Payal Kohli, MD

The relationship between atrial fibrillation (AF) and diabetes mellitus (DM) is a complicated one and the jury is still out on whether the link between the two diseases is cause or correlation.

 Multiple epidemiologic studies have shown an association between DM and AF. Theories suggest that this relationship may be causal (ie, DM leads to increased risk of AF), possibly as a result of aberrations in autonomic nervous tone or of pathologic changes in atrial tissue from hyperglycemia. Alternatively, DM and AF share multiple risk factors, including obesity, hypertension, and sleep apnea and so the relationship may instead be associative. DM certainly increases thromboembolic risk and is therefore included in the CHA

 a Swedish cohort study investigated the relationship between type 1 DM (T1DM) and AF (which has not apparently been previously studied). Using national population registries, 36,258 patients with T1DM were matched with 179,980 propensity matched controls and followed for ~10 years. The incidence of AF was higher in participants with T1DM than it was in the general population.

The study reported a statistically significant p-value for interaction (p=0.019) with a HR for incident AF of 1.13 (1.01-1.25) in men and 1.50 (1.30-1.72) in women with risk of AF increasing along with parameters that reflected worse glycemic control (glucose control, renal complications). Interestingly, in individuals who had no clear evidence of end-organ damage (ie, did not meet threshold for microalbuminuria), there was no increase in AF risk with relatively liberal A1c thresholds (men with A1c <9.7% or women with A1c <8.8%). Above these thresholds, women carried an increased risk in the setting of microalbuminuria but men had no increased risk if eGFR >60 ml/min. Risk for men only increased in the setting of advanced renal dysfunction.

This study is apparently the first of its kind to report an association between T1DM and AF and between glycemic control and AF. It also highlights an interesting gender difference, whereby, after adjusting for renal complications, women had an increased risk of AF based on A1c but men did not. This was true despite the fact that the incidence of AF was higher in men compared with women. Hyperglycemia was also a stronger risk factor for AF for women compared to men. Finally, by raising awareness of the increased risk for AF in patients with DM, the authors make a case for potentially screening patients with T1DM more carefully and also targeting strict glycemic control to minimize risk of incident AF, especially in women.
 

 The link between diabetes and atrial fibrillation: cause or correlation?  J

2. Dahlqvist S, Rosengren A, GudbjÃ¶rnsdottir S, et al. 

Risk of atrial fibrillation in people with type 1 diabetes compared with matched controls from the general population: a prospective case-control study

. Lancet Diabetes Endocrinol 2017; 5: 799–807.

Articles

A recent study, the first of its kind, reports an association between T1DM and AF, and between glycemic control and AF. Plus, there are interesting gender differences.

Afib and T1D: Linked by Cause or Correlation? 

SGLT2 inhibitors, the “new kid” on the scene of oral hypoglycemic medications, are rapidly growing as a class of medications with a recent explosion of research.

A recent study, published in July 2015, introduced another novel SGLT2 inhibitor (tofoglifozin) to the scene, demonstrating efficacy, safety, and tolerability of this new agent, resulting in improved glycemic control and lower body weight. In this 12-week multi-center randomized, dose-finding trial, subjects with poor glycemic control from diet/exercise or diet/exercise plus a stable dose of metformin were randomized to placebo vs. 5 escalating doses of tofogliflozin (2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg) once daily.

The drug, like others in its class, was efficacious and reduced HbA1c in a dose-dependent manner at all doses except the 2.5 mg dose; body weight and fasting blood glucose were also reduced in a dose-dependent manner, similar to its predecessors. There appeared to be no interaction between tofoglifozin and metformin with respect to safety or efficacy. Although the drug was relatively well tolerated overall, with two or less patients withdrawing due to adverse effects (AE), the overall rate of AE in each arm was quite high: 35.9%-46.3% with SGLT2 inhibition; 37.9% with placebo.

