Module 2: Diabetes Treatment and Interventions

Actually, the best predictor of progression from prediabetes to clinical diabetes is thought to be A1c. A1c has been shown in prospective studies to predict progression toward clinical diabetes. In a systematic review that followed 44,000 individuals from 16 studies for up to 12 years, those with A1c levels between 5.5-6% had a 5-year progression rate of 9-25%. A1cs ranging from 6-6.5% at baseline progressed to clinical diabetes over 5 years at the rate of 25-50% – a rate 20 times higher than those having A1c levels <5.0%.

Zhang X, Gregg EW, Williamson DF, Barker LE, Thomas W, Bullard KM, Imperatore G, Williams DE, Albright AL. A1C level and future risk of diabetes: a systematic review. Diabetes Care. 2010 Jul;33(7):1665-73. Review.

Metformin is the least expensive drug and has shown to have the greatest efficacy in preventing progression from prediabetes to clinical diabetes in obese subjects. Other drugs such as GLP-1 analogs should be considered if the patient is metformin-intolerant.

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403.

Sulfonylurea insulin secretagogues have more “secondary failure” than metformin or a TZD. This was proven in the ADOPT study. The need for additional therapies was almost twice as great in this study for glyburide as it was for rosiglitazone, with metformin somewhere in between. Whether this represents “beta-cell exhaustion” from the sulfonylureas or “beta-cell preservation” from insulin-sensitizing drugs is not known. It makes intuitive sense, however, that a drug that increases beta-cell work may lead to a hastening of that cell’s decline in function.

In general, pancreatic beta-cell function is approximately 50-80% of normal at the time of diagnosis of T2DM. Autopsy studies indicate that beta-cell mass is 40% lower in patients with T2DM in comparison to euglycemic obese controls. Hence, the progressive deterioration of glycemic control is primarily attributable to a continual loss of beta-cell function, which persists despite therapy for glycemic control.

1. Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Beta-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005 Jan;90(1):493-500. Epub 2004 Oct 13.
2. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003 Jan;52(1):102-10.
3. Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab. 2008 Nov;10 Suppl 4:32-42.

Unlike with type 1 diabetes, the progression from prediabetes to type 2 diabetes occurs over a period of several years. As lean individuals gain weight and become obese over time, insulin sensitivity decreases significantly, but glucose tolerance remains relatively normal due to a compensatory increase in insulin secretion. The higher insulin secretion is accompanied by reduced insulin activity in the liver, adipose tissue, and skeletal muscles, resulting in diminished intracellular glucose disposal. Genetically susceptible individuals progress through a spectrum of abnormal glucose states, including impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) as beta-cell function becomes impaired. Environmental factors such as poor dietary choices, inactivity, and low levels of vitamin D negatively target beta-cell survivability. Over time, patients will lose not only beta cells (as noted by the absence of first phase insulin response) but also mass, as reflected in a rise in A1c from euglycemic values toward those consistent with chronic hyperglycemia.

I’m not sure it does. If anything, insulin can put the beta cell to rest, and some studies suggest that aggressive insulin therapy can lead to the recovery of remaining beta cells. However, most patients with T2DM do experience gradual loss of insulin secretory capacity over time. So, many studies demonstrate that as the years pass, more aggressive combination therapies are needed to maintain Hgb A1c at target.

Physiologically, it is a reasonable approach but not yet approved by the FDA. Several studies show a modest benefit on A1c and weight, but this should still be considered “off label” use until we know more.

This is a protective mechanism of cardiac myocytes. Under ischemic conditions, potassium (KATP) channels within the mitochondria of these cells open, placing the cell at rest, thereby decreasing myocardial oxygen demand. Because sulfonylurea drugs close potassium channels, there has been some concern among cardiovascular specialists that this might impede ischemic preconditioning. The concept has never fully been shown to be a major problem with sulfonylureas, probably because their avidity to cardiac KATP channels is much less than to these channels in beta cells.

