Pharmacological Treatment of Diabetes Scott Ensor, OD, MS Associate Professor Southern College of Optometry

Pharmacological Treatment of Diabetes

Scott Ensor, OD, MSAssociate Professor

Southern College of Optometry

No Disclosures!

About Me…

• Native Memphian• But a fan of The University of Tennessee

• Thanks a lot for taking Peyton away from the Titans!

• 2001 SCO Graduate• Primary Care Residency 2004• Joined SCO faculty in 2008• Started teaching Systemic Pharmacology I and II in 2011• Master’s Degree in Pharmacology and Toxicology in 2013• Michigan State University

Dr. Gerstner & Dr. Ensor

Overview of Diabetes Mellitus • Diabetes is a group of metabolic disorders defined by

elevated blood glucose resulting from insulin production defects, impaired insulin action, or both

• The 1997 International Expert Committee on Diabetes Mellitus changed the classification of diabetes, criteria for the diagnosis of diabetes, and control guidelines

• Revised guidelines were published in 2003


Overview of Diabetes Mellitus

• Type 1 (no longer considered IDDM or Type I)• Pancreatic beta cell destruction (autoimmune) • Viral insult

• Congenital rubella syndrome• Other enteroviruses may be linked – lacking evidence

• 5% of all diagnosed cases

• Type 2 (no longer considered NIDDM or Type II)• Pancreatic beta cell inefficiency or insulin resistance • Age, obesity, and family history • 90% - 95% of all diagnosed cases

Figure 24.2 (still)

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Overview of Diabetes Mellitus

• Pre-diabetes• Elevated blood glucose levels but not high enough for type 2• 3 million cases in the US per year

• Gestational diabetes • Insulin resistance develops as a result of actions of placental hormones• 2% to 10% of all pregnancies • 5% to 10% will have diabetes immediately following pregnancy • 35% to 60% will develop diabetes in the next 10 – 20 years

• MODY (Maturity Onset Diabetes of the Young)• Also called Monogenic Diabetes

• Results from autosomal dominant mutation• MODY 1 – 6 • 1% to 5% of all diagnosed cases

How Many People Are Affected?

Total: 25.8 million children and adults or 8.3% of the population Diagnosed: 18.8 million peopleUndiagnosed: 7.0 million people Pre-diabetes: 79 million people* New 2013New Cases: 1.9 million

Under 20 years of age 215,0001.9 million newly diagnosed 2 million aged 12-19 are pre-diabetic (1 in 6 are overweight)

Age 20 years or older 25.6 million or 11.3% of all people in this age group

Age 65 or older 10.9 million or 26.9% of all people in this age group

Men 13.0 million or 11.8% of all men 20 years of age or older

Women 12.6 million or 10.8% of all women 20 years of age or older

Total prevalence of DM, US 2013


The Diabetes “Belt”



Diabetes Diagnosis


Diabetes – Lack of Activity

Pathophysiology of Diabetes

Simple Explanation

• Video

Pancreas

• Pancreas is both endocrine and exocrine gland• Produces insulin, glucagon, and somatostatin

• In islets of Langerhans• Responsible for homeostasis of blood glucose

• Produces digestive enzymes

The Liver and Glucose

• The liver can both store and produce glucose• Signaled by insulin and glucagon

• During a meal• Insulin increases and glucagon decreases

• Liver stores glucose

• Liver produces glucose between meals• Fasting state• If insulin remains low, the liver will continue to produce glucose…

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Type 1 Diabetes

• Destruction of beta cells in the pancreas• Basal levels of insulin are usually maintained by beta cell secretion• A burst of insulin secretion occurs within 2 minutes of eating• Type 1 diabetics are unable to maintain basal levels or respond to

variations• Decrease in insulin secretion

• 85% of type 1 patients have circulating antibodies for islet cells• Majority also have anti-insulin antibodies

Type 2 Diabetes

• Many pathological factors• Impaired insulin secretion from pancreatic beta cells

• Pancreas retains some beta cell function but secretion is insufficient to maintain glucose homeostasis

• Increased liver glucose production• Decreased peripheral glucose utilization

• Decreased insulin sensitivity

• These represent the “traditional” triad of type 2 diabetes

• Eventual beta cell failure results leading to decreased insulin secretion

Type 2 Diabetes

• Other pathological factors• Adipocyte insulin resistance• Reduced incretin secretion and senstitivity• Increased glucagon secretion• Enhanced glucose reabsorption from kidney• Central Nervous System insulin resistance

