  Due to: Severe insulin deficiency Excess counter regulatory hormones o Glucagon o Epinephrine o Cortisol o Growth hormone 41
• DKA is a true medical emergency. • In patients with type 1 DM, ketoacidosis is usually precipitated by the patient omitting insulin, or acute illness. • Infection is a common cause of DKA. • Patients with DKA may be alert, stuporous, or comatose at presentation. • The hallmark diagnostic laboratory values for DKA include hyperglycemia, acidosis, and large ketonemia or ketonuria.
DKA precipitating factors 32 1. Failure to take insulin 2. Failure to increase insulin ⚫Illness/Infection • Pneumonia • MI • Stroke ⚫Acute stress • Trauma • Emotional 3. Medical Stress ⚫Counter regulatory hormones • Oppose insulin • Stimulate glucagon release 4. Hypovolmemia ⚫Increases glucagon and catecholamine • Decreased renal blood flow • Decreases glucagon degradation by the kidney
Signs and symptoms of DKA  Polyuria, polydipsia ⚫Enuresis  Dehydration ⚫Tachycardia ⚫Orthostatic  Abdominal pain ⚫Nausea ⚫Vomiting  Fruity breath ⚫Acetone  Kussmaul breathing • Air hunger  Mental status changes ⚫Combative ⚫Drunk ⚫Coma 33
Lab findings  Hyperglycemia  Anion gap acidosis ⚫ (Na + K) – (Cl + HCO- 3) >12 ⚫Bicarbonate <15 mEq/L ⚫pH <7.3  Urine ketones and serum ketones  Hyperosmolarity o Much solute 34
Treatment…DKA 35 Metabolic treatment targets • Reduce blood ketone concentration by 0.5mmol/L/hr. and supress ketogenesis. • Increase venous bicarbonate by 3.0mmol/L/hr. • Reduce capillary blood glucose by 3.0mmol/L/hr. • Maintain serum potassium between 4.0 and 5.5mmol/L Joint British diabetes societies-2013
Treatment… fluids and electrolytes 36  Fluid replacement ⚫Restores perfusion of the tissues • Lowers counter regulatory hormones ⚫Average fluid deficit 3-5 liters  Initial resuscitation ⚫1-2 liters of 0.9% normal saline over the first 2 hours ⚫Slower rates of 500ml/hr. x 4 hr. or • 250 ml/hr. x 4 hours, when fluid overload is a concern  If hypernatremia develops ½ NS can be used
Treatment…fluids and electrolytes 37  Hyperkalemia initially present ⚫Resolves quickly with insulin drip  Phosphate deficit ⚫May want to use Kphos  Bicarbonate not given unless pH <7 or bicarbonate <5 mmol/L
Treatment…insulin therapy 38  IV bolus of 0.1-0.2 units/kg (~ 10 units) regular insulin  Follow with hourly regular insulin infusion  Glucose levels ⚫Decrease 75-100 mg/dl hour ⚫Minimize rapid fluid shifts  Continue IV insulin until urine is free of ketones
Treatment…glucose administration 39 Supplemental glucose ⚫Hypoglycemia occurs Insulin has restored glucose uptake Suppressed glucagon ⚫Prevents rapid decline in plasma osmolality Rapid increase in insulin could lead to cerebral edema ⚫Start glucose when plasma glucose <250 mg/dl Glucose decreases
DKA/HHS management …Ethiopian STG 2021 40
Prevention of DKA…sick day rules  Never omit insulin ⚫ Cut long acting in half  Prevent dehydration and hypoglycemia  Monitor blood sugars frequently  Monitor for ketosis  Provide supplemental fast acting insulin  Treat underlying triggers  Maintain contact with medical team 56
Pharmacotherapy: for DM2 · Consider initiating combination insulin injectable therapy when 1. Blood glucose >300 mg/dL or 2. A1C >10% (86 mmol/mol) or 3. If the patient has symptoms of hyperglycaemia (i.e., polyuria or polydipsia). · As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified. 42
Pharmacology: Biguanides Metformin • Enhances insulin sensitivity of mainly hepatic but also peripheral (muscle) tissues. Allows for an increased uptake of glucose into these insulin-sensitive tissues. • Has no direct effect on the β cells, although insulin levels are reduced, reflecting increases in insulin sensitivity. • Logical in overweight/obese patients, if tolerated and not contraindicated, as it is the only oral anti-hyperglycemic medication potentially proven to reduce the risk of total mortality 43
Pharmacology…pharmacokinetics • Approximately 50% to 60% oral bioavailability, low lipid solubility, and a volume of distribution that approximates body water. • It is not metabolized and does not bind to plasma proteins. • Eliminated by renal tubular secretion and glomerular filtration. • The average plasma half-life of metformin is 6 hours, although pharmacodynamically, metformin’s anti- hyperglycemic effects last more than 24 hours. 44
Pharmacology…efficacy • Consistently reduces HbA1c levels by 1.5% to 2% and FPG levels by 60 to 80 mg/dL in drug-naïve patients, and • Retains the ability to reduce FPG levels when they are extremely high (>300 mg/dL). • Also has positive effects on several components of the insulin resistance syndrome. It decreases plasma TGs and LDL-C by approximately 8% to 15%, in addition to increasing HDL-C very modestly (2%). • Metformin causes a modest reduction in weight (2 to 3 kg). 45
