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Back: Managing Prediabetes

“Doctor, how should I manage a patient with ‘prediabetes’?”

 Jeff Unger Picture

 Jeff Unger, MD
   PCMG Steering Committee Member
   Charlotte, North Carolina
   Director
   Chino Medical Group Diabetes and
   Headache Prevention Center
   Chino, Californina






Those of us who manage patients with type 2 diabetes mellitus (T2DM) have traditionally been “programmed” to do so intensively. Practice guidelines from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) have consistently advised practitioners the key to reducing long term diabetes complications is to lower one’s A1C to as near normal as possible
[i]. The Diabetes Control and Complications Trial (DCCT) defined a “normal” A1C as being 6.1 %. Despite all of the newly introduced pharmacologic tools we have acquired over the past 15 years, only 56 % of patients with T2DM are able to achieve an A1C of < 7%[ii].  

 

Our patients should not be blamed for their inability to achieve and maintain good glycemic control. Diabetes is a progressive disorder resulting from peripheral insulin resistance and loss of pancreatic cell function. Rather than refer to patients as being “non-compliant” because they are not following a strict diet or exercise regimen, we must constantly adjust our management strategies based upon our knowledge of the pathophysiology of the disease state.

 

At the American Diabetes 55th Annual Advance Postgraduate Course held in San Francisco in February 2008, Dr. Ralph DeFronzo presented several studies suggesting that pancreatic beta cell function is significantly compromised in patients with impaired glucose tolerance (IGT), also commonly referred to as “prediabetes.” Patients with IGT who have a 2- hour postprandial glucose level of 180-199 mg/dL have a 75-80% reduction in beta cell function and are maximally insulin resistant. In fact, Dr. DeFronzo considers these patients as actually having diabetes because many of them already have clinically apparent microvascular and macrovascular complications.

 

One of the most frequent questions I get asked on the lecture circuit relates to how one should manage patients with prediabetes. According to Dr. DeFronzo, any patient with prediabetes who has significant postprandial glucose excursions (2-hour postprandial levels 180-199 mg/dL) should be intensively managed with triple drug therapy. His suggested regimen includes the use of metformin, a thiazolidinedione (TZD) and an incretin mimetic- all at the same time. Although this is considered extremely intensive, such a regimen makes physiologic and clinical sense. Dr. DeFronzo suggests that the treatment of prediabetes should be based on the pathophysiologic nature of the disease state. The goals of management for any patient with type 2 diabetes include the following:

 

1) reduce peripheral insulin resistance

2) improve pancreatic insulin secretion

3) preserve pancreatic beta cell function

4) prevent short and long-term diabetes related complications, and 

5) minimize weight gain.

 

Recent studies suggest that individuals with IGT and impaired fasting glucose (IFG) have lost as much as 50% of their beta cell mass[iii], while beta cell function (insulin output) is reduced by 80-90 %[iv],[v]. Thiazolidinediones are the only class of drugs that unequivocally have been shown to improve beta cell function in patients with IGT[vi],[vii]. Metformin has no beta cell protective effect when administered to longstanding T2DM patients, yet may have some mild effect in  preserving beta cell function in newly diagnosed T2DM individuals[viii]. Metformin also improves peripheral insulin sensitivity in IGT patients[ix]. Although incretin hormones have been shown to preserve beta cell function in animal models, their role in human beta cell preservation remains to be established. A recently published study demonstrated that vildagliptin 50 mg daily reduced postprandial glucose excursions by 32 % and improved pancreatic beta cell function in patients with IGT[x]. Incretins play an important role in lowering postprandial secretion of glucagon thereby lowering postabsorbtive glucose levels, reducing oxidative stress and preventing weight gain.

 

Besides improving insulin resistance, TZDs have a positive effect on other metabolic parameters in patients with T2DM. For example, pioglitazone has been shown to ameliorate all components of the insulin resistance syndrome while improving insulin sensitivity. In the PROACTIVE study (a study of 5,238 T2DM high risk patients who had a previous macrovascular event)[xi], pioglitazone decreased the risk of myocardial infarction, stroke, all cause mortality, acute coronary syndrome, coronary artery revascularization and leg amputation by 10 % -16 %. These results are in contrast to rosiglitazone which tends to increase the hazard ratio for cardiovascular events[xii].

 

In summary, Dr. DeFronzo believes that the use of TZDs plus metformin and an incretin hormone (incretin mimetic- such as exenatide or a DPP-IV inhibitor such as vildagliptin) in patients with prediabetes can improve insulin sensitivity, insulin secretion, reduce macrovasular risk and minimize beta cell failure. Although aggressive in theory, this approach is physiologic and has important clinical implications. While awaiting investigational studies to explore pharmacologic outcomes related to the treatment of prediabetes, I believe that our patients should benefit from a more aggressive, timely and physiologic approach to management. In my own practice, I have many patients who I began treating with both metformin and a TZD more than 15 years ago when their A1C levels were 5.5 %. I explained to these patients at the time that “I had no idea what I was doing with these medications, but felt that the combination of the two drugs made perfect physiologic sense.” Because the majority of these patients were at high risk for developing diabetes, they elected to take these medications. Of interest is that fewer than 5 % of these patients have actually progressed on to develop T2DM and none requires insulin therapy at this time. My only regret is that I did not have a DPP-IV to work with in 1995!

 

Jeff Unger, MD

  

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[i] Diabetes Care 31: S12-54S

[ii] Hoerger, et al. Diabetes Care 31:81-86, 2008

[iii] Butler et al, Diabetes 52:102-110,2003

[iv] Gastaldelli et al, Diabetologia 47:160-167,2004

[v] Ferrannini et al, JCEM 90:493-500, 2005

[vi] US-DPP, TRIPOD, DREAM – Kahn, et al, NEJM 355:2427-43, 2006

[vii] Gastaldelli and DeFronzo, AJP 292:E871-883, 2007

[viii] ADOPT-Diabetes 54:2404-14, 2005

[ix] Diabetes 54:2404-14, 2005

[x] Rosenstock. Diabetes Care 31:30-35, 2008

[xi] LANCET 366:1279-1289, 2005

[xii] NEJM 356:2457-2471, 2007