• Result of neurotransmitter dysfunction

• These pathogenic mechanisms are known as the “ominous octet”

Clinical Presentation of Diabetes

Signs and Symptoms of Type 1

• Classic Symptoms• Polyuria• Polydipsia• Polyphagia• Weight loss• Blurry vision• GI symptoms

• Nausea• Abdominal discomfort

Signs and Symptoms of Type 2

• Similar to classic symptoms of type 1• For the optometrist…

• Unexplained changes in refractive error should alert you to the need for blood sugar testing

• Many patients are asymptomatic

Diagnosis of Diabetes


Diagnostic Ranges of Diabetes

• Revised guidelines 2003

Disease Criteria

Diabetes Mellitus 1. FPG > 126 mg/dL

2. Two hour PG > 200 mg/dL with the OGTT after 75 g glucose load challenge

Diagnostic Ranges of Pre-Diabetes

Disease Criteria

Pre-diabetes (impaired glucose tolerance)

1. FPG level 100 – 125 mg/dL

2. Two hour PG 140 – 199 mg/dL with OGTT after 75 g load challenge


What Is HbA1c?

• HbA1c• Glycosylated hemoglobin

• Glucose will bind to red blood cells in a certain ratio• Amount of glycosylated hemoglobin will increase as blood glucose increases

• Gives an idea of the AVERAGE blood sugar level of a patient• RBC life span is 8-12 weeks

• Very high affinity for oxygen• Higher A1c levels are associated with greater risk for retinopathy, kidney disease, and neuropathy

• Levels:• 4-5.9 = normal• 7 or less = goal of treatment• >9 = poor control• >12 = very poor control

Complications of Diabetes

Acute Complications

• Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNS)• Can occur in type 1 or type 2

• More common in type 2• Severe dehydration

• Urine production increases as blood sugar increases• Can lead to seizures, coma, and death• Symptoms

• Blood sugar level over 600 mg/dL• Dry mouth• Extreme thirst• Warm sking• High fever• Confusion• Loss of vision

Acute Complications

• Diabetic Ketoacidosis (DKA)• Cells burn fat for energy when glucose is not available

• Produces ketones• Makes blood more acidic

• Can lead to coma and/or death• Symptoms

• Thirst• Very dry mouth• Constantly feeling tired• Dry skin• Fruity odor on breath• Confusion• Nausea• Vomiting

• Sign that condition may become life-threatening in a few hours

Chronic Complications

• Usually secondary to vascular disease• Nephropathy• Usually indicated by increased protein in the urine• Occurs within a short time with retinopathy• Causes severe peripheral edema

• Neuropathy• Due to changes in nerve metabolism, abnormal cell function, and/or vascular

abnormalities• More often lower extremities

• Foot pain• Loss of sensation

Chronic Complications

• Peripheral Vascular Disease• Along with stroke

• Coronary Artery Disease• Retinal Disease

Ophthalmologic Complications

• Accelerated cataract formation• Especially anterior cortical

• Non-proliferative Retinopathy• Proliferative Retinopathy• Macular Edema• Neovascular Glaucoma





Treatment of Diabetes

Treatment begins with diet and exercise!

Diet

• Comprehensive diet plan• Created with help of professional dietitian

• Includes• Daily caloric intake prescription• Address individual nutrition needs

• Personal and cultural preferences• Barriers to change

• Recommendations for amounts of carbohydrate, fat, and protein• Instructions on how to divide calories between meals and snacks

Exercise

• Children with diabetes should get at least 60 minutes of physical activity a day• Adults should get 150 min/week of moderate-intensity aerobic

physical activity• Reduce sedentary time• Break up any time longer than 90 minutes

• Perform resistance training at least twice per week

Surgical Considerations

A Game Changer?