Therefore, although technically a “positive” study, we must take this with a grain of salt (or sugar!). The high rate of adverse events is rather alarming. One could reason that was a high signal in the placebo arm as well, so this high AE rate could simply be a function of the patients selected for this trial. Although this is partially true, AE rate with SGLT2 inhibitors was still higher than placebo in this study. Similarly, other studies with high AE rates have demonstrated that the side-effect profile of SGLT2 inhibitors (especially the urogenital mycotic effects and increased risk of volume depletion and orthostatic hypotension) may continue to pose a significant obstacle to the widespread integration of these drugs into the anti-diabetic armamentarium. The role of these drugs, therefore, will most likely be as an adjunctive agent (to metformin) in highly selected populations (i.e., those with edema and normal renal function). However, larger outcome-trials (such as the DECLARE-TIMI trial, which will randomize approximately 17,150 patients with type 2 diabetes mellitus and either known cardiovascular disease (secondary prevention cohort) or at least two risk factors for cardiovascular disease (primary prevention cohort) with follow up for estimated 4.5 years will provide definitive results on their safety and efficacy.

A novel and selective SGLT2 inhibitor, tofogliflozin, improves glycemic control and lowers body weight in patients with type 2 diabetes mellitus

. Diabetes Obes Metab. 2015 Jul 14. [Epub ahead of print]

Can tofoglifozin overcome patient adverse events to join the SGLT2 inhibitor market?

An SGLT2 Inhibitor in the Works

1. The American Association of Clinical Endocrinologists (AACE) recommends which of the following for type 2 diabetes (T2DM) patients?

 Initiating therapy with metformin, a glucagon-like peptide 1 (GLP- 1) receptor agonist, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a sodium glucose cotransporter 2 (SGLT2) inhibitor, or an alpha-glucosidase inhibitor for patients with an entry A1C ≥7.5%.

 Initiating treatment with metformin (unless contraindicated) plus a second agent (GLP-1 receptor agonist, SGLT2 inhibitor, DPP-4 inhibitor, TZD, or basal insulin) with entry A1C levels >7.5%.

 Initiating insulin therapy alone or in combination with metformin or other oral agents for patients with an entry A1C >9.0% who have symptoms of hyperglycemia.

The AACE recommends choice of therapy to be based on entry hemoglobin A1C (HbA1c) as well as individualized for each patient according to the side effect profile. For example, in a T2DM patient who has frequent episodes of hypoglycemia, sulfonylureas and glinides are the least desirable alternative due to their increased risk of hypoglycemia. In such patients, insulin analogs glargine and detemir may also be preferred over intermediate-acting neutral protamine Hagedorn (NPH) because analog insulins are associated with less hypoglycemia. Alternatively, in a diabetic patient who is obese, a GLP-1 receptor agonist may be a great choice because it results in weight loss. Minimizing hypoglycemia and weight gain should be priorities when deciding on choice of therapy, but additional issues, such as patient compliance, method of deliver (PO vs. injection), frequency of dosing, and cost must also be considered.

American Association of Clinical Endocrinologists and American College of Endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015 - Executive Summary

2.  For each of the following, select whether SGLT2 inhibitors exert a neutral, mild, moderate, or marked effect:

The magnitude of effects of SGLT2 inhibitors on each of the following parameters:

  Weight: mild, weight loss      

SGLT2 inhibitors bind to an SGLT2, which is a low-affinity, high capacity glucose transporter that is responsible for 90% of glucose reabsorption. The SGLT2 sodium-glucose transporter is upregulated in diabetes. Therefore, by inhibiting this transporter, there is decreased glucose resorption in the tubule and increased excretion into the urine, resulting in less hyperglycemia. In addition to this mechanism of action, SGLT2 inhibitors also improve phase I insulin release from beta cells and increase peripheral insulin sensitivity and uptake. SGLT-2 inhibitors have multiple beneficial effects and have been shown to result in a decrease in blood pressure and weight and have a very low incidence of hypoglycemia when used alone or in combination with metformin. 

3. SGLT2 mediates approximately what percentage of renal glucose transport?

Although SGLT2 mediates approximately 90% of renal glucose reabsorption in the renal tubule, SGLT2 inhibitors in clinical practice are only able to inhibit approximately 30-50% of the glucose load filtered by the kidneys. Surprisingly, early in vitro studies suggested that these agents would provide near complete inhibition of their targets and of glucose reabsorption. However, this has not panned out in clinical trials in humans. The mechanism of this discrepancy is largely incompletely understood. However, some experts have postulated that these findings may be a result of secretion and/or active reabsorption of the drug in the proximal tubule (ie, glomerular filtration cannot deliver sufficient levels of SGLT2 inhibitors to their targets in the renal tubule over a long period even when systemic high doses of the drugs are given). Since the drug is acting within the renal tubule and is also being cleared by the kidneys, its efficacy is exquisitely sensitive to its own pharmacokinetics/pharmacodynamics. Another mechanism of a lower than expected result may be related to a slow off-rate of these inhibitors from the target (the SGLT2 receptor).

