DIABETES
From Johns Hopkins University School of Medicine’s Endocrinology and Metabolism: The Clinical State of the Art
| STATE-OF-THE-ART MANAGEMENT OF TYPE 2 DIABETES —David M. Nathan, MD, Director, Diabetes Center, Massachusetts General Hospital, Boston |
| Diabetes Control and Complications Trial (DCCT): long-term study showed benefits of intensive metabolic control in patients with type 1 diabetes; lowering hemoglobin A1c (HbA1c ) to 7% produced significant reduction (≈75%) in risk for complications (eye, kidney, and nervous system) |
| United Kingdom Prospective Diabetes Study (UKPDS): patients had initial levels of HbA1c of 7%; 1% difference maintained between groups (intensive therapy vs standard therapy); in all patients, disease worsened metabolically with time (insulin resistance worsened, insulin secretion declined, and levels of HbA1c rose); treatment protocol—medications (eg, sulfonylurea, metformin, or insulin) added sequentially to treatment regimens once failure occurred (as indicated by rising levels of blood glucose [BG]); effect of metabolic control on complications—risk for retinopathy reduced by 37% for each decrease in HbA1c of 1 percentage point (similar to results from DCCT) |
| Diet and exercise: short-term benefits of diet and exercise well established; modest reduction in weight (eg, 5-10 lb) results in dramatic decrease in level of BG, thereby reducing requirements for medication; however, high rate of recidivism; results from UKPDS—patients saw dieticians every 3 to 4 mo for entire course of study; although patients lost weight initially, they gained weight ultimately (weight gain less than in patients undergoing intensive therapy); HbA1c rose over time; relative importance—increasing activity alone not effective, but important in maintaining weight loss; weight loss of 5 to 10 lb may lead to remission in short term; long-term maintenance of weight loss in population of overweight individuals difficult to attain; other interventions required if diet fails |
| Sulfonylureas: oldest class of medications for control of diabetes; HbA1c decreased by 1 to 2 percentage points; rates of primary and secondary failure substantial; mechanism—stimulate secretion of insulin by binding to specific receptor on β cell; problems—less effective in nonobese patients; may cause severe hypoglycemia and weight gain; fail over time (HbA1c typically returns to pretreatment level within 5 yr); study—51 patients with HbA1c \>7.5% (relatively recent onset) randomized to bid insulin or glibenclamide (glyburide); found that insulin lowered HbA1C significantly more than glibenclamide; over 2 yr, β-cell function declined more in patients treated with glibenclamide than in those treated with insulin (ie, sulfonylureas accelerate decline of β-cell function) |
| Glitinides: new class of drugs, similar to sulfonylureas; nateglinide weaker than metformin (ie, less effective at lowering HbA1c ), but in combination with metformin, HbA1C of ≤7% achieved; shorter half-life beneficial for patients with renal dysfunction; low risk for hypoglycemia; study—patients treated with combination of metformin with repaglinide (Prandin) or nateglinide (Starlix); combination with Prandin had slightly better effect on HbA1c |
| Metformin: fear of lactic acidosis kept drug off market in United States until 1995; incidence of lactic acidosis much lower than with phenformin; most common oral treatment for diabetes worldwide; mechanism—inhibits hepatic glucose output; lowers glucose with lower levels of insulin (ie, insulin sensitizer); works in obese and nonobese patients; clinical trials—1) found metformin reduces HbA1c by ≈1.5 percentage points in patients who had failed diet therapy; 2) when patients who had failed therapy with sulfonylurea (glyburide) switched to metformin, no change in HbA1C , ie, metformin and glyburide equipotent; when metformin added to glyburide, HbA1C fell by ≈1.7%; to achieve synergistic effect in combination therapy, drugs must have different mechanisms of action; adverse effects—≈10% of patients experience gastrointestinal (GI) discomfort (diarrhea, rumbling, or increased production of gas); lactic acidosis rare, but fatal in 25% to 30% of cases; hypoglycemia does not occur when metformin used as monotherapy; titrating dosage may reduce GI effects (speaker begins with 500 mg once daily, then increases to 500 mg bid, then further increases dose to ≥850 mg bid); comparison to sulfonylureas—similar potencies and long-term efficacies; adverse-effect profile may determine choice; because sulfonylureas associated with hypoglycemia, weight gain, and possible cardiovascular risk, speaker prefers metformin as first-line oral therapy; primary and secondary failure occurs in 3 to 5 yr on metformin or sulfonylurea |
