section name header

Info


A. Overview [1,2,3,4]

  1. Intensive Multifactorial Intervention Improves Outcomes [6,84]
    1. Primary goal is reduction of hemogloblin A1c (HbA1c) to 7.0-7.9 or less [2,4]
    2. Comprehensive program improves cardiovascular (CV) and microvascular outcomes [6]
    3. Hyperglycemia, hypertension (HTN), dyslipidemia, microalbuminuria all targeted [28]
    4. Diet, exercise, weight loss, behavioral therapy all instituted
    5. Both resistance and aerobic exercise improve HbA1c, but combination is best with ~1% HbA1c reduction versus no exercise plan [21]
    6. Aggressive pharmacologic therapy with monitoring is required in nearly all DM2 patients
    7. >50% reduction in CV, nephropathy, retinopathy, neuropathy endpoints compared with less intense (less comprehensive) treatment [6,84]
    8. Intensive glucose lowering (target HbA1c <6%) increases mortality and does not reduce vascular death compared with standard therapy (target HbA1c 7-7.9%) [89,90]
    9. Mortality reduced by 46% with intensive multifactorial versus usual intervention [84]
    10. Comprehensive evaluation and intervention across all disease manifestations required k Lifestyle modfications reduce risk of progression to frank DM by 43% in high risk [13]
  2. Diet, Weight Loss, Exercise
    1. All patients should undergo diet, weight loss, exercise counseling
    2. Essential to reducing morbidity and mortality in this disease
    3. Reduction in need for medications
    4. Reduction in long term sequellae
    5. Mainstay of therapy and must be encouraged and pursued vigorously
    6. In those patients with HbA1c >7.0%, add drug therapy
    7. Low carbohydrate diet for 2 weeks in obese persons with Type 2 DM lead to improvement in insulin sensitivity, HbA1c and cholesterol levels [24]
  3. Normoglycemia is Primary Goal [4]
    1. Normoglycemic Goals: HbA1c 7.0% or lower, fasting plasma glucose 90-130 mg/dL
    2. In DM2 patients, HbA1c target 7.0-7.9% associated with better outcomes and reduced mortality than intensive therapy with HbA1c target of 6.0% in one large study [89]
    3. In another large study, intensive glucose lowering therapy was associated with reduced major microvascular and macrovascular events but increased hypoglycemic events [90]
    4. Target HbA1c >7% usually requires more than 1 pharmacologic agent along with lifestyle modifications as above
    5. Diet, weight loss, exercise are essential but rarely sufficient
    6. Improved control of glycemia clearly reduces microvascular disease
    7. Microvascular disease includes nephropathy, retinopathy and neuropathy
    8. Metformin + diet also reduces risk of macrovascular complications (MI and stroke)
    9. Over time, patients may become resistant to specific therapy
  4. Suggested Oral Hypoglycemia Regimen [2,3,31]
    1. First line agents similar efficacy except alpha-glycosidase inhibitors and nateglinide (lower)
    2. Recommend metformin first line in most patients except those with renal insufficiency
    3. Thiazolidinediones (glitazones) usually second line [47], with other agents used later
    4. Assess pharmacologic therapy in 4-8 weeks; switch or add agents within 12 weeks
    5. Good control requires HbA1c <7.0% without undue risk to patient [31]
    6. If good control is not achieved, add second oral agent, GLP1 analog, or nightly NPH insulin
    7. Reassess after 4-8 weeks; add another oral agent or increase insulin doses
    8. Frequent followup (every 3 months) including lipid profiles and body weight measures
  5. Orally Active Agents [2]
    1. Metformin (Glucophage®): generally use first line
    2. Glitazones: rosiglitazone, pioglitazone; troglitazone withdrawn from market
    3. Sulfonylureas (insulin secretogogues): generally third line
    4. Meglitinides (non-sulfonylurea insulin secretogogues): repaglinide, nateglinide
    5. GLP1 Modulators: DPP-IV inhibitors are orally available (see below)
    6. Alpha-Glycosidase Inhibitors: acarbose, miglitol
    7. Use alone or (more commonly) in combination with each other and/or with insulin [2]
    8. Use combination of agents to obtain HbA1c to <7.1%
  6. Insulin [42,43]
    1. Type 2 DM have hyperinsulinemia, so other drugs are preferred iniitially
    2. Insulin is often required for HbA1c<7.1% and is reasonably added to metformin 2nd line [2]
    3. Insulin clearly improves glycemic control in moderate and severe DM2 patients
    4. However, concern with increased hypoglycemia and weight gain which may contribute to mortality increase seen with intensive glucose lowering in one large DM2 study [89]
    5. Home or other glucose monitoring should be used in most patients on insulin
    6. Typically begin with 0.25-0.3U/kg qam