Why do SGLT2 inhibitors inhibit only 30–50% of renal glucose reabsorption in humans?

This quiz will help you better assess whether or not to prescribe an SGLT2 inhibitor for your type 2 diabetes patients.

Indications and Mechanism of SGLT2 Inhibitors in Type 2 Diabetes 

With increasing use of the newer non-insulin based oral glucose lowering agents, more side effects are now beginning to emerge. On May 15, 2015 the Food and Drug Administration (FDA) issued a formal communication warning about the risk of acidosis with the use of SGLT2 inhibitors.

SGLT2 inhibitors, which work by blocking glucose reabsorption in the renal tubule, are rarely used as monotherapy. Instead they are more commonly prescribed as combination therapy with other oral glucose lowering agents, such as the DPP-4 inhibitors. They have been approved for use in type 2 diabetes (T2DM) but their safety and efficacy is not yet established in type 1 diabetes.

Post-marketing surveillance of the FDA Adverse Event Reporting System (FAERS) has identified 20 cases of acidosis (either diabetic ketoacidosis (DKA), ketosis or ketoacidosis) between March 2013 and June 2014 in individuals who were taking SGLT2 inhibitors. The unusual observation that most of these individuals had T2DM (knowing that DKA is more commonly associated with type 1 diabetes and low insulin levels) raised some concern that this may be a serious adverse effect associated with the SGLT2 inhibitor itself. 

There were many unusual features that concerned the FDA.  First, the onset of the acidosis occurred after a median of 2 weeks (range 1 to 175 days), suggesting a likely cause and effect relationship with the drug. Second, the DKA was very unusual in that glucose levels were only mildly elevated at <200mg/dL, whereas DKA is traditionally characterized by glucose levels that are extremely elevated. Third, although some patients had other possible explanations for development of the anion gap metabolic acidosis (i.e., alcohol, renal failure, etc.) and others had obvious triggering factors (infection, trauma, urosepsis), about half of the cases had no obvious trigger or etiology for acidosis. All 20 patients required emergency room visits to treat their acidosis.

The mechanism of these findings remains unclear at this time. However, because SGLT2 inhibitors create glucosuria, it is possible that osmotic diuresis could lead to dehydration and triggering of the acidosis. Direct effects of SGLT2 on acid-base metabolism in the kidney are also possible, resulting in a renal tubular acidosis, though unverified. 

When prescribing these medications, providers should make patients aware of this risk, as well as possible presenting symptoms, such as such as tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, or mental status changes that could portend the onset of acidosis. In addition, providers should evaluate any patient who presents with such symptoms with tests including anion gap, electrocardiogram, blood gas, and urine ketones, and should have a low threshold to admit to the hospital for aggressive hydration and treatment of acidosis.

FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood.  15 May 2015. 

http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm

The Food and Drug Administration (FDA) issued a formal communication warning about the risk of acidosis with the use of SGLT2 inhibitors.

FDA Warns of Ketoacidosis with SGLT2 Inhibitors

Test your knowledge of recent findings in SGLT2 inhibitor efficacy and safety research.

1. The degree of HbA1c reduction by canagliflozin (an SGLT2 inhibitor) is independent of baseline HbA1c.

Click here for answer, discussion, and next question

Based on data presented at the European Association for the Study of Diabetes (EASD) meeting in Vienna in September 2014, although all levels of HbA1c demonstrated efficacy in response to drug dose, the degree of reduction of HbA1c depended on the baseline HbA1c. In a placebo-controlled trial, those with HBA1c ≥9% achieved an HbA1c reduction of -1.25% (100 mg dose) or -1.48% (300 mg dose) compared with those with HbA1c <8%, who only achieved a reduction of -0.45% (100 mg) or -0.65% (300 mg) vs. placebo. This study found no difference in level of HbA1c reduction when stratifying by duration of diabetes. Therefore, this drug, which has an entirely insulin-independent mechanism, may be a great second-line agent, regardless of duration of disease or baseline HbA1c.

Glycaemic efficacy of canagliflozin by baseline HbA1c and known duration of type 2 diabetes mellitus

. EASD Meeting, Vienna, Austria. 16-19 Sept. 2014.

