DPP – 4 INHIBITORS Addressing Unmet Needs in Type 2 Diabetes

Issue 1 – DPP – 4 INHIBITORS Addressing Unmet Needs in Type 2 Diabetes (PDF), download here

Issue 1 – DPP – 4 INHIBITORS Addressing Unmet Needs in Type 2 Diabetes

Ronald M. Goldenberg
MD, FRCPC, FACE

The natural history of type 2 diabetes is one of progressively worsening hyperglycemia. The use of monotherapy with traditional antihyperglycemic agents is insufficient to prevent the deterioration in glycemia, likely due to worsening G-cell function over time. Furthermore, therapies such as sulfonylureas, thiazolidinedio-nes (TZDs) and insulin are associated with weight gain. Hypoglycemia is also common with insulin and sulfonylurea therapy. Newer therapies for the management of type 2 diabetes would be ideal if they not only provide A1C lowering, but do so without causing hypoglycemia or weight gain. In this issue of LMC Clinical Practice Update, the DPP-4 inhibitors will be reviewed, with a specific emphasis on their efficacy without causing weight gain or hypoglycemia. Their potential role in cardioprotection will also be discussed, as well as their use according to renal function.

Efficacy, Weight Effects and Hypoglycemia Rates

The DPP-4 inhibitors are the newest class of oral antihyperglycemic agents available in Canada, with 3 currently available: linagliptin (Trajenta), saxagliptin (Onglyza) and sitagliptin (Januvia). These incretin agents enhance insulin secretion from pancreatic G-cells released in response to eating by preventing the DPP-4 enzyme from degrading incretin hormones released from the gut. They are ideal agents to address the unmet needs in type 2 diabetes management because of their efficacy in glucose lowering with rare hypoglycemia and neutral effects on body weight. As an add-on to metformin, weight change with DPP-4 inhibitors is similar to placebo.

Head-to-head trials of DPP-4 inhibitors and sulfonylureas have demonstrated equivalent A1C lowering of up to 0.7% when each were added to metformin therapy. However, DPP-4 inhibitors were associated with a 1.1 to 1.5 kg weight loss, while sulfonylureas caused a 1.1 to 1.3 kg weight gain (see Figure 1). Furthermore, hypoglycemia rates were typically between 32% to 36% with sulfonylurea therapy, while DPP-4 inhibitor therapy had low rates of hypoglycemia (3% to 7.5%) when added to metformin therapy. In a metaanalysis of trials comparing antihyperglycemic agents to placebo as add-on therapy to metformin, DPP-4 inhibitor treated patients achieved a 0.78% reduction in A1C, were 2.5-fold more likely to achieve A1C goal compared to placebo, and had no significant weight change and no increase in the rates of hypoglycemia. In contrast, sulfonlyureas and TZDs were associated with similar efficacy, but sulfonylureas caused a 2.1 kg weight gain and a 4.6-fold greater rate of hypoglycemia, while TZDs were also associated with a 2.1 kg weight gain. Therefore, based on efficacy in conjuc-tion with low rates of hypoglycemia and no weight gain, trials support adding a DPP-4 inhibitor to metformin therapy over a sulfonylurea or a TZD.

In clinical trials adding DPP-4 inhibitors to metformin plus a sulfonylurea, A1C was lowered 0.6% to 0.7% without any significant weight change. Although hypoglycemia rates increased when DPP-4 inhibitors were used in triple therapy, rates of hypoglycemia can be reduced by lowering the dose of sulfonylurea therapy. DPP-4 inhibitors have also been studied as an add-on to insulin therapy (off-label in Canada), with A1C reductions from 0.6% to 0.8% without weight gain.

Safety: Focus on Cardiovascular Effects

DPP-4 inhibitors have placebo-like toler-ability. A recent meta-analysis studied the safety of DPP-4 inhibitors in 53 trials enrolling 20,312 and 13,569 patients on DPP-4 inhibitors and comparators, respectively. There was no significant increase in the rates of cancer, pancreatic cancer or pancreatitis. Rates of major adverse cardiovascular events were significantly reduced with DPP-4 inhibitors by 31% (p=0.006). However, the trials reviewed were not designed as cardiovascular endpoint trials, so definite conclusions regarding the cardiovascular effects of DPP-4 inhibitors cannot be made. There are a number of reasons that DPP-4 inhibitors might be cardioprotective, including modulation of endothelial progenitor cells, antiinflammatory effects, and improvements in ischemic preconditioning. In December 2008, the US FDA issued a new guidance that focuses on cardiovascular events for new therapies being developed for the treatment of T2DM. The document suggests that new agents will only be approved if a meta-analysis of cardiovascular events demonstrates an upper bound of the two-sided 95 percent confidence interval for the estimated risk ratio as being less than 1.8. All currently available DPP-4 inhibitors have met this criterion of approv-ability (see Figure 2). Saxagliptin was the first drug to undergo this intensive cardiovascular-focused review. A post hoc pooled analysis using the phase IIb/III data from eight randomized trials including 4607 patients suggested no increased cardiovascular risk with saxagliptin treatment. In fact, notwithstanding the inherent limitations of this retrospective analysis, the data support a potential reduction in cardiovascular events with saxagliptin, with a significant 57% relative risk reduction. A prespecified analysis of the linagliptin trial program also demonstrated a significant reduction in cardiovascular events. To fulfil the FDA’s requirement to demonstrate the exclusion of cardiovascular risk and to test the hypothesis of potential cardiovascular protection, a prospective car diovascular outcome study evaluating saxagliptin compared with standard of care in patients with T2DM at increased risk for cardiovascular events is currently ongoing (SAVOR- TIMI 53). Similar hard cardiovascular endpoint studies are also underway for sitagliptin (TECOS) and linagliptin (CAROLINA). The anticipated completion date of these studies is 2014-5 and beyond.