| α-glycosidase inhibitors: weak drugs; generally used in combination with other therapies; acarbose reduced HbA1c by 0.5 to 1.0 percentage point when added to treatment regimen of diet, sulfonylurea, metformin, or insulin; mechanism—inhibits absorption of carbohydrates in small intestine (increasing production of methane in large intestine); limiting intake of carbohydrates and titrating dosage may reduce adverse effects |
| Thiazolidinediones (TZDs): increase uptake of glucose in periphery and suppress release of glucose from liver by binding to specific nuclear receptors (peroxisome proliferator-activated receptor-γ [PPAR-γ]); efficacy—poor as monotherapy (HbA1c actually rose in some studies), but good in combination therapy (leads to additional decrease in HbA1c of ≈1%); study — compared pioglitazone and rosiglitizone; no differences in weight gain or effect on HbA1c , but pioglitazone had lipid-lowering effect (total cholesterol, low-density lipoprotein [LDL], and triglycerides decreased); adverse effects—generally well tolerated, but edema and congestive heart failure (CHF) may occur; although liver dysfunction not commonly seen, monitoring of liver function still required (no long-term data available) |
| Insulin: quantity more important than frequency or mode of delivery; prescribed dosage often subtherapeutic; no maximum dose; studies—benefits found for intensive treatment (beginning with 90 units daily, and increasing to maintain target level of HbA1c ); single dose of insulin suspension (NPH) at bedtime (increased every 3 or 4 days until target level of BG reached) effective at lowering HbA1c ; 85 units required, on average; other studies show lowest effective dose 60 units, with some patients requiring up to 150 units, on average; hypoglycemia—DCCT showed 3- fold increase in frequency of hypoglycemic episodes in patients on intensive therapy, compared to those on standard therapy; incidence substantially lower in other studies (maximum of 3 episodes per 100 patient-years) |
 | Monotherapy: study compared NPH and insulin glargine; 518 patients followed for 6 mo; differences in reductions in HbA1c not statistically significant; hypoglycemia less severe with glargine; other studies found no differences in HbA1c , fasting glucose, or incidence of severe hypoglycemia |
| Combination therapy: most important combination includes diet, exercise, and medication (patients often neglect diet once medications started); metformin good for controlling weight gain; triple combination therapy (3 oral agents) does not achieve lower HbA1c than 70/30 insulin bid plus metformin; insulin therapy also has positive effects on lipid profile and costs less than therapy with 3 oral agents |
| Conclusions: type 2 diabetes difficult to control over time; diet most cost-effective therapy when effective (behavior modification important to increase likelihood of success); substantial rate of failure with oral agents necessitates changing or adding medications; aggressive use of insulin recommended; treatment of other risk factors for cardiovascular disease also critical; individualization of treatment regimen important |
| Diabetes Prevention Program (DPP): randomized clinical trial; study groups—lifestyle modifications (7% reduction in weight [≈15 lb] plus 30 min of moderate-intensity activity [eg, walking] 5 days/wk); metformin; troglitazone (discontinued because of concerns about safety); patient selection criteria—impaired glucose tolerance (IGT) |
| Results: weight gain—patients in placebo group maintained weight; patients on metformin lost average of 2 kg; patients with lifestyle modifications achieved 7% weight loss initially and maintained ≈5% weight loss over course of study; development of diabetes—11% per year in placebo group; 7.8% per year with metformin therapy; 4.8% per year with lifestyle modifications; over course of therapy, interventions lead to 31% (with metformin) and 58% (with lifestyle changes) reduction in development of diabetes; reduction in risk maintained across age groups |
