Diabetes Mellitus. Intended Learning Objectives:

Transcription

1 Intended Learning Objectives: Diabetes Mellitus 1. Compare and contrast the differences between the drug therapy recommendations of several of the latest and leading diabetes guidelines. 2. Assess the different classes of hypoglycemic drugs with emphasis on the new classes as incretin-based therapies, sodium-glucose cotransporter 2 inhibitors and tell how they compare with other agents to treat hyperglycemia. 3. Convert a patient with T2DM with significant hyperglycemia to an insulin-only drug regimen. D iabetes Mellitus is a complex, chronic illness requiring continuous medical care with multifactorial risk-reduction strategies beyond glycemic control. Ongoing patient selfmanagement education and support are critical to preventing acute complications and reducing the risk of long-term complications. Classification of DM: 1. Type 1 DM (T1DM), also previously known as Insulin Dependent Diabetes Mellitus (IDDM). 2. Type 2 DM (T2DM), also previously known as Non-Insulin Dependent DM (NIDDM). 3. Gestational Diabetes Mellitus (GDM). 4. Others: Neonatal Diabetes Mellitus (NDM) subdivided into Temporary NDM (TNDM) and Permanent NDM (PNDM) Maturity-Onset Diabetes of the Young (MODY), subclassified into MODY1 to MODY6. Type 1.5 DM also known as Latent Autoimmune Diabetes in Adults (LADA) or (ADA). 1 Dr. Hisham Ah. Nematalla

2 2 Dr. Hisham Ah. Nematalla

3 The complex context of T2DM therapy: Type 2 diabetes mellitus is a multi-organ disease. For successful glycaemic control, hypoglycemic agents must target one or more of the dysfunctional organs affected by T2DM. In T2DM, the pancreas shows increased α-cell secretion and β-cell impairment, the liver shows increased gluconeogenesis because of increased α-cell secretion, and the peripheral tissue shows insulin resistance and reduction in GLUT-4 transporters. The GI tract shows reduced GLP-1 levels and increased speed of food movement from the stomach to the intestine, leading to overeating and increased post-prandial (PPG) elevations (or spikes). The brain shows disruption of satiety signaling, leading to overeating, reduced dopamine and impaired circadian rhythm. The ultimate goal of T2DM therapy is β-cell conservation to delay disease progression. Treatment selection for patients with T2DM should be guided by the goal of lowering HbA1c levels and individualized to each patient based on clinical factors and co-morbidities. Combination therapy should include classes of medications that have complementary mechanisms of action (MOA) with safety and quality of glycaemic control as treatment selection priorities. The key to optimal glycaemic control and improved health outcomes is early diagnosis and treatment with therapies that address all of the underlying T2DM pathophysiological abnormalities. Given that cardiovascular disease is a major cause of morbidity and mortality in T2DM, treatment targets include blood glucose levels (fasting, pre-prandial and postprandial), HbA1c, lipid levels and blood pressure. Weight loss is recommended for all overweight or obese individuals who have or are at risk for diabetes. Long-term glycaemic control at <7% or 6.5% has been associated with reduction in diabetes-related complications, including microvascular 3 Dr. Hisham Ah. Nematalla

4 and macro- vascular changes, for example, retinopathy, amputation, myocardial infarction and death. Gestational Diabetes Mellitus (GDM): GDM, or carbohydrate intolerance, is first diagnosed during pregnancy through an oral glucose tolerance test. 5-8% of pregnant women develop this form of diabetes. Risk factors for GDM include a family history of diabetes, increasing maternal age, obesity and ethnic group with a high risk factor. While the carbohydrate intolerance usually returns to normal after the birth, the mother has a significant risk of developing permanent diabetes. Diagnosis of DM: The diagnosis of diabetes mellitus is easily established when a patient presents with classic symptoms of hyperglycemia (thirst, polyuria, weight loss, visual blurring), Has a fasting blood glucose concentration of 126 mg/dl (7.0 mmol/l) or higher, or a random value of 200 mg/dl (11.1 mmol/l) or higher, and confirmed on another occasion. 4 Dr. Hisham Ah. Nematalla

