Diabetes Mellitus

Educational Objectives

The goal of this program is to improve the management of type 2 diabetes mellitus (T2DM). After hearing and assim­ilating this program, the clinician will be better able to:

Characterize and distinguish the main groups of oral agents used for the treatment of T2DM.

Describe modifiable risk factors for T2DM and actions necessary to reduce the risk.

Discuss challenges encountered in the treatment of T2DM.

Recognize importance of lifestyle modification in the treatment of T2DM.

Utilize the current algorithm of the American Diabetes Association in achieving treatment goals.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Weart is a consultant for Pfizer, Novartis, and Merck, and is on the Speakers’ Bureaus for Novartis, Pfizer, Merck, and sanofi aventis. Dr. Breen and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Breen was recorded at the Third Annual Update on Diabetes and Endocrine Disorders for the Practicing Physi­cian, held October 17, 2008, in New York, NY, and sponsored by the Mount Sinai School of Medicine. Dr. Weart was recorded at The New Drug Update, held May 8-10, 2008, in Charleston, SC, and sponsored by the Medical University of South Carolina. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Oral Therapies

Tracy L. Breen, MD, Assistant Professor of Medicine, Division of Endocrinology, Diabetes, and Bone Dis­eases; and Director, Diabetes Program, Mt. Sinai School of Medicine, New York, NY

Definitions: normal fasting blood glucose (FBG) <100 mg/dL currently defined as normal (in reality, normal proba­bly  <90 or 93 mg/dL); if FBG >100 mg/dL but <126 mg/dL, impaired FBG or prediabetes present (diagnosed with pre- or postprandial BG); random or postprandial BG >200 mg/dL on >1 occasion or with evidence of symptoms diagnostic of diabetes; random BG >180 mg/dL on >1 occasion possibly impaired glucose tolerance or prediabetes; historically, medical community failed to treat diabetes in timely fashion (often, microvascular complications al­ready seen at presentation)

United Kingdom Prospective Diabetes Study (UKPDS): patients with newly diagnosed diabetes or even prediabe­tes had increased risk for diabetic retinopathy (damage already under way); paradigm shift in treatment from incre­mental approach to more aggressive “treat-to-target” approach; attempt to obtain normoglycemia rapidly; evidence suggests that, particularly for newly diagnosed patient, window of opportunity to treat aggressively and benefit from tighter control, compared to older patients with established disease

Therapies for type 2 diabetes mellitus (T2DM): metformin and thiazolidinediones (TZDs)  —  decrease hepatic insu­lin resistance; in pancreas, secretagogues cause production and secretion of more insulin than would normally oc­cur in dysregulated diabetic state; act on muscle to decrease insulin resistance; in adipose tissue, decrease free fatty acid load seen as part of dysregulation or dysmetabolism of diabetes; digestion of polysaccharides  —  a-glucosidase inhibitors prevent absorption of carbohydrates; effective for treatment but have side effects (eg, bloating, flatulence, leakage of fecal contents); in T2DM, goal to target insulin resistance; acanthosis being seen more frequently in younger children and in obese adolescents; as more insulin produced to overcome insulin resistance, hyperglyce­mia avoided but dysmetabolic state present

Metformin: isolated from French lilac plant; biguanide used for long time and well studied; mechanism of action un­known; reduces hepatic gluconeogenesis, decreases insulin resistance, and inhibits glycolysis; increased risk for lactic acidosis (overplayed); adhere to creatinine cutoffs (not used if creatinine >1.5 mg/dL in men or >1.4 mg/dL in women); UKPDS data  —  metformin used; participants had newly diagnosed diabetes; randomized to intensive or nonintensive therapy; intensive therapy included insulin and sulfonylureas; small subset of overweight partici­pants received metformin; found that microvascular complications decreased in any group treated more intensively; at that time, effect on cardiovascular disease (CVD) or mortality not seen; UKPDS follow-up data  —showed that once participants released from study, HbA_1c values merged and indistinguishable (similar to Diabetes Control and Complications Trial [DCCT] with type 1 diabetes), but effect lasted (sustained legacy effect of reducing risk in fu­ture); decreased risk for CVD and death in treated groups, but more pronounced in group treated with metformin (30% reduction); side effects  —  severe gastrointestinal (GI) upset, loose bowel movements, and cramping; symp­toms disappear in 2 wk in most patients; started at low dose and taken with food; GI effects seen at initiation of therapy and during dose increases