Yes, especially if the patient is markedly hyperglycemic, eg, BGs >300 mg/dL and/or A1c >10-11%. These individuals suffer from glucotoxicity, a reversible paralysis of sorts of the beta cell, which prevents further insulin secretion. Once glucose levels are reduced, beta-cell function improves, and glucose levels are lowered further. So the initiation of insulin in a newly diagnosed patient with T2DM does not necessarily imply life-long treatment. Oral agents can be initiated at the outset, along with insulin, and then the insulin can be tapered. One caveat, however, is that if insulin requirements are high and/or if the glucose is difficult to control, then clearly tapering the insulin dose would be unwise.

Although the DPP-4 inhibitors are generally mild in their A1c lowering power, they are well tolerated with few adverse effects. Unlike conventional agents, these drugs do not have prominent GI side effects, don’t lead to weight gain or edema, and don’t increase the risk of hypoglycemia. They are indeed expensive, and that would need to be taken into consideration. They may be ideal agents for individuals with mild hyperglycemia or when combination therapy is needed and there are contraindications to other drugs.

The main advantage to glinides over sulfonylureas is that the former have a rapid onset and quick disappearance of action. This allows for more physiological stimulation of insulin secretion and better control of postprandial glucose excursions. The disadvantage is that they require thrice daily dosing. So I would consider them niche agents, perhaps optimal for those individuals with irregular meal schedules who may develop hypoglycemia between meals and in whom intermittent stimulation of insulin secretion may be desirable.

The glargine dose can be advanced by 2-4 units once or twice weekly until the morning fasting BG is controlled to at least <130 mg/dL. Several studies seem to suggest that even tighter control (90-100 mg/dL) may be required to achieve an Hgb A1c <7%. Once the dose approaches >0.5 units/kg/day however, consideration should be given to adding mealtime insulin. This need is underscored if the patient has a persistently high A1c despite good FBG control, or if hypoglycemia occurs between meals or overnight. In some patients with very poor endogenous insulin secretion, the only way to adequately control A1c is with a more advanced insulin regimen. Be careful with pioglitazone in combination with insulin; more weight gain and edema can occur, especially at the higher doses. Another option to consider is adding a DPP-4 inhibitor, although this is expensive.

In this patient, the options are basal insulin, a sulfonylurea, and a DPP-4 inhibitor. Given his age, I’d think that achieving an A1c somewhere in the mid-7 range would be ideal. Accordingly, you don’t need high potency for this next drug. A DPP-4 inhibitor might work well, with the advantage of avoiding hypoglycemia, which can be dangerous at this age.

I prefer to give any rapid-acting analogue before meals. This is the more physiological way to deliver insulin, such that the peak (1 hr) occurs with the maximum glucose excursion. The dose is really based on the carbohydrate content (1 unit for every 10-20 g), but most patients aren’t that elaborate and simply take a fixed dose (usually 4-6 units). An additional amount of insulin can be added to adjust for premeal hyperglycemia, eg, an additional 2 units for every 50 mg/dL, starting at 150-200 mg/dL. This is known as the ‘correction scale.’ It is optional, but it allows patients to really use the data they are obtaining from their fingersticks.

Probably both. It is difficult to say for certain how much insulin deficiency vs. insulin resistance is at play in an individual patient. T2DM patients tend to have both abnormalities. The more obese are probably more insulin resistant, and the leaner individuals are likely more insulin deficient. One can use this assessment to guide therapy, since various drug classes exert their antihyperglycemic action via different mechanisms. Usually combination therapy is needed.

ACE inhibitors appear to reduce mortality in diabetic nephropathy, but angiotensin receptor blockers have limited evidence for mortality outcome. This is from a systematic review of 43 randomized trials (11 unpublished) of ACE inhibitors or ARBs for at least 6 months in patients with diabetic nephropathy. ACE inhibitors reduced mortality compared with placebo (or no treatment). ARBs had no effect on mortality compared with placebo (or no treatment).

With regard to renal function, ACE inhibitors tended to reduce risk of doubling of serum creatinine compared with placebo (or no treatment) and tended to reduce risk of end-stage renal disease compared with placebo (or no treatment). ARBs also reduced risk of doubling of serum creatinine compared with placebo (or no treatment) and also reduced risk of end-stage renal disease compared with placebo (or no treatment).

Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. 2004 Oct 9;329(7470):828. Epub 2004 Sep 30.

Metformin induces vitamin B-12 malabsorption, which may increase the risk of developing vitamin B-12 deficiency.

de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181.