5 Chronic complications of DM: Diabetic retinopathy: most common cause of blindness before age 65 Nephropathy: most common cause of ESRD Neuropathy: most common cause of non-traumatic amputations 2-3-fold increase in cardiovascular disease Chronic complications can be divided into: 1. Vascular subdivided into: Microvascular (retinopathy, neuropathy, nephropathy) Macrovascular complications (coronary artery disease, peripheral vascular disease, cerebrovascular disease) 2. Nonvascular complications: Gastroparesis (managed by erythromycin) sexual dysfunction skin changes 5 Dr. Hisham Ah. Nematalla

6 Results of UKPDS 1. The UKPDS results establish that retinopathy, nephropathy, and possibly neuropathy is benefited by lowering blood glucose levels in type 2 diabetes with intensive therapy, which achieved a median HbA1c of 7.0%. (for every percentage point decrease in HbA1c, there was a 35% reduction in the risk of complications. 2. The UKPDS also demonstrated by epidemiological analysis that CVD outcomes were consistently associated with hyperglycemia in a manner similar to the relationship between microvascular complications and hyperglycemia. Nonetheless, the UKPDS did not prove definitively that intensive therapy that lowered blood glucose levels reduced the risk of CVD complications compared with conventional therapy. 3. Intensive therapy with metformin: Patients initially assigned to intensive therapy with metformin had decreased risks of diabetes-related deaths, all-cause deaths, and myocardial infarction compared with the conventionally treated patients. These risks were significantly reduced by about onethird. The beneficial effect on CVD is in contrast to the failure of insulin or sulfonylurea treatment to reduce cardiovascular outcomes when compared with conventionally treated obese patients. This difference between drugs may possibly relate to the absence of weight gain with metformin and/or to some 6 Dr. Hisham Ah. Nematalla

7 beneficial effects of metformin on the insulin resistance syndrome. Surprisingly, no significant decrease in microvascular complications was observed with intensive metformin therapy. Recent advances in diabetology: 1. Incretin-based therapy: Orally ingested glucose produces a much greater insulin-secretory response compared with intravenous administration of glucose, known as the incretin effect. The incretin effect may account for up to 70% of the total insulin secretion following oral glucose or a meal in healthy individuals, and it is impaired in patients with T2DM. 7 Dr. Hisham Ah. Nematalla

8 Incretin-based therapy takes advantage of the incretin effect that results from the action of two main insulinotropic gut hormones, glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are rapidly released after meals. GLP-1 is secreted by intestinal L cells, primarily following ingestion of food. Its glucose-lowering actions are glucose dependent, thereby limiting risk of hypoglycemia. GLP-1 increases glucose-dependent insulin secretion, suppresses glucagon secretion, reduces hepatic glucose production, delays gastric emptying/slows GI motility and decreases food intake through increased satiety/reduced hunger. Animal models show β-cell proliferation and possibly neogenesis and reduced apoptosis, suggesting that incretins may have disease-altering effects, although related effects in humans are not yet known. GIP increases glucose-dependent insulin secretion, and both GLP-1 and GIP are rapidly inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme. 8 Dr. Hisham Ah. Nematalla