Thiazolidinediones: act as peroxisome proliferator-activated receptor gamma (PPAR g) agonists; PPAR g nuclear hormone receptor has genomic effects (takes weeks to take effect and for effect to wear off); powerful effect on in­sulin sensitivity and adipogenesis; meta-analysis placed efficacy under suspicion; still reasonable glycemic agent to use but with caveats; not used in  —  those with established CV disease; those on insulin (combination leads to higher risk for heart failure and edema); concern from patient or patient’s spouse and evidence of CVD speaker’s criteria for discontinuing rosiglitazone (Avandia) or other glitazone

Incretin system: first identified in Gila monster; incretins  —produced by endocrine cells of gut in response to food; glucagon-like peptide-1 (GLP-1) and GLP-2 identified; only GLP-1 has clinical relevance; secreted in response to meal and stimulate insulin secretion from pancreatic b-cells; in animal models, shown to decrease b-cell apoptosis, increase b-cell neogenesis, inhibit glucagon secretion, delay gastric emptying, and induce satiety; rapidly inacti­vated by enzyme (lasts only few minutes); in diabetes, GLP-1 level abnormal (inappropriate secretion of GLP-1); exenatide  —  injectable; incretin mimetic; long-acting form available soon; associated with weight loss and more cases of pancreatitis; sitagliptin  — oral form of dipeptidyl peptidase (DPP)-IV (enzyme that degrades incretin) in­hibitor; similar agents in pipeline; good side effect profile; weight-neutral; has renal dosing options; issue of degree of efficacy on BG-lowering; first line in diabetic therapy control of HbA_1c or FBG

Case patient: prescribed walking 30 min daily and metformin

Questions and answers: whether to continue metformin in woman 80 yr of age  —  speaker comfortable with continu­ing metformin in healthy individual, 80 yr of age, with few medical issues and glomerular filtration rate (GFR) >50 mL/min; probably would not start metformin on individual 80 yr of age; in older person (>50 yr), look at GFR rather than creatinine; problem with combination agents  —  unable to assess or titrate individually; speaker does not like starting with dual therapy; also difficult to assess side effect profile; whether metformin extended-release (ER) better tolerated  —  alternative for patients unable to tolerate regular metformin; preferred by speaker in those with fasting morning hyperglycemia

Risk Reduction

Dr. Breen 

Risk modification: micro- and macrovascular risk reduction; lowering low-density lipoprotein (LDL) to <100 mg/dL (ideally <70 mg/dL); BP <130/80 mm Hg; HbA_1c <7% (ideally 6%; in newly diagnosed patients, aggressively treat BG levels); health maintenance  —  dilated eye examinations yearly; examine feet at every visit; electrocardiography (ECG); test urine for microalbuminuria periodically; CVD  —  seen earlier in majority of patients with diabetes, and such patients succumb more frequently; risk 3 times higher in women with diabetes, compared to nondiabetic counterparts (2 times higher in men); also seen at younger age

Modifiable risks: eyesight (diabetes leading cause of blindness in United States); kidney function (diabetes has sur­passed hypertension as leading cause of kidney failure); CV risk reduction should be at forefront of treatment; mod­ifiable risk factors  —  dyslipidemia; hypertension; tobacco use; CV risk associations  —  hyperglycemia (associated with higher CV risk, but not proven that risk reduced if glycemia decreased); microalbuminuria marker for CV risk (unknown whether lowering it has effect on risk); overweight

Dyslipidemia and CVD risk: increased CVD associated with increased LDL, increased triglycerides, and decreased high-density lipoprotein (HDL); biggest effect seen with LDL; HDL difficult to raise; not much success with med­ication to raise HDL; focus on lowering LDL, but side effects seen with more powerful lipid-lowering agents; dyslipidemia  —  affected by obesity and overweight; fat consumption and composition; physical inactivity; cigarette smoking; excess alcohol intake; hyperglycemia affects triglycerides; should treat hyperglycemia first in patient with isolated triglyceridemia and hyperglycemia; dietary fat  —  trans fats not good; artificially solidified fats (hy­drogenated; not solid at room temperature in nature); advise patients to exchange for healthy oils and decrease oils used; advise patients to remove skin from poultry, decrease meat consumption, and increase fiber intake; fiber  —  lowers BG, lipids, and BP; ideally, dietary fiber used; supplemental fiber should be given with increased fluids (otherwise, causes constipation); Mediterranean and other heart-healthy diets have in common high fiber and low fat