Pharmacology…efficacy Microvascular Complications • Found to reduce microvascular complications Macrovascular Complications • Reduced macrovascular complications in obese subjects. • It significantly reduced all-cause mortality and risk of stroke • Has also reduced diabetes-related death 46
Pharmacology…adverse effects • Metformin causes GI side effects, including abdominal discomfort, stomach upset, and/or diarrhea, in approximately 30% of patients. • Anorexia and stomach fullness is likely part of the reason loss of weight is noted with metformin. • These side effects are usually mild and can be minimized by slow titration. • GI side effects also tend to be transient, lessening in severity over several weeks. • If encountered, make sure patients are taking metformin with or right after meals, and reduce the dose to a point at which no GI side effects are encountered. • Increases in the dose may be tried again in several weeks. • Anecdotally, extended-release metformin (Glucophage XR) may lessen some of the GI side effects. 47
Pharmacology…adverse effects • Metallic taste, interference with vitamin B12 absorption, and hypoglycemia during intense exercise have been documented, but are clinically uncommon. • Metformin therapy rarely (3 to 9 cases per 100,000 patient-years) causes lactic acidosis. 48
Pharmacology…adverse effects • Eidence has reported that metformin may be fairly safe in moderate renal insufficiency. • Metformin use can be modified based on the estimated glomerular filtration rate, <60 mL/min/1.73 m2 : monitor renal function every 3 to 6 months <45 to ≥30 mL/min/1.73 m2: limit dose to 50% of maximal dose <30 mL/min/1.73 m2: stop metformin 49
Dosing and administration • Immediate-release metformin 500 mg twice a day with the largest meals to minimize GI side effects. May be increased by 500 mg as tolerated until glycemic goals or 2,500 mg/day is achieved • Metformin 850 mg May be dosed daily, and then increased every 1 to 2 weeks to the maximum dose of 850 mg three times a day (2,550 mg/day). • Approximately 80% of the glycemic-lowering effect may be seen at 1,500 mg, and 2,000 mg/day is the maximal effective dose. 50
Dosing and administration • Extended-release metformin Can be initiated at 500 mg a day with the evening meal and titrated by 500 mg as tolerated to a single evening dose of 2,000 mg/day. • Extended-release metformin 750-mg tablets May be titrated as tolerated to the maximum dose of 2,250 mg/day, although, 1,500 mg/day provides the majority of the glycemic-lowering effect. Twice-daily to three-times-a day dosing of extended- release metformin may help to minimize GI side effects and improve glycemic control, 51
Biguanides….summary 52
Pharmacology…sulfonylureas • MOA: enhancement of insulin secretion. • Bind to a specific sulfonylurea receptor (SUR) on pancreatic β cells. • Elevated secretion of insulin from the pancreas travels via the portal vein and subsequently suppresses hepatic glucose production • First-generation: acetohexamide, chlorpropamide, tolazamide, and tolbutamide. • Each of these agents is lower in potency relative to the second-generation drugs: glimepiride, glipizide, and glyburide • All sulfonylureas are equally effective at lowering BG when administered in equipotent doses 53
Pharmacology…pharmacokinetics • All are metabolized in the liver, some to active and others to inactive metabolites. • Glyburide metabolites are active, whereas glipizide and glimepiride do not have active metabolites. • Cytochrome P450 (CYP450) 2C9 is involved with the hepatic metabolism of the majority of sulfonylureas. • Agents with active metabolites or parent drug that are renally excreted require dosage adjustment or use with caution in patients with compromised renal function. 54
Pharmacology…efficacy HbA1c • Will fall 1.5% to 2% in drug-naïve patients, • FPG reductions of 60 to 70 mg/dL • But dependent on baseline values and duration of diabetes. • A majority of patients will not reach glycemic goals with sulfonylurea monotherapy. 55
Pharmacology…efficacy Microvascular Complications • A reduction of microvascular complications in type 2 DM patients. Macrovascular Complications • Reported no significant benefit or harm in newly diagnosed type 2 DM patients given over 10 years. 56
Adverse effects • The most common side effect of sulfonylureas is hypoglycemia. • Pre-treatment FPG is a strong predictor. The lower the FPG is on initiation, the higher the potential for hypoglycemia. • The following are also more likely to experience hypoglycemia Who skip meals, exercise vigorously, or lose substantial amounts of weight • Hyponatremia (serum sodium <129 mEq/L) • Associated with tolbutamide, but it is most common with chlorpropamide (5%) . Is due to increase in antidiuretic hormone secretion Risk factors include age >60 years, female gender, and concomitant use of thiazide diuretics 57