9 I. Incretin-based therapy includes two drug classes: 1. GLP-1 receptor agonists. 2. DPP-4 inhibitors. 1. GLP-1 receptor agonists: GLP-1 analogue, liraglutide (Victoza ) and the incretin mimetic, exenatide (Byetta ) exenatide-er (Bydureon ). GLP-1 receptor agonists target multiple dysfunctional organs in T2DM: the pancreas, liver, brain and GI tract. GLP-1 receptor agonists produce pharmacological levels of GLP-1 receptor stimulation, and stimulate insulin and amylin secretion from β-cells of the pancreas, suppress glucagon release from α-cells, decrease hepatic gluconeogenesis in the liver, slow gastric emptying in the GI tract and increase satiety signaling in the brain. Their primary effect is on PPG levels because of enhanced mealtime insulin secretion and GI motility regulation. They have a modest effect on fasting plasma glucose (FPG) because of the suppression of glucagon and decreased hepatic gluconeogenesis. Treatment with GLP-1 receptor agonists has also been associated with dose-dependent weight loss. Exenatide in combination with basal insulin therapy provides additional benefit in reducing A1C over either agent as monotherapy. A substantial amount of research is addressing whether these agents preserve beta-cell function over time. Agents that stimulate insulin secretion (e.g., sulfonylureas) can hasten the loss of beta-cell insulin secretion. The GLP-1 agonists have shown improvements in beta-cell insulin secretion; exenatide studies with up to 3 years of follow up show that insulin secretion does not significantly decrease and may actually increase. 9 Dr. Hisham Ah. Nematalla

10 Dosing of GLP-1 RA: 1. Exenatide (Byetta ) Twice-daily formulation: Initial: 5 mcg subcutaneously twice daily, administered no more than 60 minutes before morning and evening meals. Maximal dose: 10 mcg twice daily. Dose titration from 5 to 10 mcg twice daily after 1 month if tolerated Once-weekly formulation: Exenatide-ER (Bydureon ) 2 mg once weekly. Current formulation must be reconstituted by patient immediately before injection. 2. Liraglutide (Victoza ) 0.6 mg subcutaneously once daily for 1 week (regardless of mealtime) Dose titration from 0.6 to 1.2 mg/day if tolerated. Maximal daily dose: 1.8 mg/day Adverse effects Nausea, vomiting, diarrhea very common. Hypoglycemia common with concurrent sulfonylurea (consider reduction in sulfonylurea dose if adding exenatide). Post-marketing reports of pancreatitis and acute renal failure or impairment Contraindications/precautions Impaired renal function: CrCl less than 30 ml/minute for either exenatide formulation; less specific for liraglutide. History of severe GI tract disorder, particularly gastroparesis. History of pancreatitis. 10 Dr. Hisham Ah. Nematalla

11 Contraindicated in patients with a personal or family history of medullary thyroid carcinoma (adverse effect found in rodent studies but not in humans) Efficacy A 0.5% 1.5% reduction in A1c. Effects on postprandial hyperglycemia better than on fasting glucose concentrations with once- or twice-daily formulations. Improved A1C, fasting glucose reduction, and nausea/vomiting with once-weekly compared with twice-daily exenatide formulation. Modest weight loss. 2. DPP-4 inhibitors: DPP-4 inhibitors as Sitagliptin, Saxagliptin, Linagliptin, Alogliptin prevent endogenous GLP-1 enzymatic inactivation, resulting in physiological levels of GLP-1 receptor activation. They are taken orally, and treatment effects are targeted at glycaemic control with reduced risk for hypoglycemia and weight gain. Dosing 1. Sitagliptin: (Januvia )100 mg once daily Reduce dose with CrCl between 30 and 50 ml/minute to 50 mg once daily. Reduce dose with CrCl less than 30 ml/minute to 25 mg once daily. 2. Saxagliptin: (Onglyza ) 5 mg once daily. Reduce with CrCl of 50 ml/minute or less to 2.5 mg once daily. 3. Linagliptin: (Trajenta ) 5 mg once daily no dosage adjustment for renal impairment) 4. Alogliptin: (Zauba ) 25 mg once daily Reduce dose with CrCl between 30 and 60 ml/minute to 12.5 mg once daily. Reduce dose with CrCl less than 30 ml/minute to 6.25 mg once daily. 11 Dr. Hisham Ah. Nematalla