• There is evidence that surgery for type 2 diabetes can achieve “up to complete disease remission”• Rubino, Francesco et al. “Diabetes Surgery: A New Approach to an Old

Disease” Diabetes Care, Vol 32, Supplement 2, Nov 2009

• “Metabolic Surgery” is a sub-specialty in surgery dedicated to establishing surgical procedures for diabetes

First Impression

• Early 1980’s• Surgeons found that patients who had undergone gastric bypass experienced

a remission in diabetes• Studies since then have confirmed

• Best results with• Gastric Bypass• Biliopancreatic Diversion

Gastric Bypass

• Changes how stomach and small intestine handle ingested food• Fewer calories absorbed• Feel full early (usually after a few bites)

• Allows for rapid weight loss• Diet and exercise still recommended

Gastric Bypass

Biliopancreatic Diversion

• Similar to Gastric Bypass• “Portions of the stomach are removed. The small pouch that remains

is connected directly to the final segment of the small intestine, completely bypassing the upper part of the small intestines. A common channel remains in which bile and pancreatic digestive juices mix prior to entering the colon”.• National Library of Medicine

Biliopancreatic Diversion

Newer Procedures

• Development of surgical procedures specifically geared to treat diabetes

• Duodenal-jejunal Bypass• Spares the stomach• Bypass of short segment of proximal intestine

• Gastric bypass without the stomach stapling

Newer Procedures

• Ileal Interposition• Removal of a small segment of the ileum and inserting it into the proximal

small intestine• Causes exaggerated release of glucagon like peptide-1

• Improves glucose tolerance

• Endoluminal Duodenal-jejunal Bypass Sleeve• Delivery of a plastic coated sleeve implant that extends into the jejunum

• Excludes the duodenum• Mimics the duodenal-jejunal bypass

• Does not disrupt bowel continuity

Surgical Limitations

• Not every diabetic patient will be a candidate for surgery• Not a candidate if only mildly obese

• Indications and contraindications not yet fully known• Limited access• Poor insurance coverage• Lack of trained surgeons

Pharmacological Treatment

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Treatment With Insulin

Insulin and its Analogs

• Insulin secretion is regulated by blood glucose levels and other hormones and autonomic mediators• Glucose is transported into the B-cells and metabolized• ATP generated• Increased ATP causes block of K channels and an influx of Ca• Increased Ca causes secretion of insulin

Insulin and its Analogs

• Human insulin is produced by recombinant DNA technology• Modification of amino acid sequence yields insulin with different properties

• Usually given by subcutaneous injection• Continuous pumps have become popular

• Insulin replacement is accomplished by giving basal insulin (long-acting or intermediate-acting) and a premeal insulin (rapid-acting or short-acting)• Excessive doses of insulin can lead to symptoms of hypoglycemia• Self-monitoring is important

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Insulin Preparations

• Rapid-acting and short-acting• regular insulin, insulin lispro, insulin aspart, and insulin glulisine• Have rapid onset and short duration of action

• Offer more flexible treatment regimens• May lower risk of hypoglycemia

• Administered to mimic the mealtime release of insulin• Often used in combination with longer acting preparation


• Intermediate-acting insulin• Neutral protamine Hagedorn (NPH) insulin

• Also called insulin isophane• Slightly delayed absorption

• Less soluble• Not useful in emergency situation

• Usually used in combination with another form


• Long-acting insulin preparations• insulin glargine

• Precipitates at injection site• Prolonged effect with no peak

• insulin detemir• Enhanced association to albumin

Figure 24.7 (still)

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Common Insulin Regimens

• Split (Mixed)• NPH with rapid acting or regular insulin before breakfast and supper

• Split variant• NPH with rapid acting or regular insulin before breakfast, rapid acting or regular

before supper, and NPH before bedtime• Reduces fasting hypoglycemia

• Multiple daily injections (MDI)• Long-acting insulin once a day in morning or evening and a rapid acting insulin before

meals and snacks (adjusted dose)

• Continuous subcutaneous insulin infusion (CSII)• Rapid acting insulin infused 24 hours a day through an insulin pump at a basal rate

with correction doses administered if blood glucose goes above target levels

Synthetic Amylin Analog

• Pramlintide• Used as adjunct to mealtime insulin• Delays gastric emptying

• Decreases postprandial glucagon secretion• Improves satiety

• Injected immediately prior to meals• Dose of rapid-acting insulin should be decreased by 50%

Oral Diabetes Medications

Oral Diabetes Medications

• Will have one of the following effects:• Stimulate production/release of insulin• Regulate digestion of carbohydrates• Make cells more responsive to insulin

• Metformin also has one extra effect…

Insulin Secretagogues

Sulfonylureas

• In use for over 60 years• Examples: Glipizide, Glyburide, Glimepiride• Stimulate insulin secretion from the beta cells