Adverse effects • Weight gain is common with sulfonylureas. • In essence, patients who are no longer glycosuric and who do not reduce caloric intake with improvement of BG will store excess calories. • Other notable, although much less common, adverse effects are skin rash, hemolytic anemia, GI upset, and cholestasis. • Disulfiram-type reactions and flushing have been reported with tolbutamide and chlorpropamide when alcohol is consumed 58
Dosing and administration • Lower dosages are recommended for most agents in elderly patients and those with compromised renal or hepatic function. • The dosage can be titrated as soon as every 2 weeks based on FPG values (use a longer interval with chlorpropamide) to achieve glycemic goals. • This is possible due to the rapid increase of insulin secretion in response to the sulfonylurea. • The maximal effective dose of sulfonylureas tends to be about 60% to 75% of their stated maximum dose 59
Sulfonylureas….summary 60
Macrovascular Disease: management · Blood pressure control, lipid management, and aspirin therapy  Will reduce risk of coronary heart disease, stroke, and peripheral vascular disease · Blood pressure control:  Goal: blood pressure <140/80 mmHg (if renal disease <130/80 mmHg)  Medical nutritional therapy  ACE inhibitors or angiotensin receptor blockers (ARBs) are first line agents in patients with hypertension and diabetes  Diuretics, Hydrochlorothiazide are synergistic combo 61
Macrovascular Disease: management · Lipid management:  Goal: LDL <100 mg/dL (optional goal for high-risk patients: <70 mg/dL); total cholesterol <200 mg/dL; HDL >40 mg/dL; triglycerides <150 mg/dL.  Medical nutritional therapy: follow dietary recommendations  HMG-CoA reductase inhibitors (statins) if LDL >130 mg/dL; Fibrates if triglycerides >500 mg/dL • Over the age of 40 with a total cholesterol ≥135mg/dL, statin therapy to achieve an LDL reduction of ~30% regardless of baseline LDL 62
Macrovascular Disease: management …goals 63
Micro vascular disease: Management · Prevention and recognition of retinopathy, neuropathy and foot care, and nephropathy  Periodically evaluate after a baseline assessment  Optimize glucose and blood pressure control to reduce the risk and/or slow the progression of nephropathy  Neuropathy is most common complaint and need to be managed pharmacologically and non- pharmacologically based on severity  Nephropathy is a progressive kidney disease that takes several years to develop 64
Reading assignment Read on 1. Other oral hypoglycaemic agents 2. Insulin injection site rotation 65
Quiz 1. What is basal and bolus insulin 2. Write steps of DKA management 3. What are prevention mechanism of DKA 4. Write types of micro & macro vascular complication 5. Metformin reduce the risk of total mortality T/F. 66

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Diabetes Mellitusxdcfgvcfgvh fgh hj.pptx

  • 1.
  • 2.
    The pancreas 2  Thepancreas is composed of two major types of tissues; 1. Acini (80%), secrete digestive juices into the duodenum 2. Islets of Langerhans (2%), secrete insulin and glucagon directly into the blood. • These are crucial for normal regulation of glucose, lipid, and protein metabolism • Islets contain three major types of cells, alpha, beta, and delta cells  Pancreas also secretes other hormones with unknown functions [Amylin, somatostatin, and pancreatic polypeptide]
  • 3.
    The pancreatic insulin •Produced in response to changes in blood glucose level. • It is a polypeptide containing 51 amino acids arranged in two chains (A and B) linked by disulphide bridge. 7
  • 4.
  • 5.
    • Hyperglycemia resultsin increased intracellular ATP levels closes the ATP-dependent K channels. • Decreased outward K current through this channel results in depolarization of the β cell and opening voltage–dependent Ca channels. • The resultant influx of Ca triggers the release of insulin The pancreatic insulin 5
  • 6.
    Diabetes mellitus 6  Describesa group of chronic metabolic disorders characterized by hyperglycaemia that may result in long term microvascular complications. 🗸 These complications contribute to diabetes being the leading cause of 1. New cases of blindness among adults 2. End-stage renal disease 3. Non-traumatic lower limb amputations. • Macrovascular complications (coronary artery disease, peripheral vascular disease, and stroke)
  • 7.
    Epidemiology 7 DM affects 🖙2012: About29.1(9.3%) million persons in the US. 🖙Financial cost-approximately $245 billion 🖙Direct medical costs -$176 billion 🖙2.3 times higher in the absence of diabetes 🖙Indirect costs secondary to disability, work loss, and premature mortality- $69 billion. 🖙2010: About 3,000 lower extremity amputations
  • 8.