    7. Moderate Type 2 DM have ~1% fall in HbA1c 1 year after beginning insulin
    8. Patients with HbA1c >10% have 2-3% drop in HbA1c 1 year after beginning insulin
    9. In patients with newly diagnosed DM2, initial intensive insulin leads to improved ß-cell function and remission after 1 year compared with oral agents [52]
    10. Morning insulin glargine superior to bedtime insulin glargine or bedtime NPH insulin, all in combination with glimepiride, for glucose control and reduced hypoglycemia [15]
    11. Once-daily insulin glargine similar HbA1c control to thrice-daily prandial insulin lispro in DM2 patients on oral hypoglycemic agents and is more convenient [86]
    12. Combination oral agent + insulin is preferred over insulin alone
    13. Inhaled insulin (Exubera®) approved for pre-prandial adjunctive therapy in DM2, about as effective as regular insulin; no clinical pulmonary dysfunction [23,49]
    14. Inhaled insulin has slightly less lowering HbA1c versus sc insulin, but much better patient acceptibility and is superior to oral agents [48,71]
    15. Inhaled insulin has been withdrawn from marketing due to poor uptake
  7. Blood Pressure [11,12,73]
    1. Blood pressure (BP) should be maintained <135/80 mmHg
    2. Usually requires >1 agent
    3. Primary agent should be one of the following:
    4. Angiotensin converting enzyme inhibitors (ACE-I) OR
    5. Angiotensin II receptor blockers (ARB) OR
    6. Thiazide diuretics
    7. Combination of ACE-I or ARB with thiazide diuretic is often effective
    8. Both ACE-I and ARB reduce progression of diabetic nephropathy and are 1st line [9,10]
  8. Nephropathy [73]
    1. Intensive glucose control in DM2 reduced nephropathy >20% in one large study [90]
    2. ACE-I or ARB should be used in all DM with microalbuminuria regardless of blood pressure
    3. ARB in ALL patients intolerant of ACE-I
    4. All diabetics with HTN should be treated with ACE-I or ARB [9,10] ± thiazides
    5. ACE-I reduce decline in renal function in DM2 with normal blood pressure and normal urine albumin levels
    6. Strongly consider ACE-I or ARB for prevention of renal decline in DM2
    7. Ramipril, an ACE-I, has significant cardioprotective and renoprotective effects in DM2 with at least one additional CV risk factor [62]
    8. Combination of ACE-I and ARB is probably beneficial and should be considered in poorly controlled HTN in DM2 patients
    9. Caution with ACE-I combined with ARB with renal function and potassium monitoring
    10. Renin inhibitors combined with either ACE-I or ARB may be beneficial in DM2
    11. Renin inhibitor alikiren (Tekturna®) with losartan (Cozaar®, an ARB), reduces urinary albumin- to-creatinine ratio by 20% in type 2 DM with nephropathy versus losartan alone [88]
  9. Cholesterol Reduction [17,18,28]
    1. Fasting Lipid Goals: LDL <100mg/dL, HDL >45mg/dL, triglycerides <200mg/dL [2]
    2. Statins for all patients with type 2 DM regardless of cholesterol [37,82]
    3. Atorvastatin (Lipitor®) 10mg qd reduces cholesterol, CAD events in all type 2 DM [8]
    4. In diabetic patients on dialysis, 20mg qd atorvastatin (Lipitor®) had no effect on CV endpoints or stroke [38]
    5. Routine monitoring of liver function or muscle enzymes after initiation not routine [17]
    6. Niacin also useful in DM2 with good VLDL/triglycerides reduction, increasing HDL
    7. Combination simvastatin-ezetamib (Vytorin®) also very useful in DM2
    8. Fenofibrate 200mg qd reduced total CV events in patients with diabetes not on another lipid-lowering therapy [40]
    9. Colesevelam (Welchol®), a bile acid sequestrant, is FDA approved as adjunct to diet and exercise for treatment of type 2 DM [87]
  10. Optimal Therapy [1,2,3,6]
    1. Comprehensive therapy for all complications of DM
    2. Strongly recommend combination oral agents for tight control of glucose levels
    3. Metformin (alternative: glitazone) preferred over insulin therapy as initial treatment
    4. Adding second agent (within 3 months of initial agent if HbA1c >7.0%) usually guided by potential side effects of the agents
    5. Triple therapy (metformin, glitazone, sulfonylurea) most effective oral combination
    6. Where metformin+sulfonylurea does not achieve goals, adding a glitazone increases patients achieving HbA1c <7.0% and improves HDL levels, superior to insulin [5]
    7. Whether exenatide (GLP-1 agonist) provides improved overall disease control is unclear
    8. Adverse effects and costs of agents should be considered when initiating therapy
    9. Nearly all patients with Type II DM should be on an ACE inhibitor as well
    10. Cholesterol evaluation must be performed in all patients and most DM2 should be on statin