| Questions and answers: treatment protocol for patients with type 2 diabetes—heterogeneous disorder; insulin secretion and resistance vary among patients; speaker prefers beginning treatment with metformin, along with diet and exercise, then initiating treatment with insulin if therapeutic goals not reached; diets low in carbohydrates— epidemiology of obesity parallels consumption of fat, not carbohydrates; short-term data suggest diets high in fat and low in carbohydrates better for weight loss than diets high in carbohydrates and low in fat; however, no difference between groups at 1 yr; frequency of follow-up visits—approximately every 3 mo (especially when changing treatment regimen), important for tracking level of HbA1c ; patients most likely to lose weight early on; patients who fail dietary therapy should receive medical therapy as soon as possible |
| ASSESSMENT OF GLYCEMIC CONTROL: NEW PARADIGMS —Christopher D. Saudek, MD, Hugh P. McCormick Family Professor of Medicine, Johns Hopkins University School of Medicine, Baltimore |
| Importance: studies show significant decreases in risk for retinopathy and other complications (including myocardial infarction) as level of HbA1c decreases |
| Hemoglobin A1c: minor fraction of HbA that occurs normally (glycosylated Hb) and increases in patients with diabetes; glycosylation of Hb related to control of diabetes; periodic monitoring allows assessment of degree of control of glucose metabolism and relationship to development of sequelae; measure of long-term glycemia; distinct from levels of glucose in urine and blood; mechanism—rapid glycosylation phase followed by rearrangement to HbA1c |
| Case 1: man, 26 yr of age, with type 2 diabetes, complaining of fatigue; diabetes controlled with oral agents; records from self-monitoring of BG (SMBG) average 140 mg/dL (rarely \>200 mg/dL); findings from physical examination include pallor and tachycardia; laboratory results—HbA1c 23%; Hb 7%; hematocrit 18%; diagnosis—aplastic anemia; lack of hematopoiesis results in progressive aging of red blood cells (RBCs) and glycosylation of Hb |
| Lability of glycemic control: data from SMBG records and HbA1c levels from \>200 patients analyzed; mean BG ranged from 80 to 300 mg/dL; HbA1c ranged from 2.8% to 11%; SD of BG ranged from 8 mg/dL (very stable) to 152 mg/dL (very labile); HbA1c and SD of BG correlated with mean level of BG; once mean level of BG controlled, SD of BG (ie, lability) found to have minimal effect on HbA1c ; conclusions—HbA1c reflects average glycemia, not lability of BG; spikes and troughs do not affect HbA1c beyond their effect on mean BG; risk for complications determined by average BG, not lability |
| Clinical use: follow levels of HbA1c in all patients with diabetes; assess baseline, then reassess every 3 to 6 mo; confirm results of SMBG; set target level of HbA1c to <7%; physician compliance—HbA1c followed in <66% of patients |
| Self-monitoring of BG: benefits to patient—assesses glycemia immediately; helps patient to distinguish symptoms of hyperglycemia and hypoglycemia; shows glycemic results of patient’s actions; reduces dependence on health care professionals and empowers patients; provides information about glycemic control between assessments of HbA1c ; provides information about diurnal patterns of glycemia; benefits to physician—downloading data from meters can aid diagnosis (in type 2 diabetes, BG stable with low SD, while in type 1 diabetes, BG labile with high SD), assess lability, track progression over time, and visualize diurnal patterns |
| Guidelines for SMBG: frequency depends on lability of BG and need for follow-up after change in treatment; preprandial and bedtime measurements more stable than postprandial measurements, which vary with multiple factors (eg, specific foods ingested, amount of time between meal and monitoring, speed of absorption, fat content of meal); diabetes considered controlled when preprandial BG measurements and level of HbA1c within target ranges (evidence that level of postprandial BG affects risk for cardiovascular disease shown only in patients with prediabetic IGT); when level of HbA1c higher than expected based on BG levels, increase monitoring to include peaks and troughs; warning—nocturnal hypoglycemia common cause of unexpected death in patients with type 1 diabetes |
| Barriers to SMBG: denial—fundamental barrier; solution lies in educating and empowering patients; expense— problems with insurance; solution lies in educating payers about costs of diabetes (ie, managing complications costs more than monitoring and managing diabetes); physicians—failure or hesitation to recommend SMBG; failure to consider results of SMBG when planning treatment; convenience—current meters smaller and more convenient to use; pain—infrequent complaint among patients who routinely self-monitor |