  • 9.
    Pathogenesis: Type 1DM 9  Loss of insulin secretion results from autoimmune destruction of the insulin-producing β-cells in the pancreas  Individuals may develop; 🗸 Islet cell antibodies (most common) 🗸 More β cells destroyed, compromised glucose metabolism 🖙Reduced insulin release after a glucose load.  About 80% to 95% loss of β-cell function at diagnosis
  • 10.
  • 11.
    Pathogenesis: type 2diabetes 11  A combination of insulin deficiency, insulin resistance, and other hormonal irregularities, primarily involving glucagon.  Obesity: Visceral fat leads to the release of Bioactive peptides (adipokines), inflammatory mediators, and free fatty acids • Contribute to inflammation, insulin resistance, elevations in blood pressure, dyslipidemia (decreased HDL level, and increased TG and LDL levels), impaired thrombolysis, and further increases in body weight • Contribute to cardio-metabolic risk and cardiovascular disease among patients with type 2 diabetes
  • 12.
    Pathogenesis: type 2diabetes 12  Individuals are characterized by multiple defects: 1. Defects in insulin secretion 2. Insulin resistance involving muscle, liver, and adipocyte 3. Excess glucagon secretion 4. Glucagon-like peptide-1 (GLP-1) deficiency and possibly resistance GLP-1 • Insulinotropic action is glucose dependent Glucose concentrations must be >90 mg/dl to enhance insulin secretion • Suppresses glucagon secretion, slows gastric emptying, and reduces food intake by increasing satiety
  • 13.
    Pathogenesis …type 2diabetes 13  Failure of insulin to normalize plasma glucose, dysglycemia, including prediabetes and diabetes, can ensue  Both β-cell mass and function in the pancreas are reduced.  People will lose ~5% to 7% of β-cell function per year of diabetes.  The reasons • Glucose toxicity • Lipotoxicity • Insulin resistance • Age • Genetics • Incretin deficiency.
  • 14.
    Pathogenesis: type 2diabetes 14  The exact pathogenesis of type 2 is the least understood  Hyperglycemia: due to Glucose utilization by tissues is impaired, hepatic glucose production is increased, and excess glucose accumulates in the circulation Pancreas to produce more insulin in an attempt to overcome insulin resistance Genetic predisposition may play a role • People with type 2 diabetes have a stronger family history of diabetes than those with type 1
  • 15.
    Pathogenesis: type 2diabetes 15  Over time, β-cells lose their ability to respond to elevated glucose concentrations ⚫Leading to increasing loss of glucose control ⚫In patients with severe hyperglycemia, the amount of insulin secreted in response to glucose is diminished and insulin resistance is worsened (glucose toxicity)  Hyperinsulinemia over time leads to down regulation of insulin receptor
  • 16.
    Pathogenesis: type 2diabetes Risk predictor for type 2 DM 16
  • 17.
  • 18.
  • 19.
    Treatment: General 19  Glycemiccontrol is fundamental to the diabetes management!!!  Goals of Therapy ⚫Short-term Goals Establish and maintain optimum glycemic control No severe or nocturnal hypoglycemia episodes Control symptoms of polydipsia, polyphagia, and polyuria Keeping patients free of urine ketones Achieve optimal control of co-morbidities [hypertension and dyslipidemia]
  • 20.
    Treatment… 20 Long-term goals oftherapy: Reduce risk for microvascular 🗸 Retinopathy, neuropathy, and nephropathy and Macro vascular complications 🗸 Coronary heart disease, stroke, and peripheral vascular disease Reduce mortality
  • 21.
  • 22.
    Non-pharmacologic therapy: 22  Diet:Medical nutrition therapy o Is recommended for all persons with DM and along with activity, is a cornerstone of treatment o Type 1 DM, the focus is on regulating insulin administration with a balanced diet to achieve and maintain a healthy body weight o Type 2 DM often require caloric restriction to promote weight loss, and portion size and frequency are often issues
  • 23.
    Non-pharmacologic therapy: 23  Physicalactivity: o Most patients with DM can benefit from increased activity o Aerobic exercise improves insulin sensitivity and glycemic control in the majority of individuals, and reduces cardiovascular risk factors, contributes to weight loss or maintenance, and improves well-being o Physical activity goals include at least 150 minutes/week of moderate (50%–70% maximal heart rate) intensity exercise
  • 24.
    Pharmacologic: type 1DM:Insulin  Pharmacology: stimulates peripheral glucose uptake and inhibits hepatic glucose production  Dosage guidelines: ⚫Insulin is normally injected subcutaneously (SC) ⚫Only regular insulin may be injected intravenously (IV) ⚫The number and size of daily doses, time of administration, and diet and exercise require continuous medical supervision ⚫Insulin is prepared as a 100 Units/mL solution (or suspension) in a 10 mL vial Pramlintide 34
  • 25.