Sulfonylureas

• Mechanism of Action• Bind to receptors in the beta cells causing K channels

• Depolarizes membrane• Voltage-dependent calcium channels open in response

• Activates calcium-dependent proteins that control the release of insulin

• Pharmacokinetics• Variable duration of action

• 12 to 24 hours• Well absorbed• Highly bound to plasma proteins

• Causes many drug-drug interactions• Liver metabolism

Figure 24.12 (still)

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Sulfonylureas

• Indications• First-line therapy in many cases• Preferred for patients who are not overweight

• Can cause weight gain• Can be combined with other meds

• Do not use with another insulin secretagogue

Sulfonylureas

• Contraindications / Adverse Effects• Hypoglycemia

• Usually minor but can be life threatening• Higher risk if irregular eating habits or excessive alcohol consumption

• Skin reactions• Weight gain• Some evidence of cardiac side effects

• Contraction of cardiac and vascular muscle

Meglitinides

• Developed to decrease postprandial hyperglycemia• Taken 15-30 minutes before a meal

• Examples: Repaglinide and Nateglinide• Similar to sulfonylureas

Meglitinides

• Mechanism of Action• Bind to same receptor in beta cell as sulfonylureas

• Different site• Cause similar release of insulin

• Pharmacokinetics• Well absorbed• Liver metabolism• Short duration of action

• About 3 hours

Meglitinides

• Indications• Good for patients with irregular lifestyles

• Unpredictable or missed meals• Option for elderly patients

• Lower risk of hypoglycemia

• Contraindications / Adverse Effects• Less risk for hypoglycemia• Small amount of weight gain probable

Insulin Sensitizers

Metformin

• Goat’s rue or French lilac were historical treatments for diabetes in Europe• Rich in guanidine

• 1920’s saw the development of several guanidine derivatives• Replaced with the increasing availability of insulin

• Metformin was developed in the 1950’s along with other biguanides• Others taken off the market

• Now drug of choice for newly diagnosed type 2

Metformin

• Mechanism of Action• Increases hepatic sensitivity to insulin

• Decreases hepatic glucose production• Increases insulin-stimulated glucose uptake in skeletal muscle• Suppresses the oxidation of fatty acids and reduces triglyceride levels

• Reduces energy supply for hepatic glucose production

Metformin

• Pharmacokinetics• Rapidly absorbed and eliminated unchanged in the urine

• Requires good kidney function• Half-life is 2-5 hours

• Indications• Any weight• Can be combined with any other class or with insulin

Metformin

• Contraindications / Adverse Effects• Avoid in patients with poor kidney function• Avoid in situations of hypoxia

• Respiratory insufficiency• Cardiac insufficiency• Hypotenstion

• Avoid in patients with liver disease or history of alcohol abuse• GI distress common• Rare lactic acidosis

Thiazolidinediones

• Improve whole-body insulin sensitivity• Examples: Pioglitazone, Rosiglitazone• First used in the 1980’s

Thiazolidinediones

• Mechanism of Action• Stimulates receptor in adipose tissue (also present in muscle and liver)

• Results in transcription of a number of insulin-sensitive genes• Promote or enhance the local effects of insulin

• Pharmacokinetics• Rapidly absorbed

• Slightly delayed when taken with food• Liver metabolism• Plasma protein bound

• No drug-drug interactions found at this time

Thiazolidinediones

• Indications• Can be used as monotherapy• Any weight

• Contraindications / Adverse Effects• Can cause fluid retention

• Caution in patients with heart failure• Avoid in patients with liver disease• Combination with insulin may increase risk of heart failure

• Not allowed in Europe• Generally well-tolerated

“Other” Oral Diabetes Medications

α-Glucosidase Inhibitors

• Examples: Acarbose and Miglitol• Digestion Review• Complex carbohydrates must be broken down prior to being absorbed by the

intestine• Facilitated by alpha-amalase and several alpha-glucosidase enzymes

• Mechanism of Action• These drugs target the alpha-glucosidase enzymes

• Minimize upper intestinal digestion and absorption of carbohydrates• Decrease postprandial release of glucose


• Pharmacokinetics• Each has differing affinities for the different enzymes• Liver metabolism

• May be CYP inducer• Kidney excretion• Taken just before meals

• Indications• Approved as monotherapy and in combination with sulfonylureas• Also shown to decrease cardiovascular events in patients with type 2


• Contraindications / Adverse Effects• Avoid in patients with liver disease or kidney disease• Side effects