2. The effects of SGLT2 antagonists include which of the following?

SGLT2 antagonists have an entirely insulin-dependent mechanism. However, by leading to glycosuria (which is the mechanism by which these drugs lower blood glucose), they do result in an increase in genital infections, with women having a higher incidence of this adverse effect compared to men. Recent data on empagliflozin presented at EASD examining pooled data from 458 type 2 diabetic patients with pre-existing microalbuminuria (<300 mg/day) at baseline on background of RAAS inhibition therapy. Differences in demographics as well as baseline degree of microalbuminuria were adjusted for in the models. The authors report that both doses of empagliflozin (10 mg and 25 mg) were associated with a reduction in microalbuminuria vs. placebo of 27 mg (10 mg dose) and 29.3 mg (25 mg dose). This study is one of the first demonstrations of a reno-protective effect of this class of agents (as opposed to the concern for this class of agents that glucosuria may damage renal vasculature).

Sodium glucose cotransporter 2 inhibition with empagliflozin reduces microalbuminuria in patients with type 2 diabetes

3. Which of the following are concerns when using SGLT2 inhibitors in elderly patients?

 Neurocognitive effects and worsening of dementia

The data is not yet definitive, however, there are studies that suggest that treatment with SGLT2 inhibitors may increase risk of fractures as compared to placebo due to its effects on phosphate and parathyroid hormone. One small study (n=85) of those receiving 5 mg dapagliflozin over 104 weeks showed a bone fracture rate of 9.4% vs. 6.0% in the placebo group. Another pooled analysis of 8 clinical trials with a mean duration of 68 weeks of canagliflozin suggested a ~30% increase in the rate of bone fractures. The mechanism of this early signal may result from the increase in serum phosphate (due to increased tubular resorption) with a possible secondary increase in parathyroid hormone. There is also evidence that, via changes in FGF23, SGLT2 may decrease concentrations of 1,25-dihydroxyvitamin D.

Possible adverse effects of SGLT2 inhibitors on bone

. Lancet Diabetes Endocrinol. 2015 Jan;3(1):8-10. Epub 16 Dec 2014.

Efficacy and Safety of SGLT2 Inhibitors Quiz

Sodium glucose cotransporter 2 (SGLT2) inhibitors have a modest impact on A1c and, in some studies, have been shown to decrease blood pressure. The mechanism underling the latter effect is unclear but may be related to sodium loss. Here, one question on each topic.

What is the range of A1c reduction that has been described with monotherapy with SGLT2 inhibitors?

Click here for answer, discussion, and next question. 

The average A1c reduction is dose-dependent and varies based on the type of SGLT2 inhibitor used. However, in clinical studies to date, canagliflozin reduced mean A1c by 0.77% (100 mg dose) to 1.03% (300 mg dose) and dapagliflozin by 0.58% (2.5 mg dose), 0.77% (5 mg dose) and 0.89% (10 mg dose). Interestingly, in a study of cangliflozin in type 2 diabetes patients aged 55 to 80 years, those <65 years had a more robust A1c reduction (-0.65% and -0.82%) compared to those ≥65 years (-0.45% and -0.5%) for the 100 mg and 300 mg doses, respectively. Patients with moderately impaired renal function (GFR between 30-50 ml/min/1.73m2), however, responded with a lower A1c reduction compared to those with normal or mildly impaired renal function. This suggests that, because the drug acts in the kidney, there may be some heterogeneity by age and renal function that ought to be considered when the decision to use an SGLT2 inhibitor is made.

Which of the following parameters should be periodically monitored in patients with renal impairment who are on an SGLT2 inhibitor?

Answer: F. Serum potassium (B) and blood pressure (D).

Because SGLT2 inhibitors induce osmotic diuresis, patients at risk for intravascular volume depletion (ie, elderly patients who may be on other antihypertensives) should be carefully monitored for symptomatic hypotension. In addition, the SGLT2 inhibitors’ action on a sodium-glucose transporter in the setting of renal impairment can affect serum potassium, magnesium, and phosphate levels. Serum potassium levels should be periodically checked, until a stable dose and stable renal function have been achieved.

Let us know if these questions/answers are helpful --- and what else you would like us to "quiz" you on? Thank you! 

Farxiga [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2014

Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013.

Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2014.

Try this mid-week Q&A on 2 essential properties of the sodium glucose cotransporter 2 (SGLT2) inhibitors. 