Use According to Renal Function

Saxagliptin and sitagliptin are mainly excreted via the kidney and their pharmacokinetics are influenced by declining renal function. The renal dose of saxagliptin 2.5 mg OD (usual dose is 5 mg OD), was recently approved in Canada for patients with moderate (GFR 30 to 50 ml/min) to severe renal failure (GFR 15 to 29 ml/min). This was based on a clinical study demonstrating that A1C decreases from baseline to week 52 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate (-0.94% vs. -0.19%) and severe (-0.81% vs. -0.49%) renal impairment. Sitagliptin (usual dose 100 mg OD) has been studied with renal doses of 50 mg OD for moderate (GFR 30 to 50 ml/min) and 25 mg for severe renal impairment (GFR < 30 ml/ min). While these studies demonstrated efficacy and safety, Health Canada has not yet approved the renal doses of sitagliptin, so use is not recommended in patients with moderate to severe renal impairment. Linagliptin pharmacokinetics are not influenced by renal impairment, as this agent is eliminated non-renally, so dosage adjustments should not be required in renal failure. While linagliptin 5 mg OD has been shown to be efficacious and safe in patients with severe renal impairment (GFR < 30 ml/min), Health Canada has not yet approved its use in this population and it is currently not recommended in such patients. Figure 3 summarizes the use of DPP-4 inhibitors according to renal function.

Summary

DPP-4 inhibitors do indeed address unmet needs in the management of type 2 diabetes. They provide effective glucose lowering with low rates of hypoglycemia and without weight gain. In this regard, they are preferred over traditional agents as add-on to metformin or add-on to metformin plus sulfonylurea. They have placebo-like tolerability, with the potential of cardiovasular protection. Use of these agents according to renal function vary amongst agents. The recently approved renal dose of saxagliptin (2.5 mg) offers another treatment option for patients with renal impairment.


Focus on Fibre: Are We Getting Enough?

Dietary fibre is simply the parts of plant foods that our bodies cannot digest and absorb. This can be soluble or insoluble – although most foods contain a combination of both.

Consuming a high fibre diet can reduce the risk of developing type 2 diabetes, hypertension, obesity, and some gastrointestinal disorders. Fibre can improve glycemic control, cholesterol levels, increase satiety, and reduce hyperinsulinemia.

As Canadians, we’re certainly not getting enough fibre -most people fall below half of the recommended intake each day. Health Canada recommends a daily intake of 25-38g, and the Canadian Diabetes Association goes a step further with 25-50g for those with diabetes. The best (and perhaps most realistic) approach is just to take it one meal at a time – break down a day’s worth of fibre into 8-10 grams per meal, and it won’t seem so daunting.

Increasing dietary fibre can be rather easy – start the day with a cup of oatmeal topped with a tablespoon of peanut butter and a diced apple, mash V2 cup of beans and V of an avocado into a whole grain wrap as part of lunch, choose a banana and an ounce of mixed nuts for a snack – over 20 grams of fibre already and the day isn’t even done!

Meeting fibre goals by choosing a variety of plant foods means also enjoying a dazzling array of vitamins, minerals, phytochemicals and antioxidants.

Sources of Fibre:

A cautionary note about isolated fibres – inulin is a popular one – added to processed foods with the message “high fibre” splashed across the front of the package. While there is nothing inherently wrong with inulin (a natural prebiotic fibre found in onions, beans, and asparagus), adding an isolated fibre to a packaged snack food will not confer the same level of benefits as choosing whole foods with the fibre naturally occurring. Moreover, the typical commercial fibre supplement offers anywhere from 3-6 grams per serving – roughly the same as a pear or a cup of cooked spinach. Always aim for food first!

“..take it one meal at a time – break down a day’s worth of fibre into 8-10 grams per meal!”

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