Type II Diabetes Improving Blood Sugar Control. Geneva Clark Briggs, Pharm.D., BCPS

Transcription

1 Type II Diabetes Improving Blood Sugar Control Geneva Clark Briggs, Pharm.D., BCPS

2 Overview Importance of glucose control State of control Review available therapies Helping patients achieve control

3 The Diabetes Epidemic 7.0% of US children and adults have diabetes. 54 million have prediabetes 1.5 million new cases diagnosed in people aged 20 years or older in % Type million undiagnosed 14.6 million diagnosed National Diabetes Statistics Fact Sheet

4 Natural History of Type 2 Diabetes Prediabetes/IGT/IFG T2DM Postprandial glucose Glucose Fasting glucose 126 mg/dl Relative Function 100% Insulin level Beta-cell function Insulin resistance hepatic and peripheral Years from Diabetes Diagnosis IGT=impaired glucose tolerance; IFG=impaired fasting glucose. Diabetes Care 1992;15:

5 American Diabetes Association Glycemic Targets Parameter Normal Goal Additional Action Suggested Fasting < to 130 <80 or >140 (or pre-prandial) glucose Bedtime glucose < to 140 <100 or >160 Postprandial < 140 <180 >180 A1C <6% <7% >8% Diabetes Care 2007;30:S4-S41.

6 What is A1C and Why is it Important? Glycated or glycosylated hemoglobin HbA1C, A1C Normal range: 4.0% to 6.7% Reflects mean glucose levels over preceding 120 days Elevated in: Uncontrolled diabetes mellitus, lead toxicity, alcoholism, iron deficiency anemia, hypertriglyceridemia

7 A1C Goal Achievement Elusive But Important Elevated A1C risk factor for CV disease Every percentagepoint in A1C reduced the risk of microvascular complications by 25% to 37% (UKPDS). 36% A1C Goal Achievement 64% > 7% < 7% Lancet 1998;352: BMJ 2000;321: Diabetes Care 2004;27:17-20.

8 Successful Diabetes Management

9 Type 2 Treatment Options Early Type 2 diabetes insulin resistance with hyperinsulinemia improve insulin sensitivity caloric restriction, exercise, weight management Late Type 2 diabetics patients require exogenous insulin therapy to achieve optimal glucose control

10 yp e 2 tments for T Increase insulin responsiveness Biguanides Metformin (Glucophage, Fortamet ) Thiazolidinediones Rosiglitazone (Avandia ) Pioglitazone (Actos ) Stimulate insulin release Sulfonylureas Glipizide (Glucotrol ), glipizide XL (Glucotrol XL ) Glyburide (DiaBeta, Glynase, Micronase ) Glimepiride (Amaryl ) Meglitinides Nateglinide (Starlix ) Repaglinide (Prandin ) Modify intestinal absorption of carbohydrate Alpha-glucosidase inhibitor Acarbose (Precose ) Miglitol (Glyset ) Reduce postprandial glucose Amylin Analog Pramlintide (Symlin ) Incretin mimetics Exenatide (Byetta ) Incretin enahancers Sitagliptin (Januvia ) T ea Correct Insulin Deficiency r Insulin

11 Biguanides Metformin (Glucophage,Fortamet ) Mechanism of action Decreases hepatic glucose production reduces gluconeogenesis Improves insulin sensitivity (increases peripheral glucose uptake and utilization)

12 Metformin Efficacy Decrease fasting plasma glucose mg/dl Reduce A1C % Other Effects Cause small decrease in LDL cholesterol level and triglycerides No weight gain, with possible modest weight loss

13 Metformin Starting dose 500 mg bid with morning and evening meals Can be increased at rate of 1 tab/week Maximum daily dose 2550 mg/day Adverse reactions GI N/V/D, bloating, flatulence, anorexia Resolve spontaneously with continued treatment Decreased with gradual dose escalation and administration with food Unpleasant metallic taste (3%)

14 Metformin Precautions Lactic acidosis Rare, but very serious (50% mortality) Occurs due to metformin accumulation 0.03 cases/1000 patient years Increased risk with significant renal insufficiency, HF Hepatic disease increases risk not often used Excessive alcohol intake Metformin should be D/C d prior to radiocontrast dye and held for 24 hours after administration

15 Metformin Precautions Renal function Should be assessed before starting metformin and at least yearly thereafter Not generally used in patients with SrCr above upper limits of normal for age (SrCr > 1.5 for males, 1.4 for females) Caution with elderly patients Contraindicated in HF requiring drug therapy

16 Thiazolidinediones Pioglitazone (Actos ) & Rosiglitazone (Avandia ) Mechanism of Action Improve glycemic control by improving insulin sensitivity Highly selective and potent agonists for the peroxisome proliferator-activated receptor-gamma (PPARg) Require insulin to be present for action May also lower liver glucose production

17 Thiazolidinediones Efficacy Decrease fasting plasma glucose mg/dl Reduce A1C % 6 weeks for maximum effect

18 Rosiglitazone Dose Monotherapy or in combo. with metformin- 4 mg administered qd or divided bid, dose may be increased to 8 mg/day with inadequate response after 12 weeks Taken without regard to meals Hepatic Impairment Therapy not initiated with evidence of active liver disease or increased ALT (>2.5x upper limit of normal) at baseline No evidence of induced hepatotoxicity

19 Rosiglitazone Adverse reactions Edema and anemia mild to moderate Weight gain Precautions Ovulation - In premenopausal anovulatory patients, treatment may result in resumption of ovulation Cardiovascular risks