12 Adverse effects Upper respiratory and urinary tract infections, headache Hypoglycemia with monotherapy is minimal, but increased frequency with concurrent sulfonylurea therapy (can lower dose of sulfonylurea when initiating). Sitagliptin has had some post-marketing reports of acute pancreatitis, angioedema, Stevens-Johnson syndrome, and anaphylaxis. Contraindications/precautions Previous hypersensitivity to the agents History of pancreatitis Efficacy: 0.5% 0.8% reduction in A1c In a glucose-dependent manner, both GLP-1 receptor agonists and DPP-4 inhibitors increase insulin secretion and decrease glucagon secretion, resulting in a low risk for hypoglycemia, unless used in combination therapy with sulphonylureas. II. Sodium-glucose co-transporter 2 inhibitors (SGLT2 inhibitors): The major change in treatment options guidelines since 2012 has been the availability of a new class of glucose-lowering drugs, the sodium glucose co-transporter2 (SGLT2) inhibitors. These agents reduce HbA1c by %. When compared with most standard oral agents in head-to-head trials, they appear to be roughly similarly efficacious with regard to initial HbA1c lowering. Their mechanism of action involves inhibiting the SGLT2 in the proximal nephron, thereby reducing glucose reabsorption and increasing urinary glucose excretion by up to 80 g/day. Because this action is independent of insulin, SGLT2 inhibitors may be used at any stage of type 2 diabetes, even after insulin secretion has waned significantly. Additional potential advantages include modest weight loss and consistent lowering of systolic and diastolic blood pressure. 12 Dr. Hisham Ah. Nematalla

13 Side effects of SGLT2 inhibitor therapy include genital mycotic infections, they also possess a diuretic effect, and so symptoms related to volume depletion may occur. Consequently, these agents should be used cautiously in the elderly, in any patient already on a diuretic, and in anyone with a tenuous intravascular volume status. Due to their mechanism of action, SGLT2 inhibitors are less effective when the estimated GFR (egfr) is <45-60 ml/min. Members include Canagliflozin (Invokana ), Dapagliflozin (Farxiga ) and Empagliflozin (Jardiance ). Dosing (Canagliflozin); Note Dapagliflozin approved in US January mg once daily before the first meal of the day Maximal daily dose: 300 mg. Reduce dose with CrCl between 45 and 59 ml/minute to 100 mg daily. Adverse effects Increased urination. Urinary tract infections. Genital mycotic infections Contraindications/precautions Avoid or discontinue if CrCl is less than 45 ml/minute. Suggested to ensure euvolemia before initiating Canagliflozin, given its diuretic effect Efficacy 0.3% 1.0% reduction in A1c. Effect on both fasting and postprandial glucose concentrations. Mild weight loss 13 Dr. Hisham Ah. Nematalla

14 Class Compound (s) Physiological action (s) Primary glycemic effect Benefits Limitations & precautions HbA1c lowering (%) 1. Biguanides Metformin hepatic glucose output Fasting No hypoglycemia GIT side effects 1.5 Low cost Good tolerability CVD events (UKPDS) Weight neutral/loss Lactic acidosis (rare) Contraindicated in CKD Vit. B12 deficiency 2. Sulphonylureas (SUs) Hypoglycemia risk, weight gain, Hastens β-cell dysfunction TZDs (Glitazones) 4. DDP-4 inhibitors (Gliptins) 2 nd generation: Glibenclamide (glyburide) Gliclazide Glimepiride Insulin secretion Fasting & prandial Efficacy, low cost Microvascular risk (UKPDS) Pioglitazone Insulin sensitivity Fasting & prandial No hypoglycemia, Weight gain, risk of osteoporosis, risk heart failure, risk of bladder cancer, edema. Sitagliptin Saxagliptin Linagliptin Alagliptin Insulin secretion (glucose-dependent) Glucagon secretion (glucose-dependent) Slows gastric emptying Satiety Prandial (some fasting) No hypoglycemia Well tolerated Weight neutral High cost? acute pancreatitis Dr. Hisham Ah. Nematalla