| Continuous monitoring of BG: will provide many benefits, including alarms for high and low levels of BG and information about diurnal patterns; will address research questions about specific effects of each meal, stressor, and exercise, and about correlations between levels of BG and risk for complications; will permit development of closed-loop artificial pancreas |
Educational Objectives
| The goal of this activity is to help the clinician improve quality of care for patients with type 2 diabetes by providing information about prevention, treatment, and monitoring. After hearing and assimilating this program, the clinician will be better able to: |
| Discuss the importance of diet and exercise in treatment regimens for patients with type 2 diabetes. |
| Compare efficacies, rates of failure, and adverse effects of medications commonly used to treat patients with type 2 diabetes. |
| Educate patients about factors that help prevent development of diabetes and its progression. |
| Discuss the effect of glycemic control on level of hemoglobin A1c (HbA1c) and progression of type 2 diabetes. |
| Educate patients about the importance of self-monitoring blood glucose (SMBG), and use SMBG records to assess the efficacy of the treatment regimen. |
Discussed on This Program
Acarbose [ Precose] Glyburide (glibenclamide) [DiaBeta, Glynase PresTab, Micronase] Insulin (various formulations and trade names) Insulin glargine [Lantus] Insulin suspension, isophane (NPH) [Humulin N, Novolin N, Novolin N PenFill, Novolin N Prefilled, NPH Iletin II] Metformin HCl [Fortamet, Glucophage, Glucophage XR] Nateglinide [Starlix] Phenformin hydrochloride [DBI] (available only under IND exemption) Pioglitazone HCl [Actos] Repaglinide [Prandin] Rosiglitazone maleate [Avandia] Troglitazone [Rezulin] (withdrawn)
Suggested Reading
Abuissa H, et al: Strategies to prevent type 2 diabetes. Curr Med Res Opin 21:1107, 2005; Franciosi M, et al: Self-monitoring of blood glucose in non-insulin-treated diabetic patients: a longitudinal evaluation of its impact on metabolic control. Diabet Med 22:900, 2005; Gaede P, Pedersen O: Multi-targeted and aggressive treatment of patients with type 2 diabetes at high risk: what are we waiting for? Horm Metab Res 37(Suppl 1):69, 2005; Guerrero-Romero F, Rodriguez-Moran M: Complementary therapies for diabetes: the case for chromium, magnesium, and antioxidants. Arch Med Res 36:250, 2005; Monnier L, et al: An overview of the rationale for pharmacological strategies in type 2 diabetes: from the evidence to new perspectives. Diabetes Metab 31:101, 2005; Pennock T: Diabetes and nutrition: the latest thinking on dietary management. Prof Nurse 20:27, 2005; Pitale S, et al: Health-related quality of life in the VA Feasibility Study on glycemic control and complications in Type 2 diabetes mellitus. J Diabetes Complications 19:207, 2005; Rhee MK, et al: Barriers to diabetes education in urban patients: perceptions, patterns, and associated factors. Diabetes Educ 31: 410, 2005; Roges OA, et al: The incretin effect and its potentiation by glucagon-like peptide 1-based therapies: a revolution in diabetes management. Expert Opin Invest Drugs 14:705, 2005; Scheen AJ: Drug interactions of clinical importance with antihyperglycaemic agents: an update. Drug Saf 28:601, 2005; Tuomilehto J: Cardiovascular risk: prevention and treatment of the metabolic syndrome. Diabetes Res Clin Pract 68(Suppl 2):S28, 2005; Vijan S, et al: Brief report: the burden of diabetes therapy: implications for the design of effective patient-centered treatment regimens. J Gen Intern Med 20:479, 2005; Ward A, et al: Cost-effectiveness of oral hypoglycaemic agents for the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother 6:601, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported nothing to disclose.
Drs. Nathan and Saudek were recorded in Baltimore, at Endocrinology and Metabolism: The Clinical State of the Art, sponsored by Johns Hopkins University School of Medicine, and held April 23-24, 2004. The Audio-Digest Foundation thanks the speakers and Johns Hopkins University School of Medicine for their cooperation in the production of this program.
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