Dietary Approaches to Stop Hypertension (DASH) diet: lowering BP shown to affect all aspects of diabetic risk (micro- and macrovascular); should reduce sodium in diet (many people salt-sensitive); decreasing alcohol con­sumption and tobacco use also affects BP; original DASH diet  —  actually high-fiber low-fat diet; decreased BP by 11 points in hypertensive group; also decreased BP in normotensive group; low-salt component had greatest effect on blacks

Tobacco use: worsens lipid profile and increases BP; negative effect on diabetic eye disease, neuropathy, and kidney disease; study showed that 10% of patients stop smoking after minimal physician counseling

Exercise: significant difference seen between 2 individuals with same body mass index (BMI) but one exercising and other not exercising; short-term effect  —  increased glucose uptake; long-term effects  —  regular exercisers dispose of glucose faster, due to increased translocation of glucose transporters; metabolic effects of physical activity inde­pendent of weight loss; study of efficacy of walking interventions  —  most effective those given on 1:1 basis (ie, phy­sician, patient, and patient’s family in room); most sedentary and most motivated patients benefitted most

Foot examination: 80% of all amputations for diabetes start from single foot ulcer; examination emphasizes good foot care

Questions and answers: angiotensin-converting enzyme (ACE) inhibitors for normotensive diabetic patients  —  appropriate in patients with established microalbuminuria (delays progression of kidney disease); added at first sign of increased BP or microalbuminuria; scenarios for insulin therapy  —  beneficial in newly diagnosed patient who is profoundly gluco-toxic, feeling unwell, and in catabolic state; tell patient insulin therapy probably tempo­rary (»2 mo) and to let body rest (patients usually receptive); also in patient on >2 agents and unable to lower HbA_1c to <7%

Important Concepts in T2DM

C. Wayne Weart, PharmD, Professor of Clinical Pharmacy and Outcome Sciences and Professor of Family Medicine, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston  

Diabetes Prevention Program: looked at participants with metabolic syndrome; goal 7% weight loss over 3 yr; also had exercise component (brisk, purposeful walking of 150 min/wk or 30 min ³5 times/wk) compared to usual care vs metformin vs troglitazone (Rezulin); looked at risk of developing new-onset diabetes over 3 yr; results  —  in those who got usual care (standard lifestyle recommendations and placebo), 11% developed diabetes; 7.8% in those who received metformin (31% relative risk [RR] reduction); 4.8% in those who received intensive lifestyle modifi­cation (58% RR reduction); drug therapy not equivalent to lifestyle; follow-up from study  —  suggests that lifestyle intervention (diet and exercise) delayed development of T2DM by »11 yr (with metformin, delay 3 yr); walking probably best medicine for prevention and treatment of diabetes; exercise  —  up-regulates insulin receptors (more responsive to lower amounts of insulin); single most important factor in management of diabetes; American Diabe­tes Association (ADA) exercise recommendations  —  aerobic exercise (eg, brisk purposeful walking, riding bike, jogging, swimming) of moderate intensity >150 min/wk, with resistance (weight) training 3 times/wk; combination better than either alone

Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial: >5200 partici­pants, ³30 yr of age, with impaired FBG or impaired glucose tolerance and no history of CVD; randomized to rosi­glitazone or placebo for average of 3 yr; looked at risk of developing new-onset diabetes; found significant reduction of risk, with number needed to treat (NNT) of 7 with TZD; also seen with troglitazone; CV events same in both groups, except that more participants in rosiglitazone group developed new-onset heart failure; ramipril (Al­tace) arm did not show significant reduction