    Pharmacologic: type 1DM: Insulin 35 Pramlintide • Approximately 50% of total daily insulin replacement should be basal insulin • The other 50% will be bolus insulin, divided into doses before meals. • Patients may be begun on ≈0.6unit/kg/day with basal insulin and prandial insulin 20% of total dose pre-breakfast, 15% pre- lunch, and 15% pre-supper. • Type 1 DM patients generally require between 0.5 and 1 unit/kg/day. ⚫For those patients who insist on only two injections daily, intermediate-acting insulin and a rapid-acting insulin or regular insulin
  • 26.
    Pharmacologic: type 1DM: Insulin • All patients should have extensive education in the recognition and treatment of hypoglycemia. 37 • Many patients experiencing hypoglycemia are tempted to over-treat episodes of hypoglycemia resulting in rebound hyperglycemia afterwards
  • 27.
    Pharmacologic: insulin…..Hypoglycemia 27  Treatment:follow the “rule of 15.” • If BG <70 mg/dL • Ingestion of glucose- or carbohydrate containing foods • Consume 15 g of simple carbohydrate (~250 mL orange juice or four glucose tablets)  Retest BG 15 minutes later. • If BG is still <70 mg/dL  May repeat the rule of 15 until BG has normalized.  BG normalized :counsel to eat a meal or snack to prevent recurrent hypoglycaemia  Glucagon : in people unable or unwilling to consume carbohydrates by mouth
  • 28.
    Pharmacologic: insulin…..Hypoglycemia 28  Treatment:follow the “rule of 15.”  Glucagon 1mg IM  May take up to 15 minutes to take effect, to mobilise glycogen from the liver  Less effective in  Chronically malnourished (e.g. Alcoholics)  Prolonged period of starvation  Patients prescribed sulphonylurea therapy  Depleted glycogen stores  Severe liver disease and recurrent hypoglycaemia
  • 29.
    Insulin action times 4 0 Type of Insulin Onset (Hours) Peak (Hours) Duration (Hours) Maximum Duration (Hours) Appearance Rapidacting Aspart 15–30 min 1–2 3–5 5–6 Clear Lispro 15–30 min 1–2 3–4 4–6 Clear Glulisine 15–30 min 1–2 3–4 5–6 Clear Short-acting Regular 0.5–1.0 2–3 4–6 6–8 Clear Intermediate acting NPH 2–4 4–8 8–12 14–18 Cloudy Long acting Detemir 2 hours — 14–24 24 Clear Glargine 4–5 — 22–24 24 Clear
  • 30.
    Acute complications: DKA Due to: Severe insulin deficiency Excess counter regulatory hormones o Glucagon o Epinephrine o Cortisol o Growth hormone 41
  • 31.
    • DKA isa true medical emergency. • In patients with type 1 DM, ketoacidosis is usually precipitated by the patient omitting insulin, or acute illness. • Infection is a common cause of DKA. • Patients with DKA may be alert, stuporous, or comatose at presentation. • The hallmark diagnostic laboratory values for DKA include hyperglycemia, acidosis, and large ketonemia or ketonuria.
  • 32.
    DKA precipitating factors 32 1.Failure to take insulin 2. Failure to increase insulin ⚫Illness/Infection • Pneumonia • MI • Stroke ⚫Acute stress • Trauma • Emotional 3. Medical Stress ⚫Counter regulatory hormones • Oppose insulin • Stimulate glucagon release 4. Hypovolmemia ⚫Increases glucagon and catecholamine • Decreased renal blood flow • Decreases glucagon degradation by the kidney
  • 33.
    Signs and symptomsof DKA  Polyuria, polydipsia ⚫Enuresis  Dehydration ⚫Tachycardia ⚫Orthostatic  Abdominal pain ⚫Nausea ⚫Vomiting  Fruity breath ⚫Acetone  Kussmaul breathing • Air hunger  Mental status changes ⚫Combative ⚫Drunk ⚫Coma 33
  • 34.
    Lab findings  Hyperglycemia Anion gap acidosis ⚫ (Na + K) – (Cl + HCO- 3) >12 ⚫Bicarbonate <15 mEq/L ⚫pH <7.3  Urine ketones and serum ketones  Hyperosmolarity o Much solute 34
  • 35.
    Treatment…DKA 35 Metabolic treatment targets •Reduce blood ketone concentration by 0.5mmol/L/hr. and supress ketogenesis. • Increase venous bicarbonate by 3.0mmol/L/hr. • Reduce capillary blood glucose by 3.0mmol/L/hr. • Maintain serum potassium between 4.0 and 5.5mmol/L Joint British diabetes societies-2013
  • 36.