15 5. GLP-1 RA (Incretin mimetics) Exenatide (twice daily) Liraglutide (once daily) Exenatide-ER (once weekly) Insulin secretion (glucose-dependent) Glucagon secretion (glucose-dependent) Slows gastric emptying Satiety Fasting & prandial (once weekly exenetide-er greater fasting effect) No hypoglycemia Postprandial glucose excursion. Weight loss Efficacy CV risk factors Nausea & vomiting High cost? acute pancreatitis C-cell hyperplasia/medullary thyroid tumors in exp. Animals Injection aversion Glinitides Repaglinide Nateglinide 7. SGLT2 inhibitors 8. Amylin mimetics Canagliflozin Dapagliflozin Empagliflozin Pramlintide (not licensed in EU for T2DM) 9. Insulin Rapid-acting Short-acting Inter-acting Basal analogs Pre-mixed Insulin secretion Prandial Postprandial glucose excursion. Use in kidney impairment Blocks glucose reabsorption by kidney, increasing glycosuria Satiety, Glucagon secretion Slows gastric emptying glucose disposition Hepatic glucose output Fasting & prandial Prandial Basal: Fasting Bolus: Prandial No hypoglycemia Weight loss Blood pressure (diuretic effect) Effective at all stages of T2DM Postprandial glucose excursion. Weight loss Significant A1c reduction Flexibility in dosing & titration. Microvascular risk (UKPDS) Hypoglycemia, Weight gain, mealtime dosing High cost, Genitourinary infections Polyuria, hypovolemia, hypotension High cost Nausea & vomiting Hypoglycemia with insulin Injection aversion Hypoglycemia Weight gain Injection aversion & patient reluctance Dr. Hisham Ah. Nematalla

16 10. Dopamine Agonist 11. Bile acid sequestrant Bromocriptine Colosevelam Modulates hypothalamic regulation of metabolism & insulin sensitivity? Hepatic glucose production? Incretin level Fasting & prandial No hypoglycemia Nausea & vomiting CNS adverse effects Prandial No hypoglycemia Lipid benefits High cost, Constipation, TGs, alter absorption of drugs small 16 Dr. Hisham Ah. Nematalla

17 Guidelines of T2DM: 1. American Diabetes Association / European Association for the Study of Diabetes. ADA/EASD. 2. American Association of Clinical Endocrinologists / American College of Endocrinology. AACE/ACE. Two keys differences between ADA & ACE/AACE: 1. ADA is less aggressive for glycemic control goal (7%), 3-to 6-months trial of lifestyle modification can be used before pharmacotherapy if patient is highly motivated and their A1c is less than, ACA/AACE had a goal of 6.5% which is more stringent and start monotherapy at A1c 7.5% or less. 2. ACE/AACE is more prescriptive & restrictive in the dual & triple therapy choice, on the other hand ADA is more flexible and more patient-centered approach to drug therapy recommendation (patient individualization) 17 Dr. Hisham Ah. Nematalla

18 Two important keys facts are to be noticed: 1. Results from large trials have also suggested that overly aggressive control in older patients with more advanced disease may not have significant benefits and may indeed present some risks. Accordingly, instead of a one-size-fits-all approach, personalization (patient centeredness) is necessary, balancing the benefits of glycaemic control with its potential risks, taking into account the adverse effects of glucose lowering medications (particularly hypoglycemia), and the patient s age and health status, among other concerns. 18 Dr. Hisham Ah. Nematalla

19 ADA 2015 approach to management of hypoglycemia 2. Delay or failure to modifying treatment in a patient who has not achieved the evidence-based goal in the treatment of T2DM must be avoided. It has been shown that fewer than 41% of patients with an HbA1c above the ADA goal of 7% had their medication changed. Most patients with T2DM eventually require combination therapy to achieve their glycaemic target, and an average of months delay between the loss of glycaemic control with monotherapy and the introduction of another blood glucose lowering agent. Appropriately timed introduction of combination therapy could reduce the patient s risk of diabetes-related complications and improve the patient s quality of life. 19 Dr. Hisham Ah. Nematalla

