Protocol Approach for IOM Priority Vascular Conditions

Brian’s Note: In the post below, Dr. Bestermann, a highly regarded vascular physician, has developed and posted a field-tested protocol for the treatment of vascular conditions deemed high priority by the Institute of Medicine.

This is a work in progress that is likely to undergo significant change as new data emerges. But it is here and available in hopes that clinicians will make use of it, patients will benefit from it, and that by sharing important information we can provide better care for lower cost.

Protocol Approach for:

Type 2 diabetes, prediabetes, hyperlipidemia, hypertension, CAD, cerebrovascular disease, PAD, congestive heart failure


This protocol is field tested, weight-centric and has been used in my personal practice for ten years[1] with ongoing adjustment to reflect newer knowledge[2] and products[3], [4].   Consistently applied, the protocol accomplishes risk factor control levels consistent with optimal medical therapy while facilitating weight loss and renal function improvement in most patients.

Bestermann (WHB) Diabetes patients treated for longer than 1 year.

Report generated 2/5/2010

This weight loss was achieved prior to making Glp-1 agonists our usual second step and before we used very much symlin.

Overall Holston Medical Group practice performance in type 2 diabetes

Moving the Needle on 6806 patients

Crossing the Quality Chasm

An essential foundation for understanding the need to develop new science and systems is the executive summary from Crossing the Quality Chasm from the Institute of Medicine.  The IOM recommended the following essential components for focused programs aimed at improving the management of chronic conditions.

  1. Follow evidence-based protocols consistent with best practices
  2. Organize major prevention programs to target key health risk behaviors
  3. Develop the information infrastructure to support the provision of care and measurement of care processes and outcomes.
  4. Adjust payment for care to reward improvement in the management of chronic conditions

Protocol for the Management of Cardiometabolic Conditions

Careful definition of the product  is critical for  success.  The product is optimal medical therapy for cardiometabolic conditions-specifically hypertension, hyperlipidemia, type 2 diabeters, prediabetes, the metabolic syndrome, CAD, cerebrovascular disease, PAD, AAA, and CHF. The best benchmarks for optimal medical therapy are the levels of risk factor control achieved in the COURAGE and Steno 2[5] trials. The greatest impact in community practices would come from the application of updated version of these protocols modified by the latest science and data collected from treated patients.

The COURAGE trial established that coronary stent intervention added to optimal medical therapy for stable angina does not prevent cardiovascular death or myocardial infarction[6]. By now, 13 different studies have confirmed this finding[7].  Conversely, Steno II showed that optimal medical therapy produces a 4 fold reduction in myocardial infarction when compared with usual care[8]. This product can be produced in most care settings by consistently applying very well defined  processes based on the best evidence and proven in hundreds of patients to produce consistent results.   Members of the team should look at the process critically and make suggestions concerning ways that the approach may be modified to continuously improve.  Excessive variation in the way these conditions are treated is one of the major problems in our current care system.  This process should be applicable to 80% of cardiometabolic patients and should improve outcomes and consistency.

  1. Follow evidence-based care processes consistent with best practices.

Patient Education as a Base for Increased Adherence and Success

Volumes have been written about the fact that most patients do not take medications or change their life style with the consistency and persistence required to produce optimal medical therapy.  Substantial medical literature addresses patient readiness-to-change.  Readiness to change does not just happen.   Understanding vascular disease is a highly visual process and patients are ready to change when they understand how this illness works.  In teaching the new science of vascular disease  a picture may be worth 1000 words.  Patients need to understand that revascularization does not prevent heart attack or death in high risk patients, even in those with stable angina.  On the other hand, optimal medical therapy produces a 4 fold reduction in heart attack and a 5 fold reduction in stroke.  Taking 30 minutes in the first encounter to work with models or a powerpoint presentation to help that patient understand unstable plaque, plaque rupture, goals and the power of optimal medical therapy pays big dividends and makes patients more likely to invest the time and effort to do what needs to be done.  Car owners put oil in their engine, change it frequently, add water to the radiator, and antifreeze to the water because they understand the benefits of the effort. This information can be effectively delivered in a group setting.  Another benefit of this initial session is that it is very different from the care that they are accustomed to receiving and the message they receive is that “this organization cares and they take my problem seriously.”  The more a patient understands about their condition and how certain interventions protect them, the more they are engaged in improving their health.  The care plan should be carefully crafted so that patients are only asked to do something if it really makes a substantial difference in their health.