20 Pioglitazone Characteristics very similar to rosiglitazone Therapy should not be initiated if clinical evidence of active liver disease or ALT exceeds 2.5 times the upper limit of normal Dose 15 or 30 mg po qd, maximum 45 mg qd Without regard to meals Used in combination with sulfonylureas, metformin, insulin

21 Sulfonylureas Stimulates insulin release from pancreatic β-cells Primary acute mechanism Down-regulation of this affect over time Other pancreatic actions: Reduce hepatic clearance of insulin Suppress glucagon release slightly Stimulate somatostatin release

22 Sulfonylureas Extrapancreatic effects Responsible for long-term efficacy Reduce hepatic gluconeogenesis May increase insulin receptor sensitivity and number Potentiation of post-receptor insulin effects - Stimulate synthesis of glucose transporters

23 Sulfonylureas Characteristics Administered orally Few therapeutic differences among agents Should be administered 30 min. before breakfast for maximal absorption Dose can be increased every 1-2 weeks Metabolized in liver, mainly excreted in urine (glyburide 50% in feces)

24 Drug Tolbutamide Acetohexamide Onset (h) 1 1 Sulfonylureas Duration (h) Starting Dose 1-2g/d in 2 or 3 doses mg/d Max. dose/day 2-3 g 1.5 g Tolazamide mg/d in 1 or 2 doses 750mg 1 g Chlorpropamide mg/d 500 mg Glyburide mg/d 20 mg Glyburide, micronized mg/d 12 mg Glipizide mg/d 40 mg* Glimeperide mg/day 8 mg * Doses above 15 mg/day should be divided and administered twice daily

25 Sulfonylureas Efficacy Decrease fasting plasma glucose mg/dl Reduce A1C by % Adverse effects Hypoglycemia fairly common Skin reactions (3%) rashes, pruritis GI Rare hematologic reactions Weight gain

26 Meglitinides Repaglinide (Prandin ) & Nateglinide (Starlix ) Pharmacologic effect is similar to sulfonylureas Shorter duration of action Efficacy Decreases peak postprandial glucose Decreases plasma glucose mg/dl Reduce A1C %

27 Repaglinide Starting Dose 0.5 mg po tid taken immediately before eating each meal Can increase dose every week Maximum dose = 4 mg po tid Main adverse effect hypoglycemia weight gain

28 Nateglinide Starting and maintenance dose 120 mg po tid 1-30 minutes before meals Dose should be skipped if meal is skipped Main adverse effect hypoglycemia weight gain

29 Alpha-Glucosidase Inhibitors Acarbose (Precose ) & Miglitol (Glyset ) Mechanism of Action Inhibition of membrane bound intestinal brush border alpha glucosidase enzyme Membrane-bound intestinal alpha-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine Enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia

30 Alpha-Glucosidase Inhibitors Efficacy Decrease peak postprandial glucose mg/dl Decrease fasting plasma glucose mg/dl Decrease A1C %

31 Acarbose Not absorbed from the GI tract Onset 0.5 hrs. Half-life 1 to 2 hrs. Duration 4 hrs. Recommended starting dose 25 mg/d with first bite of main meal, possibly 25 mg po tid Max. dose/day 300 mg

32 Miglitol Absorption not related to therapeutic efficacy Excreted in urine as unchanged drug (95%) Initial dose 25 mg po tid with first bite of each main meal, some may need lower dose to minimize GI adverse events Max. daily dose 100 mg po tid

33 Adverse Events Mainly GI Abdominal pain 11% Diarrhea 29% Flatulence 42% Abdominal pain and diarrhea diminish with continued treatment AE s minimized by starting at low dose and utilizing slow dosage titration Skin rash 4.3%

34 Other Considerations Not recommended for patients with inflammatory bowel disease May alter liver function at high doses Diet and activity may have to be altered to limit production of gas Often used in combination with other antidiabetic agents

35 Gliptins Incretin Enhancers Sitagliptin (Januvia ) Orally active, selective inhibitor for the DPP-IV enzyme Stimulates glucose dependent insulin secretion, slows gastric emptying, suppresses postprandial glucagon levels, and decreases liver glucose release Oral dosing: mg once daily Can be administered with or without food Moderate renal dysfunction: 50 mg qd Severe or ESRD: 25 mg qd

36 Gliptins Efficacy Decrease peak postprandial glucose mg/dl Decrease fasting plasma glucose mg/dl Decrease A1C %

37 Gliptins Adverse Effects Sitagliptin 100 mg versus placebo Hypoglycemia (1.2% vs 0.9%) Abdominal pain (2.3%, 2.1%) Nausea (1.4%, 0.6%) Diarrhea (3.0%, 2.3%) Weight neutral

38 Combination Therapies Combo Glipizide/metformin Glyburide/metformin Rosiglitazone/metformin Pioglitazone/metformin Pioglitazone/glimepiride Rosiglitazone/glimepiride Sitagliptin/metformin Brand generic, Metaglip generic, Glucovance Avandamet ActoPus Met Duetact Avandaryl Janumet 2.5/250, 2.5/500, 5/ /250, 2.5/500, 5/500 1/500, 2/500, 2/1000, 4/500, 4/ /500, 15/850 30/2, 30/4 Strengths 4/1, 4/2, 4/4 50/500, 50/1000

39 Treatment of Type 2 Diabetes Diagnosis Therapeutic Lifestyle Change Monotherapy Combination Therapy - Oral Drugs Only Combination Therapy - Oral Drug with Insulin

40 Helping Patients Get to Goal Educate about A1C and why it is important to get to goal set by PCP Reinforce adherence with diet and exercise Seek ways to assist patient with medication adherence

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