20 American Diabetes Association/ European Association for the Study of Diabetes (ADA/EASD) algorithm for glycemic control (2015) ADA/EASD algorithm for glycemic control Potential sequences of anti-hyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications. Metformin remains the initial treatment of choice (barring contraindications), though guidelines suggest if patients are highly motivated and their A1C is less than 7.5%, a 3- to 6-month trial of lifestyle modifications can be used before pharmacotherapy is initiated. 20 Dr. Hisham Ah. Nematalla

21 The guidelines continue to recommend adding, rather than changing to additional agents when metformin no longer provides adequate glycemic control or when A1C remains elevated after about a 3-month trial. Despite a failing metformin regimen, there may still be some clinical benefit with its continued use. One criterion for stopping the drug is an egfr of <30 ml/min. Of course, any use in patients with CKD mandates diligent follow-up of renal function. In circumstances where metformin is contraindicated or not tolerated, one of the second-line agents may be used, although the choices become more limited if renal insufficiency is the reason metformin is being avoided. In these circumstances it is unwise to use sulfonylureas, particularly glibenclamide (known as glyburide in the USA and Canada), because of the risk of hypoglycaemia. DPP-4 inhibitors are probably a preferable choice, although, with the exception of linagliptin dosage adjustments are required. If the HbA1c target is not achieved after ~3 months, consider one of the six treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist or basal insulin. (The order in the chart, not meant to denote any specific preference, was determined by the historical availability of the class and route of administration, with injectable to the right and insulin to the far right.) Drug choice is based on patient preferences as well as various patient, disease and drug characteristics, with the goal being to reduce glucose concentrations while minimizing side effects, especially hypoglycaemia. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas in patients with irregular meal schedules or who develop late postprandial hypoglycaemia on a sulfonylurea. Other drugs not shown (α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide) may be tried in specific situations (where available), but are generally not favored because of their modest efficacy, the frequency of administration and/or limiting side effects. In 21 Dr. Hisham Ah. Nematalla

22 patients intolerant of, or with contraindications for, metformin, consider initial drug from other classes. (b): Consider initiating therapy with a dual combination when HbA1c is 9% ( 75 mmol/mol) to more expeditiously achieve target. (c): Usually a basal insulin (e.g. NPH, glargine, detemir). (d): Consider initial therapy at this stage when blood glucose is mmol/l ( mg/dl) and/or HbA1c 10 12% ( mmol/mol), especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen. 22 Dr. Hisham Ah. Nematalla

23 American Association of Clinical Endocrinologist /American College of Endocrinology (AACE/ACE) algorithm for glycemic control (2015) 23 Dr. Hisham Ah. Nematalla

24 Conversion from oral DM agents to insulin-only therapy: Some patients, because of significant hyperglycemia, adverse effects, or contraindications to other T2DM drugs, require an insulin-only regimen to control their hyperglycemia. Current ADA recommendations are to initiate insulin early in patients with significant baseline hyperglycemia (A1C of 10% or greater; glucose greater than 300 mg/dl) and in those with symptoms of hyperglycemia (e.g., polyuria, polydipsia, polyphagia) if catabolic features (weight loss, ketosis) are present. Monotherapy with a long-acting basal insulin alone (e.g., glargine, detemir) in patients with T2DM will not provide control of hyperglycemic excursions after meals. 24 Dr. Hisham Ah. Nematalla