Life Style Interventions

Patients need instruction in practical lifestyle interventions that work[9].  There can be little wonder that patients today are mostly unsuccessful in their efforts to lose weight and improve risk factors with life style treatments.  Patients are confused by a constant barrage of conflicting information about diet and exercise.  What they need is relatively simple, practical advice that works.

Dr. David Kessler was head of the US Food and Drug Administration for years.  He has just written an important book, The End of Overeating, that helps us understand the current related epidemics of obesity, diabetes, and other cardiometabolic conditions.  He does us the great service of helping us to understand that excess weight is not a personal failing.  The overweight person is not lacking in willpower, burdened by impaired self esteem or weak.  Heavy people are not inadequate and these stereotypes are powerful obstacles to successful chronic disease management.  Women in their 20s in the United States today are on average 30 pounds heavier than their 1960 counterparts.  All of these women did not lose their willpower. They do not suffer from some deep-seated psychological inadequacy.  Obesity and unhealthy food change genetic expression(view video) so that the children and grandchildren of these women are more likely to be diabetic.

While Dr. Kessler (view video) agrees that exercise is important, he makes a compelling case that 90% of the problem is food.  It takes a lot of exercise to neutralize the effects of one piece of cheesecake.  In 1960, almost all that we ate was real food prepared in the home.  Today, over half of what we eat is prepared outside of the home.  The businesses preparing that food are in a very competitive market and their goal is to have you come back and buy more of their food.  Dr. Kessler says that they accomplish that goal by combining fat, salt, and sugar or white, highly processed starch in a perfect blend where taste and texture are ideal.  Customers will eat it when they are not hungry.  The more they eat, the more they want.  Lab animals will work nearly as hard to get this toxic food as they will to get a cocaine tablet.  It has to be supersized to satisfy the craving.  Traditional southern cooking and soul food also combine excess fat, salt, sugar and/or white starch; possibly offering an explanation for the very high rates of obesity and cardiovascular disease in the southeast.  These facts may explain the failure of traditional approaches.  The overwhelming majority of metabolic syndrome/type 2 diabetic patients eat too much starch and/or sugar.  Asking them to “count carbs” (sugar is included) may be very much like asking a cocaine addict to cut back on cocaine.  It simply cannot happen.  In order for the patient to achieve optimal medical therapy, the type of food generally consumed has to change.

All of the dietary programs that produce sustained weight loss address this fundamental reality.  Nutrasystems, The Zone, The Glycemic index diet, the South Beach diet all restrict fat while severely restricting sugar, a primary driver of excess eating.  Highly processed, white starch becomes sugar in the body in minutes and these programs all encouraged reducing starch intake and changing to high fiber, whole foods with a low glycemic index when starches are consumed.  White starch and sugar consumption drive hyperglycemia and triglyceride elevation as well, giving us another reason to reduce the amounts of these foods in the diet.

Dr Arthur Agatston is a preventive cardiologist and has been very innovative in helping us with the lifestyle required to achieve optimal medical therapy.  He has written two books that we have found useful in helping patients understand that they do not have to have  a heart attack or a stroke.  They can eat good, appealing, tasty food and they never have to be hungry.  The South Beach Heart Health Revolution help patients understand the dramatic reduction in vascular risk that can be achieved with life style changes that are sustainable.  No one does this perfectly and we coach patients that just eating right 19-20 meals a week will produce slow, sustainable, progressive weight loss over time.

Protocol for hypertension[10]


  1. For the low-risk patient-140/90
  2. For patients with higher risk-130/80

Higher risk patients include patients with microalbuminuria and other renal disease, diabetics, and patients with coronary artery disease, cerebrovascular disease, PAD, AAA, metabolic syndrome, or other coronary risk equivalents.