    Treatment… fluids andelectrolytes 36  Fluid replacement ⚫Restores perfusion of the tissues • Lowers counter regulatory hormones ⚫Average fluid deficit 3-5 liters  Initial resuscitation ⚫1-2 liters of 0.9% normal saline over the first 2 hours ⚫Slower rates of 500ml/hr. x 4 hr. or • 250 ml/hr. x 4 hours, when fluid overload is a concern  If hypernatremia develops ½ NS can be used
  • 37.
    Treatment…fluids and electrolytes 37 Hyperkalemia initially present ⚫Resolves quickly with insulin drip  Phosphate deficit ⚫May want to use Kphos  Bicarbonate not given unless pH <7 or bicarbonate <5 mmol/L
  • 38.
    Treatment…insulin therapy 38  IVbolus of 0.1-0.2 units/kg (~ 10 units) regular insulin  Follow with hourly regular insulin infusion  Glucose levels ⚫Decrease 75-100 mg/dl hour ⚫Minimize rapid fluid shifts  Continue IV insulin until urine is free of ketones
  • 39.
    Treatment…glucose administration 39 Supplemental glucose ⚫Hypoglycemiaoccurs Insulin has restored glucose uptake Suppressed glucagon ⚫Prevents rapid decline in plasma osmolality Rapid increase in insulin could lead to cerebral edema ⚫Start glucose when plasma glucose <250 mg/dl Glucose decreases
  • 40.
  • 41.
    Prevention of DKA…sickday rules  Never omit insulin ⚫ Cut long acting in half  Prevent dehydration and hypoglycemia  Monitor blood sugars frequently  Monitor for ketosis  Provide supplemental fast acting insulin  Treat underlying triggers  Maintain contact with medical team 56
  • 42.
    Pharmacotherapy: for DM2 ·Consider initiating combination insulin injectable therapy when 1. Blood glucose >300 mg/dL or 2. A1C >10% (86 mmol/mol) or 3. If the patient has symptoms of hyperglycaemia (i.e., polyuria or polydipsia). · As the patient’s glucose toxicity resolves, the regimen may, potentially, be simplified. 42
  • 43.
    Pharmacology: Biguanides Metformin • Enhancesinsulin sensitivity of mainly hepatic but also peripheral (muscle) tissues. Allows for an increased uptake of glucose into these insulin-sensitive tissues. • Has no direct effect on the β cells, although insulin levels are reduced, reflecting increases in insulin sensitivity. • Logical in overweight/obese patients, if tolerated and not contraindicated, as it is the only oral anti-hyperglycemic medication potentially proven to reduce the risk of total mortality 43
  • 44.
    Pharmacology…pharmacokinetics • Approximately 50%to 60% oral bioavailability, low lipid solubility, and a volume of distribution that approximates body water. • It is not metabolized and does not bind to plasma proteins. • Eliminated by renal tubular secretion and glomerular filtration. • The average plasma half-life of metformin is 6 hours, although pharmacodynamically, metformin’s anti- hyperglycemic effects last more than 24 hours. 44
  • 45.
    Pharmacology…efficacy • Consistently reduces HbA1clevels by 1.5% to 2% and FPG levels by 60 to 80 mg/dL in drug-naïve patients, and • Retains the ability to reduce FPG levels when they are extremely high (>300 mg/dL). • Also has positive effects on several components of the insulin resistance syndrome. It decreases plasma TGs and LDL-C by approximately 8% to 15%, in addition to increasing HDL-C very modestly (2%). • Metformin causes a modest reduction in weight (2 to 3 kg). 45
  • 46.
    Pharmacology…efficacy Microvascular Complications • Foundto reduce microvascular complications Macrovascular Complications • Reduced macrovascular complications in obese subjects. • It significantly reduced all-cause mortality and risk of stroke • Has also reduced diabetes-related death 46
  • 47.
    Pharmacology…adverse effects • Metformincauses GI side effects, including abdominal discomfort, stomach upset, and/or diarrhea, in approximately 30% of patients. • Anorexia and stomach fullness is likely part of the reason loss of weight is noted with metformin. • These side effects are usually mild and can be minimized by slow titration. • GI side effects also tend to be transient, lessening in severity over several weeks. • If encountered, make sure patients are taking metformin with or right after meals, and reduce the dose to a point at which no GI side effects are encountered. • Increases in the dose may be tried again in several weeks. • Anecdotally, extended-release metformin (Glucophage XR) may lessen some of the GI side effects. 47
  • 48.
    Pharmacology…adverse effects • Metallictaste, interference with vitamin B12 absorption, and hypoglycemia during intense exercise have been documented, but are clinically uncommon. • Metformin therapy rarely (3 to 9 cases per 100,000 patient-years) causes lactic acidosis. 48
  • 49.