25 Therefore, the most common insulin-only regimens include the use of twice-daily premixed insulin preparations or basal/bolus insulin therapy. Initial estimates vary by clinician and are most commonly weightbased. Estimates of unit/kg/day are common, and patients with T2DM often require considerably more insulin compared with patients with type 1 diabetes mellitus because of insulin resistance. Premixed insulin regimen: The premixed option uses existing commercial insulin products containing more than one type of insulin (e.g., 70% neutral protamine Hagedorn, 30% regular insulin or 50:50), or has the patient draw two types of insulin into the same syringe. Premixed insulin therapy administers two-thirds of the total daily insulin requirements before the morning meal and the remaining one-third before the evening meal. Administration time before meals depends on the specific short- or rapid-acting insulin selected. Advantages of using premixed insulin therapy include fewer injections per day, less calculation by the patient, lower costs with older insulin formulations, and ease of use in patient s incapable of or unwilling to determine and manage their daily insulin needs. The primary disadvantage of this therapy option is that dosage adjustment alters both administered insulins, and patients may not have issues with both fasting and postprandial glucose control. The risk of hypoglycemia using older, less expensive insulin options is higher than with newer insulin analogs. Patients also need to make sure they are consistent in their food intake because increases in dosage are not as flexible. 25 Dr. Hisham Ah. Nematalla

26 Basal/bolus Insulin regimen Basal/bolus Insulin therapy employs a long-acting insulin preparation either once or twice daily basal therapy) and pre-meal injections with a rapid-acting insulin (bolus therapy). The intent of the basal therapy is to mimic the natural insulin secretion that occurs throughout the day and night even while fasting, whereas the bolus therapy controls for hyperglycemic excursions after meals. Alterations in basal insulin dosage can then be based on assessing glycemic control in the morning and before the evening meal. With basal/bolus therapy, one-half of the total daily insulin requirement is provided as basal insulin, with the other half used for pre-meal bolus dosing. The daily bolus requirement is then equally divided for morning, midday, and evening meals. Advantages of basal/bolus therapy are that it is more patient-specific given the insulin needs and can be more easily adjusted to patient lifestyles. If a patient eats more carbohydrates at one meal, the bolus therapy can be increased accordingly. If the patient skips a meal, the bolus therapy can be skipped at that time. Disadvantages include a higher number of daily injections than with premixed formulations because neither of the currently available basal insulins should be mixed with other insulins in the same syringe. 26 Dr. Hisham Ah. Nematalla

27 27 Dr. Hisham Ah. Nematalla

28 Conclusion Glycemic therapy goals 1. A1C less than 7.0% (Note: ACE/AACE recommend 6.5% or less.) Obtain every 6 months in patients at goal A1C and every 3 months in those over goal. Less-stringent A1C targets may be appropriate in those with a short life expectancy (e.g., terminal cancer), advanced diabetic complications, long-standing diabetes that is difficult to control (e.g., frail elderly patients with a history of hypoglycemia at risk of falls), or extensive other comorbidities. (In such situations, a higher A1C [e.g., less than 8%] may be sufficient to limit the risk of acute complications of hyperglycemia such as dehydration and electrolyte deficiencies.) 2. FPG or pre-meal mg/dl. Frequency of monitoring depends on regimen, type of DM, and current glycemic control. 3. Peak postprandial glucose (1 2 hours after a meal) less than 180 mg/dl Non-glycemic therapy goals 1. Blood pressure less than 140/80 mm Hg (ADA guidelines) ADA guidelines suggest lower systolic blood pressure goals are appropriate in younger patients to reduce nephropathy risk and in those with higher risk of stroke. Eighth Joint National Committee recommends less than 140/90 mm Hg 2. Lipids ADA: LDL-C less than 100 mg/dl; less than 70 mg/dl an option in those with existing cardiovascular disease ACC/AHA 2013 guidelines suggest lowering LDL-C by 30% 49% in patients with diabetes years of age and by at least 50% if 10- year risk of cardiovascular event is at least 7.5% TG less than 150 mg/dl 28 Dr. Hisham Ah. Nematalla