  1. CHF -125/75

This protocol will achieve aggressive goals in most patients including the elderly while allowing side effects to be minimized

This sequence would be used in the absence of allergy intolerance or contraindication

Pharmcologic Treatment

Every effort has been made to priotize agents with proven event reduction, improved endothelial function, and reduced insulin resistance and diabetes.

Agents with negative effects on these parameters are used later an in the least effective dose.

  1. Block the renin-angiotensin system

Begin with an ACE (angiotensin converting enzyme) inhibitor.  Lisinopril is an excellent choice.


  1. On the market many years with few adverse surprises
  2. Strong evidence of event reduction from multiple studies
  3. This was the specific ACE inhibitor used in the COURAGE trial
  4. Lowers insulin resistance and reduces future cases of diabetes
  5. Improves endothelial function.
  6. Available for $4.00 a month at multiple pharmacies
  7. Very well tolerated
  8. In renal disease, slows renal function deterioration and lowers proteinuria

Side effects and precautions

  1. Most common is a dry cough which does not require cessation unless intolerable
  2. Hyperkalemia may occur occasionally in patients with renal insufficiency, renal artery stenosis, or diabetes and lab should be followed closely at initiation and with dosage change
  3. Renal function may deteriorate in patients with renal insufficiency or renal artery stenosis and lab should be followed.  Not a problem if mild.
  4. Most urgent side effect is angioedema.  Lip swelling or laryngeal swelling require immediate cessation

If there are side effects with the ACE inhibitor-specifically cough or angioedema-then switching to an Angiotensin Receptor Blocker may eliminate those side effects while reducing insulin resistance, improving arterial structure and function, and reducing events.  ARBs also prevent new cases of diabetes and slow the deterioration of renal function.  We have many years of experience with these drugs also.  There is one generic available (losartan).  ARBs may be associated with a deterioration of renal function and hyperkalemia just as we see with ACE inhibitors.

Renin blockers like Tekturna offer a third way to block the renin angiotensin system.  There are no generics and the cost is high.  There is no evidence available yet for event reduction.

  1. Add a calcium channel blocker.

Amlodipine is an excellent choice

  1. On the market many years with an excellent safety profile and very few drug interactions.
  2. Strong evidence of event reduction[11] compared with other combination therapy.
  3. This was the specific CCB used in the COURAGE and ACCOMPLISH trials. The ACCOMPLISH trial produced the best  control of blood pressure[12] ever achieved in a clinical trial.
  4. Lowers insulin resistance
  5. Improves endothelial dysfunction
  6. Cost $13.00 at Sam’s
  7. Very well tolerated with the major side effect being edema which is attenuated when used in combination with ACE inhibitor.
  8. Comes in a fixed combination with the ACE inhibitor benazepril and that combination can be prescribed for a single copay.  A strategy based on that combination produced the lowest average blood pressure ever seen in a clinical trial.  The ACCOMPLISH trial also showed that ACE/Amlodipine reduced CV events 20% more effectively than ACE/Diuretic
  9. Diltiazem is the best 2nd choice CCB and may be especially appropriate when rate control is necessary in atrial fibrillation.

Side effects and precautions

  1. The major side effect of amlodipine is edema which is important only for cosmetic and comfort reasons.  This edema seldom causes  real harm and it is dramatically attenuated by combining amlodipine with ACE/ARB.
  2. The major side effects of cardizem are uncommon with bradycardia, negative inotropic effects and constipation being the leading considerations.
  1. Add a thiazide-type diuretic

Chlorthalidone is the most potent in lowering the pressure and has been proven in multiple clinical trials to reduce events.  Hydrochorothiazide has been used most frequently on a clinical basis but there is less evidence for  event reduction.  There are concerns about increased insulin resistance and adverse effects on lipids profiles with production of increased incidence of type 2 diabetes.  These adverse effects are attenuated by using the lowest dose possible.