    Pharmacology…adverse effects • Eidencehas reported that metformin may be fairly safe in moderate renal insufficiency. • Metformin use can be modified based on the estimated glomerular filtration rate, <60 mL/min/1.73 m2 : monitor renal function every 3 to 6 months <45 to ≥30 mL/min/1.73 m2: limit dose to 50% of maximal dose <30 mL/min/1.73 m2: stop metformin 49
  • 50.
    Dosing and administration •Immediate-release metformin 500 mg twice a day with the largest meals to minimize GI side effects. May be increased by 500 mg as tolerated until glycemic goals or 2,500 mg/day is achieved • Metformin 850 mg May be dosed daily, and then increased every 1 to 2 weeks to the maximum dose of 850 mg three times a day (2,550 mg/day). • Approximately 80% of the glycemic-lowering effect may be seen at 1,500 mg, and 2,000 mg/day is the maximal effective dose. 50
  • 51.
    Dosing and administration •Extended-release metformin Can be initiated at 500 mg a day with the evening meal and titrated by 500 mg as tolerated to a single evening dose of 2,000 mg/day. • Extended-release metformin 750-mg tablets May be titrated as tolerated to the maximum dose of 2,250 mg/day, although, 1,500 mg/day provides the majority of the glycemic-lowering effect. Twice-daily to three-times-a day dosing of extended- release metformin may help to minimize GI side effects and improve glycemic control, 51
  • 52.
  • 53.
    Pharmacology…sulfonylureas • MOA: enhancementof insulin secretion. • Bind to a specific sulfonylurea receptor (SUR) on pancreatic β cells. • Elevated secretion of insulin from the pancreas travels via the portal vein and subsequently suppresses hepatic glucose production • First-generation: acetohexamide, chlorpropamide, tolazamide, and tolbutamide. • Each of these agents is lower in potency relative to the second-generation drugs: glimepiride, glipizide, and glyburide • All sulfonylureas are equally effective at lowering BG when administered in equipotent doses 53
  • 54.
    Pharmacology…pharmacokinetics • All aremetabolized in the liver, some to active and others to inactive metabolites. • Glyburide metabolites are active, whereas glipizide and glimepiride do not have active metabolites. • Cytochrome P450 (CYP450) 2C9 is involved with the hepatic metabolism of the majority of sulfonylureas. • Agents with active metabolites or parent drug that are renally excreted require dosage adjustment or use with caution in patients with compromised renal function. 54
  • 55.
    Pharmacology…efficacy HbA1c • Will fall1.5% to 2% in drug-naïve patients, • FPG reductions of 60 to 70 mg/dL • But dependent on baseline values and duration of diabetes. • A majority of patients will not reach glycemic goals with sulfonylurea monotherapy. 55
  • 56.
    Pharmacology…efficacy Microvascular Complications • Areduction of microvascular complications in type 2 DM patients. Macrovascular Complications • Reported no significant benefit or harm in newly diagnosed type 2 DM patients given over 10 years. 56
  • 57.
    Adverse effects • Themost common side effect of sulfonylureas is hypoglycemia. • Pre-treatment FPG is a strong predictor. The lower the FPG is on initiation, the higher the potential for hypoglycemia. • The following are also more likely to experience hypoglycemia Who skip meals, exercise vigorously, or lose substantial amounts of weight • Hyponatremia (serum sodium <129 mEq/L) • Associated with tolbutamide, but it is most common with chlorpropamide (5%) . Is due to increase in antidiuretic hormone secretion Risk factors include age >60 years, female gender, and concomitant use of thiazide diuretics 57
  • 58.
    Adverse effects • Weightgain is common with sulfonylureas. • In essence, patients who are no longer glycosuric and who do not reduce caloric intake with improvement of BG will store excess calories. • Other notable, although much less common, adverse effects are skin rash, hemolytic anemia, GI upset, and cholestasis. • Disulfiram-type reactions and flushing have been reported with tolbutamide and chlorpropamide when alcohol is consumed 58
  • 59.
    Dosing and administration •Lower dosages are recommended for most agents in elderly patients and those with compromised renal or hepatic function. • The dosage can be titrated as soon as every 2 weeks based on FPG values (use a longer interval with chlorpropamide) to achieve glycemic goals. • This is possible due to the rapid increase of insulin secretion in response to the sulfonylurea. • The maximal effective dose of sulfonylureas tends to be about 60% to 75% of their stated maximum dose 59
  • 60.
  • 61.
    Macrovascular Disease: management ·Blood pressure control, lipid management, and aspirin therapy  Will reduce risk of coronary heart disease, stroke, and peripheral vascular disease · Blood pressure control:  Goal: blood pressure <140/80 mmHg (if renal disease <130/80 mmHg)  Medical nutritional therapy  ACE inhibitors or angiotensin receptor blockers (ARBs) are first line agents in patients with hypertension and diabetes  Diuretics, Hydrochlorothiazide are synergistic combo 61
  • 62.