Natural history of T2DM: T2DM late finding; before individual develops T2DM, insulin resistance and hyperinsu­linemia present; occurs 8 to 10 yr before symptoms develop; b-cell function starts to deteriorate, and insulin level increases due to insulin resistance in skeletal muscle and liver; takes more insulin to utilize glucose to maintain nor­mal BG; increasing insulin in response to insulin tissue sensitivity leads to down-regulation of insulin and worsen­ing resistance; eventually, b-cells unable to overcome resistance, leading to increased BG; T2DM resistance problem, not insulin problem; postprandial BG increases first (not FBG); ADA uses FBG for diagnosis, but World Health Organization uses postprandial BG tolerance test to make diagnosis sooner; once diagnosis made, over time, insulin level declines; no drug prevents eventual decline in b-cell function; European Association for the Study of Diabetes (EASD) states that if patient with T2DM lives long enough,  insulin therapy will be required

Glycemic goals: from ADA (2008) and from American Association of Clinical Endocrinologists (AACE; 2007); nor­mal FBG <100 mg/dL (ADA goal 70-130 mg/dL; AACE <110 mg/dL); normal HbA_1c <6% (ADA goal <7%; AACE <6.5%); normal postprandial BG <140 mg/dL (ADA goal <180 mg/dL; AACE goal <140 mg/dL); postpran­dial BG (1-2 hr after largest meal) probably correlates better with poor outcomes than FBG

Current ADA algorithm: updated January 2008; lifestyle modification and metformin at top of algorithm (reduces morbidity and mortality); HbA_1c goal <7%; if >7%, 3 options; most effective option adding basal insulin (Neutral Protamine Hagedorn [NPH] insulin at bedtime or insulin glargine [Lantus] at bedtime or in morning, or insulin de­temir [Levemir] at bedtime); other option adding sulfonylurea (speaker’s preference generic glipizide [Glucotrol] or glimepiride [Amaryl]; least expensive but with greater risk for hypoglycemia); third option adding glitazones (increased risk for edema, heart failure [black box warning for both], and fractures); rosiglitazone associated with increased risk for myocardial infarction

Goals of treatment: reduce events; if goal not achieved  —intensify insulin by adding immediate-release short-acting insulin with or before each meal; add glitazone to sulfonylurea and metformin; add basal insulin to sulfonylurea and metformin, or metformin plus TZD, or add sulfonylurea to metformin and TZD; if goal still not achieved and >2 to 3 drugs required, intensify insulin and/or metformin or glitazone, but withdraw sulfonylurea; higher the base­line HbA_1c, the greater FBG contribution to it; the closer to achieving goal, the more important postprandial BG be­comes; metformin and TZDs target FBG, while sulfonylureas, short-acting insulin, and meglitinides mainly target postprandial BG (also sitagliptin and exenatide)

Suggested Reading

Araki S et al: Reduction in microalbuminuria as an indicator for renal and cardiovascular risk reduction in patients with type 2 diabe­tes. Diabetes 56:1727-30, 2007; Basu R et al: Comparison of the effects of pioglitazone and metformin on hepatic and extra-hepatic insulin action in people with type 2 diabetes. Diabetes 57:24-31, 2008; Blake GJ et al: Hemoglobin A1c level and future cardiovas­cular events among women. Arch Intern Med 164:757-61, 2004; Cavalot F et al: Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gon­zaga Diabetes Study. J Clin Endocrinol Metab 91:813-9, 2006; Deatcher JV: Prediabetes. Am J Nurs; 108:77, 2008; Edmisson KW: Multidimensional pharmacologic strategies for diabetes. Nurs Clin North Am 40:107-17, 2005; Holman RR et al: 4-T Study Group. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 357:1716-30, 2007; Knop FK et al: Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes 56:1951-9, 2007; Lipscombe LL  et al: Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 298:2634-43, 2007; Muscelli E et al: Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 57:1340, 2008; Nissen SE et al: Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457-71, 2007 Erratum in: N Engl J Med 357:100, 2007; Rodondi N et al: Therapy modifications in response to poorly controlled hypertension, dyslipidemia, and diabetes mellitus. Ann Intern Med 144:475-84, 2006; Sargrad KR et al: Effect of high protein vs high carbohydrate intake on insulin sensitivity, body weight, hemoglobin A1c, and blood pressure in patients with type 2 diabetes mellitus. J Am Diet Assoc 105:573-80, 2005; Sigal RJ et al: Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med 147:357-69, 2007; Yudkin JS: Very tight glucose control: May be high risk, low benefit. BMJ 336:683, 2008.