  1. Resistant hypertension-see consensus guideline by Calhoun et al-resistant hypertension is defined as blood pressure that is not at goal in spite of adequate doses of 3 anti-hypertensive agents.
  1. The drug of first choice for the 4th agent is spironolactone/eplerenone .  Spironolactone in a dose of 12.5 to 50 mg produced an average pressure reduction of 25/12 according to the resistant hypertension article. There is a relative excess of aldosterone in metabolic syndrome patients that is actually part of the underlying pathophysiology.[13] Blockade of the mineralcorticoid receptor interferes with the activation of growth factors and signaling pathways that impact metabolism, inflammation, proliferation, and oncogenesis[14].  Aldosterone blockade may  interrupt the vicious cycle of CHF which is most often hypertensive in origin.   It is best to start with small doses.  Many patients with resistant hypertension have renal insufficiency and may develop hyperkalemia, hyponatremia, or worsened renal function when spironolactone is added to our first three interventions.  Start with 12.5 mg every other day (long half life) and gradually increase the dose while watching renal function, sodium and potassium levels weekly.  If any of these side effects develop, they can sometimes be overcome by switching the thiazide diuretic to a loop diuretic like furosemide which raises sodium, lowers potassium, and improves renal function.  Some men will develop gynecomastia at higher doses and so in males the dose should remain under 25 mg.  Eplerenone  blocks aldactone with fewer side effects and is now generic..Eplerenone is much less likely to cause gynecomastia.
  2. An alternate 4th choice is a B-Blocker like carvedilol or metoprolol.  Patients with a history of MI or CHF have a compelling indication for B-blocker therapy.  Most of these patients have the metabolic syndrome and traditional B-blockers like propranolol, metoprolol, and atenolol increase insulin resistance, make it more likely that the patient will progress to diabetes, increase triglycerides, cholesterol and LDL, and lower HDL.  The challenge is to control all risk factors simultaneously and therefore ordinary B-blockers are problematic.  Carvedilol provides the benefit of B-blockade without any of these other disadvantages.  Metoprolol and atenolol are selective B-blockers that do not aggravate bronchospasm at lower doses.  Carvedilol may worsen bronchospasm since it is not selective and should be avoided in that setting.
  3. CHF patients should be on B-blockers, ACE/ARB, spironolactone in the absence of intolerance or contraindication.

Lipid Management

By far the majority of patients have a mixed hyperlipidemia related to the metabolic syndrome.  The typical insulin resistant pattern is characterized by high triglycerides and low HDL with moderate elevations of total and LDL cholesterol.


  1. 1. For the low-risk patient-LDL 100, Trig 150
  2. 2. For patients with higher risk-LDL 70, Trig 150, HDL over 45

Higher risk patients include patients with microalbuminuria and other renal disease, diabetics, metabolic syndrome and patients with coronary artery disease, cerebrovascular disease, PAD, AAA, or other coronary risk equivalents.


  1. Statin therapy.All high risk patients should be on statin therapy[15] equivalent to 40mg of simvastatin regardless of their LDL level.  (Heart Protection Study) and the LDL target in this population should be 70 because that is the point at which plaque regresses.  The most dangerous side effect is rhabdomyolysis which is rare and associated with higher doses/interfering medications.  The most common side effect is muscle aching/cramping.  This is reduced in some patients by taking coenzyme Q10 100 mg bid with it.  The myalgia/cramp is dose-related and drug specific.  The statins are metabolized by different pathways and some are water soluble while others are lipid soluble.  There is almost always some dose of some statin that a patient can safely take.  Patients may tolerate half the usual starting dose and that can even be reduced to every other day.  Patients still receive some benefit.  Liver side effects are mentioned in the literature but are uncommon and statin can be continued as long as ALT or AST are not over 3x elevated.
  2. Niacin.  Niacin lowers triglycerides and provides a significant increase in HDL.  Small studies including the FATS and HATS trials have shown dramatic effects on cardiovascular outcomes.  The main problem with niacin is a flushing side effect that is most like a post-menopausal hot flash and may be very unpleasant but not dangerous.  The flushing may be prevented in many patients by taking a slow-release form at bedtime with a low-fat snack 30 minutes after taking an uncoated 325mg aspirin tablet.  A much less common but more dangerous side-effect is liver injury and LFTs should be monitored. Rescue therapy for the hot flash that is widely available would be Aleve and Benadryl
  3. Metformin.  The abnormal lipid panel seen in metabolic syndrome patients might best be termed an insulin resistant lipid profile.  In fact, the high triglyceride, low HDL pattern that is commonly seen in insulin resistance is the  biochemical profile that best identifies the insulin resistant patient..  When metformin is given with a statin while reducing fat, sugar and processed starch intake there are usually dramatic effects on the insulin resistant lipid panel.  Metformin activates AMPK which switches nutrient use towards energy production and away from synthesis of LDL cholesterol (decreased activity of HMG-CoA reductase) and triglycerides (decreased activity of ACC).
  4. Fenofibrate may be justified at higher triglyceride level.  Recent ACCORD data does no justify use at modest elevations