    Macrovascular Disease: management ·Lipid management:  Goal: LDL <100 mg/dL (optional goal for high-risk patients: <70 mg/dL); total cholesterol <200 mg/dL; HDL >40 mg/dL; triglycerides <150 mg/dL.  Medical nutritional therapy: follow dietary recommendations  HMG-CoA reductase inhibitors (statins) if LDL >130 mg/dL; Fibrates if triglycerides >500 mg/dL • Over the age of 40 with a total cholesterol ≥135mg/dL, statin therapy to achieve an LDL reduction of ~30% regardless of baseline LDL 62
  • 63.
  • 64.
    Micro vascular disease:Management · Prevention and recognition of retinopathy, neuropathy and foot care, and nephropathy  Periodically evaluate after a baseline assessment  Optimize glucose and blood pressure control to reduce the risk and/or slow the progression of nephropathy  Neuropathy is most common complaint and need to be managed pharmacologically and non- pharmacologically based on severity  Nephropathy is a progressive kidney disease that takes several years to develop 64
  • 65.
    Reading assignment Read on 1.Other oral hypoglycaemic agents 2. Insulin injection site rotation 65
  • 66.
    Quiz 1. What isbasal and bolus insulin 2. Write steps of DKA management 3. What are prevention mechanism of DKA 4. Write types of micro & macro vascular complication 5. Metformin reduce the risk of total mortality T/F. 66

Editor's Notes

  • #25 Basal insulin is the background insulin your body needs to maintain normal blood glucose levels throughout the day and night, even when you're not eating. It mimics the low, steady amount of insulin released by a healthy pancreas.  Bolus insulin is like the big burst your body needs to handle meals and snacks. It's the rapid-acting insulin taken to manage the rise in blood glucose that happens right after you eat
  • #43 Metformin is the only biguanide available in the United States. It has been used clinically for more than 50 years, and has been approved in the United States since 1995. All the mechanisms of how metformin accomplishes glucose reduction are still being investigated, although adenosine 5′-monophosphate–activated protein kinase activity, tyrosine kinase activity enhancement, increased adenosine 5′-monophosphate, and partial inhibition of the mitochondrial respiratory chain are involved.
  • #44 Red blood cells are a second compartment of distribution for metformin, delivering an effective half-life of 17 hours.
  • #45 The sulfonylureas’ ability to stimulate insulin release from β cells at extremely high glucose levels is often impaired, a concept commonly referred to as glucose toxicity. Metformin reduces levels of PAI-1 and causes a modest reduction in weight (2 to 3 kg). In preliminary findings, metformin may also lower the risk of pancreatic, colon, and breast cancer in type 2 DM patients. Metformin, potentially through multiple mechanisms including adenosine 5′-monophosphate–activated protein kinase activity, may act as a growth inhibitor in some cancers and help to kill cancer “stem cells” which are resistant to chemotherapy, and liver kinase B1, which is an upstream kinase of adenosine 5′-monophosphate–activated protein kinase. More controlled studies are needed.
  • #46 Metformin (n = 342) was compared with intensive glucose control with insulin or sulfonylureas in the UKPDS. No significant differences were seen between therapies with regard to reducing microvascular complications, but the power of the study is questionable. MIs versus the conventional treatment arm of the UKPDS. It should be noted that the UKPDS had very few people on lipid-lowering therapy, anti-hypertensives, or aspirin.
  • #48 Lactic acidosis Metformin partially blocks the mitochondrial respiratory chain.
  • #53 Binding closes an adenosine triphosphate–dependent K+ channel, leading to decreased potassium efflux and subsequent depolarization of the membrane. Voltage-dependent Ca 2+ channels open and allow an inward flux of Ca2+. Increases in intracellular Ca2+ bind to calmodulin on insulin secretory granules, causing translocation of secretory granules of insulin to the cell surface and resultant exocytosis of the granule of insulin.
  • #56 The University Group Diabetes Program study documented higher rates of coronary artery disease in type 2 patients given tolbutamide, when compared with patients given insulin or placebo, although this study has been widely criticized Some sulfonylureas bind to the SUR-2A receptor that is found in cardiac tissue. Binding to the SUR-2A receptor has been implicated in blocking ischemic preconditioning via K+ channel closure in the heart. Ischemic preconditioning is the premise that prior ischemia in cardiac tissue can provide greater tolerance of subsequent ischemia. Thus, patients with heart disease potentially have one compensatory mechanism to protect the heart from ischemia blocked. Conclusions are controversial, but alternative treatments are available if questioned.
  • #59 Of note, immediate-release glipizide’s maximal dose is 40 mg/day, but its maximal effective dose is about 10 to 15 mg/day.