B. Metformin (Glucophage®, Glumetza®) [35]

  1. Efficacy in DM2
    1. Efficacy demonstrated with good reduction in Hemoglobin A1c (HbA1c) levels
    2. Minimal hypoglycemic effects and induces weight loss
    3. Metformin alone has beneficial effects on plasma lipids
    4. Generally recommended first line in all DM2 patients without renal failure [2,3]
    5. Well tolerated and good glucose / HbA1c control over long term, superior to glyburide [47]
    6. Increased efficacy of metformin with sulfonylureas, glitazones, insulin
    7. Adding glitazone to metformin+sulfonylurea improves HbA1c and cholesterol [5]
    8. Metformin added to insulin allows reduction in insulin dose, reduced weight gain, and ~10% additional reduction in HbA1c
  2. Efficacy in IRS Patients
    1. Reduced risk of developing type 2 DM in patients with glucose intolerance by 31% [30]
    2. Both metformin and lifestyle modifications delay the onset of DM2 in patients with IRS [7]
    3. Lifestyle modifications more effective than metformin delaying DM2 in IRS patients [7]
  3. Polycystic Ovary Syndrome (PCOS) [83]
    1. Women with PCOS regardless of weight should be screened for glucose intolerance
    2. Glucose tolerance test at initial presentation and every 2 years thereafter recommended
    3. Metformin should be considered initial intervention in most women with PCOS, particularly with overweight problems
    4. Metformin will also likely increase the frequency of ovulation
    5. Restores ovulation in patients with polycystic ovary syndrome (with clomiphene)
    6. Weight-loss, diet and exercise are strongly indicated
  4. Dosing
    1. Begin with single dose 500mg or 850mg po qd with morning meal
    2. Increase graudally (every 2 weeks) to maximal 850mg tid or 500mg qid
    3. Monitor glucose weekly and hemoglobin A1c monthly
    4. Drug shows effects at 500mg po qd; maximal effects at maximal doses
    5. May be given safely at bedtime alone, combined with NPH insulin and/or sulfonylurea
    6. Glucophage® XR can be taken once daily with dose equivalent to bid-qid metformin [54]
  5. Side Effects [54]
    1. Metallic taste, nausea, diarrhea, anorexia, decreased B12 and folate uptake
    2. Lactic acidosis is uncommon; increased in patients with renal insufficiency, heart failure
    3. Lactic acidosis also increased with alcohol ingestion and after intravenous contrast
    4. Avoid use in patients with active hepatic disease, renal insufficiency, alcohol abuse
    5. Contraindicated in heart failure particularly with any renal insufficiency [16]
  6. Combination Oral Agents
    1. Glucovance®: glyburide with metformin (1.25/250, 2.5/500, 5/500) [56]
    2. Metaglip®: glipizide with meformin (2.5/250, 2.5/500, 5/500) [33]
    3. Avandamet®: rosiglitizone with metformin (1/500, 2/500, 4/500) [33]
    4. Actoplus met®: pioglitazone/metformin (15/500, 15/850) [50]
    5. Janumet® (sitagliptin/metformin) 50/500mg and 50/1000mg

