Empowering prevention of type 2 diabetes
When it comes to type 2 diabetes (T2D) prevention, understanding risk is the first step in taking action of reducing the likelihood of developing the disease. The incidence of T2D is rising rapidly throughout the industrialized world. The American Diabetes Association estimates there are more than 20 million diabetics in the United States alone. The vast majority have T2D, and perhaps a third of diabetics are undiagnosed. In addition, more than 50 million Americans are prediabetic (impaired fasting glucose and impaired glucose tolerance). About a third of these patients will convert to T2D within three years, while another third will remain as prediabetics and the remaining third will return to normal glucose levels without intervention. Diabetes Prevention Program Research Group, “Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin” ( N Engl J Med 346:393-403 (2002)). The ADA has recently focused on prediabetes as the clinical tipping point for intervention to prevent or delay conversion to T2D. Its recommendation is yearly screening for prediabetes using fasting blood glucose in patients with higher risk for T2D and more aggressive strategies for prevention in obese prediabetics with other risk factors for conversion.
As a physician, you likely have many patients with well known risk factors for T2D including family history, obesity, ethnicity, and history of gestational diabetes, who need to lose weight, get more exercise and improve their diet. You probably also have patients who are prediabetic which itself is a risk factor for T2D. Moreover, your efforts to get your patients to change their lifestyle and address known risk factors for T2D are often unsuccessful. Additional information on which of your patients have increased genetic risk may give your advice greater weight and specificity, and provide your patients added incentive to implement and stick to lifestyle modification regimes that can reduce their chances of becoming diabetic. Furthermore, knowing which prediabetic patients are at greater risk of progressing to T2D might enable you to focus your more intensive efforts and to identify those for whom medication might be useful.
deCODE T2™ may provide an important new means of helping to identify those who are at elevated inherited risk of developing T2D independent of other risk factors, as well as those prediabetics most likely to progress to full-blown T2D. deCODE T2™ detects versions of four SNPs (single nucleotide polymorphism) –one letter variations in the sequence of the genome – in or near genes that have been linked to increased risk of T2D. Of these the deCODE TCF7L2 risk variant is the strongest DNA marker found for T2D risk and has been replicated in over 40 populations.
In deCODE’s findings, published in 2005 and which have since been validated in studies by independent researchers in tens of thousands of people from populations around the globe, between 8-11% of the general population have been shown to carry two copies of the TCF7L2 risk variant, but approximately twice that number of type 2 diabetics. In other words, having two copies of the risk variant has been shown to correspond to an approximate doubling of the likelihood of developing T2D compared to those with no copies of the risk variant. (Remember that we all have two copies of each chromosome in every cell in our bodies. We inherit one copy from our mother, and one from our father.) The risk variant is the “T” allele of SNP rs7903146, located within the transcription factor 7-like 2 (TCF7L2) gene. A published analysis of data from a U.S. government supported clinical trial involving prediabetics, the Diabetes Prevention Program, also showed that prediabetics with two copies of the risk variant were at a roughly 1.8 times greater risk of progressing to T2D within the next three years as were prediabetics with one or no copies of the risk variant (Florez et al, N Engl J Med 2006; 355:241-250). This was confirmed by a similar clinical trial in Europe (the DPS study). Overall, about a third of prediabetics in these studies went on to develop T2D within the three to four years; but nearly 50 to 70% of those with two copies of the risk variant became diabetic within the same time frame.
Both studies showed that an effective weight loss program worked as well if not better for patients at highest genetic risk for conversion, reducing conversion to T2D by over 60%. The U.S. study demonstrated that even in those who did not lose weight, drug treatment with metformin also reduced progression rates of prediabetics to T2D.
The deCODE T2™ measures three other risk variants that multiply with the TCF7L2 risk and include markers in or near the CDKAL1, CDKN2A, and PPARG genes. All have been shown to be significantly contribute to the risk of T2D, but to some lesser extent than the TCF7L2 variant.. For example, after deCODE discovered the CDKAL1 variant, it found that it correlates with lower insulin response to glucose which is consistent with its expression in pancreatic beta cells. (Steinthorsdottir, V. et al. Nat Genet. 2007; 39:770-5).
The deCODE T2™ genetic risk profile reported for your patient is simply the risk of each DNA marker multiplied by each other and ranges from 0.6 to 2.2 fold. This is justified based on large studies which showed that each genetic marker is an independent risk factor for T2D.
The remaining lifetime risk is defined as the risk to develop T2D after a certain age, assuming the patient has not already been diagnosed with T2D. It is dependent on known risk factors, such as obesity, ethnicity, family history, prediabetes, and age. The genetic risk identified by the deCODE T2™ test is largely independent of any other risk factors that the patient may have and therefore may be multiplied by the relative risks conferred by them.
The remaining lifetime risk for an individual (see table below) can be multiplied by the combined genetic risk identified by deCODE T2™ profile to obtain his/her specific residual lifetime risk. For example, for an overweight white male who is 45 years of age, the remaining lifetime risk according to the table is 23.7%. If his identified deCODE T2™ is 1.8 his remaining lifetime risk has increased to 42.6% However, not all genetic risk factors are known or measured by deCODE T2™ but deCODE T2 measures the strongest known and validated markers.
Remaining lifetime risk by age, BMI, race and sex (modified from Naryan et al. JAMA. 2003 Oct 8;290(14):1884-90)
The deCODE T2™ may therefore provide a new means to help physicians to decide which prediabetics they wish to treat more aggressively either through lifestyle change or through drug treatment. Published studies have shown that certain medications do appear to effectively slow the rate of progression from prediabetes to T2D. The 2002 Diabetes Prevention Program study showed that metformin could decrease conversion by 31% overall and even higher in patients younger than 60 ( N Engl J Med 346, op. cit.). Recent ADA guidelines state: “In addition to lifestyle counseling, metformin may be considered in those who are at very high risk (combined IFG and IGT plus other risk factors) and who are obese and under 60 years of age”