Glucose Management

Recent well-designed clinical trials designed to show benefit of intensive glucose management on cardiovascular outcomes (ACCORD and ADVANCE) have been disappointing and in fact the intensive glucose reduction arm of ACCORD was shut down because of excessive deaths.(Roughly a 20% increase compared with less aggressive glucose reduction.


FBS 80-110

2 hour postprandial 140

A1c 7

Treatment Intensive life-style management.   The recent consensus statement on pre-diabetes by the American College of Endocrinology recommends “a program of regular moderate-intensity physical activity for 30-60 minutes daily, at least 5 days weekly…The diet should be low in total, saturated fat, and transfatty acids, and with adequate dietary fiber, as per recommendations from the DPP”

  1. Metformin[16].  Both the ADA and the corresponding European society have developed a consensus guideline for managing type 2 diabetes.  This consensus guideline recommends that all type 2 diabetics receive metformin therapy at the time of diagnosis.[17] This recommendation is very important because in general we have done too little too late in the diabetic and prediabetic patient.  A very good case can be made for starting metformin prior to the onset of diabetes.  The best answer to diabetic risk is not to become diabetic and metformin given to prediabetics lowers the risk of developing diabetes by 30% while improving weight , lipids, and coagulation parameters.  Virtually all adverse outcomes in the type 2 diabetic are vascular.  The increased vascular risk begins years before the diagnosis of diabetes.  Metformin has the most impressive data of any diabetic medication for the reduction of vascular events in diabetic patients.  In UKPDS metformin treated patients experienced a 39% reduction in myocardial infarction and a 42% reduction in all cause mortality when compared to patients treated with diet and exercise.  In the Steno 2 trial, in which  the aggressive treatment arm for obese patients was metformin based, there were 4 times as many heart attacks and 5 times as many strokes in usual care patients.  There is every reason to think that the vascular protection from metformin therapy would extent to the prediabetic patient.  The prediabetic patient that does not achieve excellent global risk factor control with lifestyle management should be placed on metformin.  Emerging evidence shows that small amounts of metformin may dramatically reduce heart attack size in non-diabetic animals indicted mechanisms of action that have nothing to do with glucose control.[18]
  2. Incretins. Type 2 diabetes is a disease of relative insulin deficiency and glucagon excess.  Glucagon is used in the Emergency Room to rapidly increase glucose levels in hypoglycemic patients.  Incretins increase insulin output from the B cell at mealtime while lowering glucagon.  Incretins combined with metformin effectively lower glucose while facilitating weight loss. DPP4 agents less helpful but oral.
    1. Insulin-self adjusted basal insulin shot after the protocol of Jarvinen[19].

Type 2 diabetics are insulin deficient at diagnosis. If the combination of metformin and incretin treatment fails, it would be because of insulin deficiency.  The combination of metformin and basal insulin treatment would be a logical next step.

  1. If the patient is on metformin and basal insulin and requires intensification of therapy, in usual care most of these patients will be placed on a short acting insulin before meals which is most powerful in producing weight gain.  Substituting pramlintide (Symlin) prior to meals avoided a 10 pound weight gain over 6 months.[20]
  2. Pioglitazone useful but side effects including CHF and weight gain make it less appealing.

[1] Bestermann WH, Lackland DT, Riehle JE, Egan BM.  A systematic approach to managing hypertension and the metabolic syndrome in primary care.  South Med J 2004;97(10):932-8.