C. Glitazones (Thiazolidinediones) [27,60,69]

  1. PPAR gamma agonists, insulin sensitizers
    1. Pioglitazone (Actos®) [63]
    2. Rosiglitazone (Avandia®) [64]
    3. Ciglitazone - in clinical studies
    4. Englitazone - in clinical studies
    5. Troglitazone (Rezulin®) has been withdrawn from the market
    6. Pioglitazone or rosiglitazone can substitute for troglitazone [58]
  2. Efficacy
    1. HbA1c levels reduced >0.84-1.4% as single agent therapy
    2. Better tolerated and better consequent long term control than glyburide (sulfonylurea) [47]
    3. May be used as monotherapy, or with sulfonylureas or insulin or metformin
    4. Generally second line following, or in addition to, metformin [2,3]
    5. Appears slightly less effective on HbA1c levels than sulfonylureas or metformin
    6. Combination with metformin led to average HbA1c levels of <8.3% [59]
    7. Improves metabolic parameters except cholesterol levels [59]
    8. May be combined with metformin, sulfonylurea, or insulin
    9. Rosiglitazone added to sulfonylurea + metformin normlizes HbA1c in 43% of patients
    10. Pioglitazone + sulfonylurea ± metformin leads to improved HbA1c levels and lipid profiles [5,29]
    11. Pioglitazone 15-45mg qd reduced composite of all-cause mortality, myocardial infarction, and strokeby 16% but increased non-cardiac edema and heart failure rates [22]
    12. Pioglitazone 150-45mg/d for 18 months reduced carotid intima-media thickness [34] and coronary atherosclerosis [85] versus glimepiride 1-4mg/d
    13. Rosiglitazone had no benefit in one study [19] and was beneficial in another study [20] in HIV-1 associated lipodystrophy
  3. Dosages
    1. Pioglitazone: 15-45mg po qd
    2. Rosiglitazone: 4-8mg po qd or 2-4mg bid
    3. Pioglitazone and rosiglitazone may be used alone or in combination with other agents
    4. Fixed dose combinations of these glitazones with metformin are available (see above)
    5. Combinations with sulfonylureas also available
  4. Side Effects
    1. Generally well tolerated
    2. Peripheral edema and weight gain are most common
    3. Increased intravascular volume, congestive heart failure reported
    4. May increase intravascular volume and should be avoided in heart failure [16]
    5. Increased risk of heart failure, non-cardiac peripheral edema, weight gain with pioglitazone [22,61,79]
    6. Reduction in combined MI, stroke, death with pioglitazone verus placebo [61]
    7. Increased edema and heart failure (1.11-2.1X risk) with rosiglitazone at 1-3.75 years [45,70,79]
    8. Rosiglitazone showed no increase [45,79,80] or a 1.43X increase in MI risk [70,74]
    9. Rosiglitazone showed 1.4X increased risk of acute MI and 1.29X increased death compared with other oral hypoglycemic agents in age >65 year DM2 patients [81]
    10. No overall increase in mortality or CV events with rosiglitazone in other studies [70,77,80]
    11. Transaminase elevations with current agents are similar to placebo (<1.5%) [63,64]
    12. Transaminase levels checked every 2 months up to 12 months
    13. Total cholesterol levels may increase (both LDL and HDL)
    14. Triglyceride and VLDL levels generally decrease
  5. Combinations
    1. Pioglitazone+glimepiride (Duetact®) single pill [72]
    2. Rosiglitazone+metformin (Avandamet®) single pill [33]
    3. Rosiglitazone+glimepiride (Avandaryl®) single pill [51]
  6. Muraglitazar [39]
    1. Combined PPARalpha and PPARgamma agonists
    2. Improves glucose and lipid parameters
    3. Excess (~2X) of cardiovascular events including MI reported based on pre-approval data