• Flatulence, diarrhea, and abdominal cramping• Patients with GI disease should avoid (especially inflammatory bowel disease)

Dipeptidyl Peptidase-IV Inhibitors

• Examples: Linagliptin, Sitagliptin and Saxagliptin

• Mechanism of Action• Inhibit DPP-IV

• DPP-IV responsible for inactivation of incretin hormones• Results in an increase in glucose-mediated insulin secretion and a decrease in glucagon

levels


• Pharmacokinetics• Liver metabolism• Kidney excretion (mostly)• Once daily dosing

• Indications• Approved as adjunct therapy to diet and exercise


• Contraindications / Adverse Effects• Avoid in patients with liver or kidney disease• Side Effects

• Upper respiratory irritation and/or infection• Headache• Pancreatitis• Severe allergic reactions

Figure 24.11 (still)

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Figure 24.13 (part 1)

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Figure 24.13 (part 2)

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Glucagon-Like Polypeptide-1 Agonists• Examples: Exenatide and Liraglutide• Release of glucagon-like polypeptide is reduced in type 2 diabetics• Results in inadequate glucagon suppression and excessive liver glucose output

• Mechanism of Action• Bind to GLP-1 receptors and help restore activity• Results in

• Potentiation of glucose-mediated insulin secretion• May actually increase beta-cell mass

• Suppression of postprandial glucagon release• Slowed gastric emptying and loss of appetite

Glucagon-Like Polypeptide-1 Agonists• Pharmacokinetics• Injection only

• Absorbed from arm, abdomen, or thigh• Kidney excretion• Liraglutide allows once daily dosing

• Exenatide is injected within an hour before a meal

• Indications• Approved as an adjunct therapy

Glucagon-Like Polypeptide-1 Agonists• Contraindications / Adverse Effects• Side Effects

• Headache• Nausea• Diarrhea• Immune reactions• Pancreatitis

• Liraglutide is contraindicated in patients with a family history of cancer• Produced thyroid tumors in rodents

Sodium-Glucose Cotransporter 2 Inhibitors• Examples: Canagliflozin (Invokana) and Empagliflozin

• First approved in 2013

• Mechanism of Action• Sodium-glucose cotransporter 2 is responsible for reabsorbing filtered glucose

in the kidney• These drugs inhibit this activity

• The result is an increase in urinary glucose excretion• May also reduce blood pressure (not a HTN treatment)

Sodium-Glucose Cotransporter 2 Inhibitors• Pharmacokinetics• Kidney metabolism• Dose is once daily in the morning

• Adverse Effects• UTIs and yeast infections• Urinary frequency• Hypotention

• Especially in patients also taking diuretics

Current Treatment Paradigm

Current Treatment Paradigm

• Patients diagnosed with type 2 diabetes are most often started on a regimen of lifestyle modification and metformin• Goal is A1c of less than 7%

• Addition of sulfonylurea or basal insulin is recommended if A1c goal not reached• Clinically more common to add sulfonylurea due to complications of insulin

therapy

• Next addition would usually be pioglitazone or a GLP-1 receptor agonist

Problems With Current Treatment

• The current treatment paradigm focus on HbA1c levels but do not offer much in terms of beta cell preservation or reduced rate of disease progression

• Some are now recommending early triple-combination therapy with a thiazolidinedione, metformin, and exenatide

References

• American Diabetes Association “Standards of Medical Care in Diabetes-2015; Abridged for Primary Care Providers” Clinical.DiabetesJournals.org Vol 33, No 2, Spring 2015. 97-111

• Krentz, Andrew J and Bailey, Clifford J “Oral Antidiabetic Agents; Current Role in Type 2 Diabetes Mellitus” Drugs Vol 65, No 3, 2005. 385-411

• Rubino, Francesco et al. “Diabetes Surgery: A New Approach to an Old Disease” Diabetes Care Vol 32, Supplement 2, Nov 2009. s368-s372

• DeFronzo, Ralph “Overview of Newer Agents: Where Treatment is Going” The American Journal of Medicine Vol 123, No 3A, March 2010. s38-s46

• The Foundation of the American Academy of Ophthalmology Basic and Clinical Science Course; Update on General Medicine 2001-2002

• Katzung, Bertram et al. Basic and Clinical Pharmacology 12th ed; McGraw-Hill Companies 2012. 743-769

Questions?

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Pharmacological Treatment of Diabetes Scott Ensor, OD, MS Associate Professor Southern College of Optometry