[2] Houston MC, Basile J, Bestermann WH, Egan B, Lackland D, Hawkins RG, Moore MA, Reed J, Rogers P, Wise D, Ferrario CM.  Addressing the global cardiovascular risk  of hypertension, dyslipidemia, and insulin resistance in the southeastern United States.  Am J Med Sci 2005;329(6):276-91.

[3] Bestermann WH, Houston MC, Basile J, Egan B, Lackland D, Hawkins RG, , Reed J, Rogers P, Wise D, Ferrario CM,  Moore MA, .  Addressing the global cardiovascular risk  of hypertension, dyslipidemia, and insulin resistance in the southeastern United States, Part II: Treatment recommendations for management of global cardiovascular risk of hypertension, dyslipidemia, diabetes mellitus, and the metabolic syndrome.  Am J Med Sci 2005;329(6):292-305.

[4] Neutel JM, Bestermann WH, Dyess EM, Graff A, Kursun A, Sutradhar S, Yunis C.  The use of a single-pill calcium channel blocker statin combination in the management of hypertension and dyslipidemia: a randomized placebo-controlled multicenter study. J Clin Hyperten 2009:11(1):22-30.

[5] Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O.  Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.  N Engl J Med 2003;348(5):383:93.

[6] Boden WE, O’Rourke RA, Koon KT, Hartigan PM, Maron DJ, Kostuk MD.  Optimal medical therapy with or without PCI for stable coronary disease.  N Engl J Med 2007;356(15):1503-16.

[7] Cecil WT, Kasteridis P, Barnes JW, Mathis RS, Patrick K, Martin S.  A meta-analysis update: percutaneous coronary interventions. Am J Managed Care 2008;14(8):521-528.

[8] Gaede P, Lund-Andersen H, Parving HH, Pedersen O.  Effect of a multifactorial intervention on mortality in type 2 diabetes.  N Engl J Med 2008;358:581-591.

[9] Bestermann WH  Incorporating practical lifestyle management for obesity J Fam Pract 2010;59(5 suppl):S3-S8.

[10] Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM.  Resistant hypertension: diagnosis, evaluation, and treatment:a scientific statement from the American Heart Association Professional Education Committee of the Councilo for High Blood Pressure Research  Circulation 2008;117 (25):e510-26.

[11] Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Valesquez EJ;  ACCOMPLISH  Trial Investigators.  Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high risk patients.  N Engl J Med  2008;359(23):2417-28.

[12] Jamerson K, Bakris GL, Dahlof B, Pitt B, Velazquez E, Gupte J, Lefkowitz M, Hester A, Shi V, Kjeldsen SE, Cushman W, Papademetriou V, Weber M; ACCOMPLISH Investigators.  Exceptional early blood pressure control rates: The ACCOMPLISH Trial.  Blood Press 2007;16(2):80-6.

[13] Sowers JR,  Whaley-Connell A, Epstein M, Narrative Review:  The emerging clinical implications of the role of aldosteronism in the metabolic syndrome and resistant hypertension.  Ann Intern Med 2009; 150:776-783.

[14] Huang S, Zhang A, Ding G, Chen R.  Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation  Am J Physiol Renal Physiol 2009;296:F1323-F1333.

[15] Heart Protection Study Collaborative Group   MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial.  Lancet 2002; 360(9326)::7-22.

[16] UKPDS Prospective Diabetes Study Group  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352(9131):854-865.

[17] Nathan DM, Bise JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B.  Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy.  Diabetes Care  2008;31:1-11.

[18] Calvert JW, Gundewar S, Jha S, Greer JJ, Bestermann WH, Tian R, Lefer DJ.Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS mediated signaling.Diabetes 2008;57(3):696-705.

[19] Yki-Jarvinen H, Ryysy L, Nikkila K, Tulkolas T, Vanamo R, Heikkila M.  Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus: a randomized, controlled trial.  Ann Intern Med 1999; 130:389-396.

[20] Riddle M, Pencek R, Charenkavanich S, Lutz K, Wilhelm K, Porter L.  Randomized comparison of pramlintide of mealtime insulin added to basal insulin treatment for patients with type 2 diabetes.  Diabetes Care 2009;32:1577-1582.

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