D. Glucagon-Like Peptide 1 (GLP1) Modulators [44,76]

  1. GLP1 [32]
    1. GLP1 is a glucagon antagonist which stimulates insulin secretion (incretin)
    2. GLP1 is catabolized by dipeptidyl peptidase 4 (DPP-4)
    3. GLP1 is released from gastrointestinal tract when food is ingested
    4. GLP1 stimulates insulin and reduces glucagon secretion; preserves ß-cell mass
    5. 6 week continuous sc infusion reduced HbA1c 1.3%
    6. Fructosamine normalized; insulin sensitivity improved
    7. Promotes weight loss
  2. Exenatide (Byetta®) [25,26]
    1. GLP1 agonist (mimetic) peptide for sc administration
    2. Approved based on three 30 week trials with combination therapy
    3. May be added to sulfonylureas or metformin or both
    4. Reduces fasting and postprandial glucose and HbA1c in combination with oral agents
    5. As effective as insulin glargine in combination with oral agents (reduce HbA1c ~1.1%)
    6. Dose initially 5mg sc bid; may increase to 10mg sc bid after 30 days
    7. Circulating half-life 60-90 minutes
    8. Promotes weight loss (independent of nausea)
    9. No or minimal risk of hypoglycemia with metformin; 14-36% risk with sulfonylureas
    10. Improved glycemic control and reduced weight in combination with thiazolidinediones [36]
    11. Nausea is major adverse effect, ~55% of patients
    12. Second line therapy in most cases
  3. Liraglutide (experimental)
    1. Partly DPP-4 resistant GLP1 analog with increased albumin binding
    2. Circulating half-life 10-14 hours
    3. Reduces HbA1c up to 1.75%
  4. DPP-IV Inhibitors [76]
    1. Orally available agents which block GLP-1 breakdown
    2. Similar actions to GLP1 and analogs, but do not promote weight loss
    3. Sitagliptin (Januvia®)
    4. Vildagliptin
  5. Sitagliptin (Januvia®) [46,57]
    1. Oral DPP-4 inhibitor with 0.6-0.9% HbA1c reduction alone, slightly higher in combination
    2. Prevents weight gain, and showed 1.5kg weight loss compared with placebo
    3. Well tolerated, even in patients with reduced renal function
    4. Improved ß-cell function and reduced insulin and glucose levels
    5. Dose is 100mg po qd
    6. Sitagliptin/Metformin (Janumet®) 50/500mg bid and 50/1000mg bid [75]
  6. Vildagliptin [44]
    1. Oral DPP-4 inhibitor with 0.8% HbA1c reduction when added to metformin
    2. Very well tolerated without significant nausea
    3. Prevents weight gain but does not appear to induce weight loss
    4. Dose is 100mg po qd or 50mg po bid

E. Alpha-Glucosidase Inhibitors

  1. Competitive inhibitors of intestinal brush border alpha-glucosidase
    1. Acarbose (Precose®) [78]
    2. Miglitol (Glyset®) [67]
  2. Efficacy
    1. Improved diabetic control in Type II DM patientsversus placebo
    2. Independent of which other agents (including insulin) the patients were on
    3. Acarbose plus metformin or sulfonylureas is better than single agents alone
    4. Acarbose efficacy similar to and additive with tolbutamide
    5. Direct comparison of 100mg po tid acarbose with 850mg po bid metformin showed similar control of glucose (1.1-1.3% reduction in HbA1c)
    6. Acarbose 100mg tid reduces risk of developing frank DM2 ~25% in patients with impaired glucose tolerance (IGT) [53]
    7. Acarbose also reduced risk of cardiovascular disease and hypertension in IGT [66]
    8. Miglitol reduced HbA1c from 9.9 to 8.3% (placebo 9.9 to 9.6%) in 6 month study [67]
  3. Dosing
    1. Acarbose and miglitol both initiated at 25mg po tid for most patients
    2. Full dose is 50-300mg per day po divided (100mg po tid is maximal dose)
    3. Use in combination with sulfonylureas and/or insulin
    4. Inhibits the absorption of metformin (concern with combination therapy)
  4. Side Effects [78]
    1. Mainly gastrointestinal due to increased carbohydrate load delivered to colon
    2. Dose-dependent flatulence, cramps, abdominal distension, borborygmi, diarrhea
    3. These symptoms usually lesson over time
    4. May decrease intestinal iron absorption, leading to anemia in some cases
    5. Mild hepatic enzyme elevations are occasionally reported with acarbose
    6. Thusfar miglitol has not shown increases in hepatic enzymes
    7. Slight risk of hypoglycemia when used with insulin or sulfonylureas
    8. Acarbose reduces bioavailability of metformin

F. Sulfonylureas
[Figure] "General Structure of Sulfonylureas"

  1. Stimulate basal insulin secretion through actual sulfonylurea receptors
    1. Glyburide (Micronase®, DiaBeta®)
    2. Glyburide or glipizide + metformin combination (see above)
    3. Glipizide (Glucotrol®)
    4. Glimepiride (Amaryl®): usual dose is 4mg po qd; start 1mg po qd; max 8mg po qd
    5. First generation agents (tolbutamide, chlorpropamide) are not covered here
  2. Efficacy
    1. Useful in Type II DM when endogenous insulin is still produced
    2. Nearly as effective as metformin and acarbose in terms of HbA1c reductions
    3. May be combined with insulin or with metformin to potentiate their effects
    4. Good control and low hypoglycemia risk in combination with morning insulin glargine [15]
    5. Most effective agents in treating MODY forms of DM2 [65]
  3. Dosing
    1. Begin with low dose and increase after 1-2 weeks
    2. Glyburide: 2.5-20mg qd usually in bid divided doses
    3. Glipizide: 5-40mg qd sustained release (XL) form is inexpensive and qd
  4. Side Effects
    1. Increased incidence of hypoglycemia with these agents compared with other oral agents
    2. Most patients on sulfonylureas gain weight

G. Meglitinides [14,55]

  1. Bind and inhibit (closes) ATP sensitive K+ channels on pancreatic ß-cells
    1. Repaglinide (Prandin®)
    2. Nateglinide (Starlix®)
  2. Efficacy
    1. Reduce HbA1c when used alone by 0.9-1.9%
    2. About as effective as sulfonylureas but does not cause weight gain
    3. Main side effect is hypoglycemia, less common than with sulfonylureas
    4. When used with metformin, reduces glucose more than single therapy
  3. Dosing
    1. Repaglinide - initial dose 0.5mg before each meal (up to 4 meals per day)
    2. Nateglinide - initial dose is 60-120mg po before each meal (up to 3 times daily)

H. Other Agents

  1. Pramlintide (Symlin®) [68]
    1. Synthetic analog of human hormone amylin
    2. Amylin is synthesized by pancreatic ß-cells and cosecreted with insulin after food intake
    3. Administration of pramlintide to insulin treated patients before meals reduces glucose
    4. Incresaes the number of patients with HbA1c <7% compared with insulin alone 2-3 fold
    5. Dose initially 60µg before meals, titrated up every 3 days to maximum 120µg
    6. Nausea, vomiting, anorexia occur more than placebo
    7. Increased risk of hypoglycemia so reduce preprandial short-acting insulin dose 50%
  2. Aldose-Reductase Inhibitors
    1. Aimed at reducing complications of hyperglycemia
    2. Early compounds had marginal efficacy for diabetic neuropathy
    3. Tolrestat has been withdrawn from the market
    4. Zopolrestat (Alond®) in Phase III studies for diabetic retinopathy
  3. Dehydroepiandrosterone (DHEA) 50mg qd in elderly persons reduced subcutaneous and visceral fat, reduced insulin levels, and improved glucose handling [41]

I. Summary of Oral Hypoglycemic Agents [3,14]Table: Summary of Oral Hypoglycemic Agents
Agents:SulfonylureaMeglitinidesMetforminGlitazonesAcarbose
Reduction in
Fasting Glucose~65mg/dL~50mg/dL~65mg/dL~40mg/dL~25mg/dL
Reduction in
HbA1c (%)1.5-2.00.6-1.01.2-2.01.0-1.20.7-1.0
TriglyceridesNE*NEdecreasedecreaseNE
HDL cholesterolNENEsmall increaseincreaseNE
LDL cholesterolNENEdecreaseincreaseNE
Body WeightincreaselittledecreaseincreaseNE
Plasma InsulinincreaseincreasedecreasedecreaseNE
Side Effectshypoglycemiasome lactic acidosisGI distrubance anemiahepatitis intoleranceGI
*NE=No Effect

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